Beware of Potential Drug Interactions With Coadministered Statins and Amiodarone
Samantha Ellingson, PharmD, BCPS, and Timothy H. Self, PharmD—Series Editor
Ellingson S, Self TH. Beware of potential drug interactions with coadministered statins and amiodarone. Consultant. 2018;58(5):e165.
Approximately 38.75 million adults in the United States are on cholesterol-lowering medications, most of whom are on HMG-CoA reductase inhibitors (statins).1 Statins are used in the treatment of dyslipidemia and the primary and secondary prevention of cardiovascular disease (CVD). Most statins, such as simvastatin, atorvastatin, and lovastatin, undergo hepatic metabolism via cytochrome P450 isoenzyme 3A4 (CYP3A4). Fluvastatin and rosuvastatin undergo metabolism via CYP2C9. Of note, pravastatin and pitavastatin have no major cytochrome P450 metabolism.2-5 When considering potential drug interactions with statin therapy, it is important to consider the hepatic pathways that could be negatively impacted with the addition of new medications. One such example of a potential drug interaction is the coadministration of statins with amiodarone.
MECHANISM OF DRUG INTERACTION
Amiodarone is a class III antiarrhythmic agent used in the treatment of atrial tachyarrhythmias and ventricular arrhythmias. This medication undergoes metabolism via CYP2C8 and CYP3A4, and it inhibits CYP450 isoenzymes 1A2, 2C9, 2D6, and 3A4. When amiodarone is given concomitantly with a statin that undergoes hepatic metabolism, the inhibition of the metabolizing enzyme by amiodarone leads to an excess of statin. This increase in statin concentrations may lead to an increased risk of myopathy, hepatotoxicity, and rhabdomyolysis.
In 2014, Marot and colleagues6 described the case of an 80-year-old man who had been on simvastatin, 40 mg daily, for 3 years with no adverse events. He presented to an emergency department with proximal pain and weakness in his lower extremities. Four days prior to presentation, he had received a diagnosis of atrial fibrillation for which amiodarone, 200 mg daily, had been initiated. Simvastatin was discontinued, and the man was asymptomatic by day 16. This case demonstrates the acute nature in which myopathies can present once this drug interaction has been introduced. Several other cases of this drug interaction have been reported.7-9
The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial10 evaluated whether 80 mg daily of simvastatin safely produces greater reductions in CVD risk than does 20 mg daily of simvastatin for secondary prevention of cardiovascular events. A subgroup analysis of participants who were receiving 80 mg of simvastatin found that participants who were also taking amiodarone had almost a 9-fold increase in the incidence of myopathy within the first year of therapy.
While this drug interaction can occur with any of the statins that undergo hepatic metabolism (Table), most reports in the literature cite specific interactions between amiodarone and simvastatin. This may be due to the fact that simvastatin is more susceptible to CYP3A4 inhibitors and has been on the market significantly longer than some of the other drugs in this class such as atorvastatin and rosuvastatin.
There are specific recommendations about simvastatin dosing when the medication is coadministered with amiodarone10,11; however, this should not lead to the belief that the interaction with amiodarone occurs only with simvastatin. Health care providers should remain vigilant in monitoring drug interactions that could lead to serious adverse events such as myopathy, hepatotoxicity, and rhabdomyolysis with the coadministration of amiodarone and hepatically metabolized statins.
Samantha Ellingson, PharmD, BCPS, is a second-year postgraduate internal medicine pharmacy resident at the University of Tennessee Health Science Center and Methodist University Hospital in Memphis, Tennessee.
Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and the program director of the Postgraduate Year 2 Internal Medicine Pharmacy Residency at Methodist University Hospital in Memphis, Tennessee.
- Mercado C, DeSimone AK, Odom E, Gillespie C, Ayala C, Loustalot F. Prevalence of cholesterol treatment eligibility and medication use among adults—United States, 2005-2012. MMWR Morb Mortal Wkly Rep. 2015;64(47):1305-1311.
- Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150(12):858-868.
- Kruger D, Han J. Assessing acquired rhabdomyolysis in adults. JAAPA. 2017;30(1):20-26.
- Interaction between amiodarone (marketed as Cordarone and Pacerone) and simvastatin (marketed as Zocor and generics) or simvastatin-combination products (marketed as Vytorin and Simcor): amiodarone potentiates the risk for simvastatin-associated rhabdomyolysis. FDA Drug Safety Newsletter. 2008;1(4):46-48.
- Food and Drug Administration. Information for healthcare professionals: simvastatin (marketed as Zocor and generics), ezetimibe/simvastatin (marketed as Vytorin), niacin extended-release/simvastatin (marketed as Simcor), used with amiodarone (Cordarone, Pacerone). FDA Alert. August 8, 2008.
- Marot A, Morelle J, Chouinard VA, Jadoul M, Lambert M, Demoulin N. Concomitant use of simvastatin and amiodarone resulting in severe rhabdomyolysis: a case report and review of the literature. Acta Clin Belg. 2011;66(2):134-136.
- Roten L, Schoenenberger RA, Krähenbühl S, Schlienger RG. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother. 2004;38(6):978-981.
- Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin–amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother. 2006;40(4):753-757.
- 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. 2007;20(4):411-416.
- SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789-799.
- Wiggins BS, Saseen JJ, Page RL II, et al; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; Council on Functional Genomics and Translational Biology. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2016;134(21):e468-e495.
- Merz T, Fuller SH. Elevated serum transaminase levels resulting from concomitant use of rosuvastatin and amiodarone. Am J Health Syst Pharm. 2007;64(17):1818-1821.