Basic Information
ID DDInter1098 and DDInter76
Interaction The use of amiodarone with higher dosages of simvastatin or lovastatin may be associated with an increased risk of myopathy. The proposed mechanism is inhibition by amiodarone of intestinal and hepatic CYP450 3A4, resulting in enhanced bioavailability as well as reduced clearance of simvastatin and its active metabolite, simvastatin acid. Although not studied, the interaction is also expected to occur with lovastatin due to its similar metabolic profile to simvastatin. In general, the risk of myopathy associated with the statin class of drugs is thought to be dose-related and increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.
Management Simvastatin dosage should not exceed 20 mg daily and lovastatin dosage not exceed 40 mg daily when used in combination with amiodarone. The benefits of this combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving amiodarone, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.
References [1] Chouhan UM, Chakrabarti S, Millward LJ "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother 39 (2005): 1760-1 [2] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [3] Schmidt GA, Hoehns JD, Purcell JL, Friedman RL, Elhawi Y "Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir." J Am Board Fam Med 20 (2007): 411-6 [4] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [5] de Denus S, Spinler SA "Amiodarone's role in simvastatin-associated rhabdomyolysis." Am J Health Syst Pharm 60 (2003): 1791; author reply 1791-2 [6] Worz CR, Bottorff M "The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statins." Expert Opin Pharmacother 2 (2001): 1119-27 [7] Roten L, Schoenenberger RA, Krahenbuhl S, Schlienger RG "Rhabdomyolysis in association with simvastatin and amiodarone." Ann Pharmacother 38 (2004): 978-81 [8] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [9] Libersa CC, Brique SA, Motte KB, et al. "Dramatic inhibition of amiodarone metabolism induced by grapefruit juice." Br J Clin Pharmacol 49 (2000): 373-8 [10] Meng X, Mojaverian P, Doedee M, Lin E, Weinryb I, Chiang ST, Kowey PR "Bioavailability of Amiodarone tablets administered with and without food in healthy subjects." Am J Cardiol 87 (2001): 432-5 [11] "Product Information. Cordarone (amiodarone)." Wyeth-Ayerst Laboratories, Philadelphia, PA. [12] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [13] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [14] Thompson PD, Clarkson P, Karas RH "Statin-associated myopathy." JAMA 289 (2003): 1681-90 [15] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [16] Kantola T, Kivisto KT, Neuvonen PJ "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 63 (1998): 397-402 [17] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [18] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [19] Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther 64 (1998): 477-83
Alternative for Lovastatin C10A
Fenofibric acid Evinacumab Evolocumab Dextrothyroxine Cholestyramine Clofibrate
Colestipol Bempedoic acid Alirocumab

C10B
Bempedoic acid
Alternative for Amiodarone C01B
Propafenone Tocainide Procainamide Flecainide Disopyramide Mexiletine
Bretylium Moricizine Ibutilide
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.