Amiodarone with Simvastatin Interaction Details

Brand Names Associated with Amiodarone

Brand Names Associated with Simvastatin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 27, 2024

Interaction Effect

Increased exposure to simvastatin and an increased risk of myopathy or rhabdomyolysis

Interaction Summary

Myopathy and rhabdomyolysis have been reported in patients receiving simvastatin and amiodarone concomitantly[1]. Inhibition of CYP3A4-mediated simvastatin metabolism by amiodarone has been proposed as a possible mechanism for this interaction [2]. Do not exceed simvastatin 20 mg daily in patients receiving concomitant amiodarone therapy [3]. Monitor for signs and symptoms of myopathy or rhabdomyolysis. Monitor creatine kinase (CK) levels and discontinue use if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected. Cessation of amiodarone, simvastatin or both agents may halt and possibly reverse the progression of rhabdomyolysis if identified early. Alternatively, consider substituting simvastatin with another HMG-CoA inhibitor such as pravastatin which is not metabolized by CYP3A4 [2]. [1].

Severity

Major

Onset

Rapid

Evidence

Established

How To Manage Interaction

Concomitant use of amiodarone with simvastatin has resulted in significant increase in simvastatin exposure and risk of myopathy or rhabdomyolysis. If coadministration is necessary, do not exceed simvastatin 20 mg daily[3]. Monitor for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness, or weakness). Monitor creatine kinase (CK) levels and discontinue use if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected. Cessation of amiodarone, simvastatin or both agents may halt and possibly reverse the progression of rhabdomyolysis if identified early. Alternatively, consider substituting simvastatin with another HMG-CoA inhibitor, such as pravastatin [1][2].

Mechanism Of Interaction

Inhibition by amiodarone of CYP3A4-mediated simvastatin metabolism

Literature Reports

A) Exposure to simvastatin increased with coadministration of simvastatin and amiodarone in a pharmacokinetic study. Subjects received amiodarone 400 mg every day for 3 days and on day 3 a single, 40-mg dose of simvastatin was administered. The mean ratio (with amiodarone/without amiodarone) of simvastatin was 1.76 for AUC and 1.79 for Cmax. The corresponding ratios for simvastatin acid (beta-hydroxyacid of simvastatin) were 1.75 for AUC and 1.72 for Cmax [3].

B) Fifty-two cases of rhabdomyolysis associated with the concurrent use of simvastatin and amiodarone were reported to the US Food and Drug Administration adverse events reporting database between January 2003 to January 2008. Patients were between the ages of 50 to 88 years (median age, 73) with 71% being male and 19% being female. Gender was unreported in 10% of patients. Amiodarone was administered with a simvastatin dose of 80 mg (50% of patients), 40 mg (25%) 20 mg (8%), and 5 mg (2%). Thirty-seven (71%) patients reported taking concomitant medications such as gemfibrozil, clarithromycin, protease inhibitors, angiotensin-converting enzyme inhibitors and atorvastatin. In 42% of patients, the onset of rhabdomyolysis appeared within 2 months of induction with amiodarone and simvastatin therapy (mean onset 5 months), however time to onset was not reported in 40% of patients. Hospitalization was required in 92% of patients and 25% of cases were considered life-threatening. It was noted that 10% of patients who developed rhabdomyolysis became disabled. One death was reported. Symptoms and lab values tended to decrease once one or both agents were discontinued [1].

C) Rhabdomyolysis, accompanied by renal failure and possible hepatotoxicity, developed in a 72-year-old man after simvastatin 80 milligrams/day (mg/day) was added to an established regimen of amiodarone 200 mg/day which was initiated after a coronary artery bypass. The patient had a history of diabetes, hypertension, hyperlipidemia, and mild azotemia and had previously taken pravastatin 20 to 40 mg/day and fluvastatin 40 to 80 mg/day without any adverse effects. Approximately 1 month after initiation of simvastatin, the patient developed symptoms of thigh weakness, achiness, and dark urine. Laboratory analysis showed an elevated CK level of 19,620 units/liter (reference range 60 to 224 units/liter), AST level of 912 units/liter (30 to 60 units/liter), ALT level of 748 units/liter (30 to 60 units/liter), and highly elevated serum and urine myoglobin levels. In addition, serum creatinine level (2.6 mg/dL or 230 mcmol/L) and BUN (50 mg/dL or 18 mmol/L) were also elevated and the 24-hour urine protein level was 549 mg. Both simvastatin and amiodarone were immediately discontinued and the patient was hydrated with forced alkaline diuresis. After 13 days, hepatic enzyme levels dropped significantly and 3 months later, ALT, AST, and CK levels were 49, 32, and 640 units/liter, respectively. Inhibition of CYP3A4-mediated simvastatin metabolism by amiodarone was proposed as a possible mechanism for this interaction [2].

D) Rhabdomyolysis developed in a 63-year-old man after amiodarone (1 gram/day for 10 days, followed by 200 milligrams (mg)/day)) was added to an established treatment regimen that included simvastatin 40 mg daily. Approximately 11 days after beginning amiodarone therapy, the patient showed signs of rapid exertional exhaustion, followed 5 days later by complaints of diffuse muscle pain and generalized weakness. Laboratory analysis revealed a creatine phosphokinase (CK) serum concentration of 18,852 units/liter accompanied by an aspartate aminotransferase and lactic dehydrogenase serum concentrations of 438 units/liter and 807 units/liter, respectively. Despite the discontinuation of simvastatin, serum CK concentration continued to rise, reaching a peak of 40,392 units/liter 3 days later. Amiodarone and phenprocoumon were both stopped and pravastatin 20 mg daily was substituted for simvastatin, after which the patient's CK serum concentration declined to within normal limits and the patient showed a slow improvement in muscle strength. The case study authors assign to the proposed interaction a Naranjo causal probability relationship of 'probable'[4].

E) Rhabdomyolysis and acute renal failure occurred in a 72-year-old man receiving simvastatin concomitantly with amiodarone and atazanavir. The patient presented with a 4-day history of generalized pain, weakness, and fatigue, and a 3-day history of dark orange urine. He had been on atorvastatin 40 mg daily for 2 years and was switched to simvastatin 80 mg 27 days before current presentation. Additionally, amiodarone 400 mg daily was initiated 19 days prior to current presentation, and then decreased to 200 mg daily after 7 days. His other chronic medications included atazanavir, stavudine, and delavirdine, all taken for 2 years. Laboratory results revealed a creatine kinase level of 66,680 units/liter, nearly 300 times the upper limit of normal. The patient was diagnosed with rhabdomyolysis and oliguric acute renal failure. Simvastatin, amiodarone, and HIV medications were all temporarily discontinued, and the patient was given forced alkaline diuresis and dialysis. He was discharged on day 9 (creatine kinase level, 1695 units/liter), restarted on amiodarone, and outpatient dialysis was continued for one month. His HIV medications were restarted after 6 weeks, but the statin was not initiated. This patient had additional risk factors of advanced age and concomitant use of atazanavir, where atazanavir may have contributed by further decreasing simvastatin's metabolism. The Naranjo adverse drug event probability scale indicated a "probable" rating that the effects were due to an interaction between simvastatin and amiodarone/atazanavir [5].

References

1 ) US Food and Drug Administration: FDA Drug Safety Newsletter. US Food and Drug Administration. Rockville, MD. 2008. Available from URL: http://www.fda.go... .

2 ) Ricaurte B, Guirguis A, Taylor HC, et al: Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006; 40(4):753-757.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

3 ) Product Information: ZOCOR(R) oral tablets, simvastatin oral tablets. Organon & Co (per FDA), Jersey City, NJ, 2022.

4 ) Roten L, Schoenenberger RA, Krahenbuhl S, et al: Rhabdomyolysis in association with simvastatin and amiodarone.. Ann Pharmacother 2004; 38:978-981.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

5 ) Schmidt GA, Hoehns JD, Purcell JL, et al: 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.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

Amiodarone Overview

• Amiodarone is used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias (a certain type of abnormal heart rhythm when other medications did not help or could not be tolerated. Amiodarone is in a class of medications called antiarrhythmics. It works by relaxing overactive heart muscles.

Simvastatin Overview

• Simvastatin is used together with diet, weight-loss, and exercise to reduce the risk of heart attack and stroke and to decrease the chance that heart surgery will be needed in people who have heart disease or who are at risk of developing heart disease. Simvastatin is also used to decrease the amount of fatty substances such as low-density lipoprotein (LDL) cholesterol (''bad cholesterol'') and triglycerides in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol (''good cholesterol'') in the blood. Simvastatin may also be used to decrease the amount of cholesterol and other fatty substances in the blood in children and teenagers 10 to 17 years of age who have familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally). Simvastatin is in a class of medications called HMG-CoA reductase inhibitors (statins). It works by slowing the production of cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block blood flow to the heart, brain, and other parts of the body.

• Accumulation of cholesterol and fats along the walls of your arteries (a process known as atherosclerosis) decreases blood flow and, therefore, the oxygen supply to your heart, brain, and other parts of your body. Lowering your blood level of cholesterol and fats with simvastatin has been shown to prevent heart disease, angina (chest pain), strokes, and heart attacks.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.