Pharmacology Consult

Risk for severe muscle toxicity when combining simvastatin, amiodarone

Because patients with coronary heart disease often experience cardiac arrhythmias, the combined use of a statin and amiodarone is often indicated.

In August 2008, the FDA released a safety alert highlighting the increased risk for severe muscle toxicity and rhabdomyolysis in patients receiving simvastatin concomitantly with amiodarone. As a drug class, all statins have been associated with various minor muscle symptoms such as tenderness and pain. Conversely, severe muscle toxicity and subsequent progression to rhabdomyolysis is rare.

Drug interactions are among the many patient-specific factors that increase the risk for statin-induced myotoxicity. The results of one study, for example, indicated that more than half of the patients experiencing statin-induced rhabdomyolysis were receiving an interacting drug.

A major mechanism by which many drugs increase the risk for statin muscle toxicity is inhibition of the cytochrome P450 enzymes, particularly CYP3A4. Inhibition of this metabolizing enzyme effectively increases serum concentrations of the statin, similar to a dosage increase, thus raising the risk for muscle toxicity. Amiodarone, a known inhibitor of CYP3A4, has been associated with numerous interactions with other drugs metabolized by this isoenzyme.

Patricia A. Howard, PharmD, FCCP, BCPS
Patricia A. Howard

Among the available statins, atorvastatin (Lipitor, Pfizer), lovastatin and simvastatin undergo metabolism by the CYP3A4 isoenzyme. However, CYP3A4 metabolism accounts for approximately only 20% of atorvastatin¡¯s metabolism and the overall use of lovastatin is relatively low. Thus, it is not surprising that simvastatin has emerged as the statin most frequently associated with interactions involving CYP3A4 inhibitors such as amiodarone. Although somewhat controversial, another contributing factor may be simvastatin¡¯s high lipid solubility, which enhances the drug¡¯s penetration into muscle tissue.

A continued interaction

The FDA first warned of a possible interaction between simvastatin and amiodarone in 2002. However, despite this warning and revised prescribing information, the FDA continues to receive reports of this interaction, particularly with simvastatin doses ¡Ý20 mg daily.

There are several probable explanations for the increasing awareness of this drug interaction. Simvastatin use has increased due to generic availability, which prompted many third party insurance providers and hospital formularies to designate simvastatin as their preferred statin. The 2004 ATP III Update supported the option of more aggressive LDL lowering in high-risk patients, thus exposing more patients to higher statin doses. The clear relationship between simvastatin dose and muscle toxicity has been demonstrated through analysis of data from 41,050 patients in the simvastatin clinical trials database. Among patients receiving simvastatin daily, the incidence of myopathy was 0.02% for 20 mg, 0.08% for 40 mg and 0.53% for 80 mg.

In patients for whom amiodarone is the antiarrhythmic of choice and statin therapy is indicated, several strategies may be employed to minimize the risk for severe muscle toxicity. Most importantly, when used in combination with amiodarone, simvastatin doses should not exceed 20 mg daily as outlined in the 2008 FDA advisory. This recommendation applies to all medications that have a simvastatin component such as simvastatin/extended-release niacin (Simcor, Abbott) or ezetimibe/simvastatin (Vytorin, Merck/Schering Plough). In fact, the risk is likely greater with these combination drugs because the additional lipid-lowering agents also carry an independent risk for myotoxicity. A second option for amiodarone patients is to choose a different statin that is not primarily metabolized via the CYP3A4 pathway such as fluvastatin, pravastatin or rosuvastatin (Crestor, AstraZeneca). This strategy may be preferred for many patients who are receiving multiple other medications that also affect CYP3A4 activity. Additionally, this may be the most appropriate alternative for patients requiring LDL reductions beyond that typically reached with simvastatin 20 mg daily. For example, many high-risk patients may require LDL reductions in excess of 50%. This degree of LDL lowering can usually be reached with a potent noninteracting statin such as rosuvastatin in daily doses of 10 mg to 40 mg. Conversely, the use of simvastatin would likely require doses of at least 40 mg to 80 mg daily and in some cases combination drug therapy, thus greatly increasing the risk for severe muscle toxicity.

In most patients, statins are well tolerated and the risks for severe muscle toxicity and rhabdomyolysis are low. However, many factors affect the overall risk, including comorbidities, the individual statin used, statin daily dose and concomitant therapy with potentially interacting drugs. The risk appears to be significantly increased when simvastatin doses greater than 20 mg daily are used in patients receiving other drugs that inhibit the CYP3A4 isoenzyme, such as amiodarone. When the need for aggressive lipid lowering necessitates the use of higher simvastatin doses, an alternative regimen should be considered.

Patricia A. Howard, PharmD, FCCP, BCPS, is a Professor and Vice Chair of Pharmacy Practice, University of Kansas Medical Center, School of Pharmacy, Kansas City.

Rhonda Cooper-DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainsville, is Cardiology Today¡¯s regular Pharmacology Consult columnist and a member of the CHD and Prevention section of Cardiology Today¡¯s editorial board.

For more information:

  • Bottorff MB. Am J Cardiol. 2006;97:27C-31C.
  • FDA.gov/medwatch/safety/2008/safety08.htm#Simvastatin. Accessed June 2, 2009.
  • Pasternak RC. J Am Coll Cardiol. 2002;40:567-572.
  • Zocor [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2008.

Because patients with coronary heart disease often experience cardiac arrhythmias, the combined use of a statin and amiodarone is often indicated.

In August 2008, the FDA released a safety alert highlighting the increased risk for severe muscle toxicity and rhabdomyolysis in patients receiving simvastatin concomitantly with amiodarone. As a drug class, all statins have been associated with various minor muscle symptoms such as tenderness and pain. Conversely, severe muscle toxicity and subsequent progression to rhabdomyolysis is rare.

Drug interactions are among the many patient-specific factors that increase the risk for statin-induced myotoxicity. The results of one study, for example, indicated that more than half of the patients experiencing statin-induced rhabdomyolysis were receiving an interacting drug.

A major mechanism by which many drugs increase the risk for statin muscle toxicity is inhibition of the cytochrome P450 enzymes, particularly CYP3A4. Inhibition of this metabolizing enzyme effectively increases serum concentrations of the statin, similar to a dosage increase, thus raising the risk for muscle toxicity. Amiodarone, a known inhibitor of CYP3A4, has been associated with numerous interactions with other drugs metabolized by this isoenzyme.

Patricia A. Howard, PharmD, FCCP, BCPS
Patricia A. Howard

Among the available statins, atorvastatin (Lipitor, Pfizer), lovastatin and simvastatin undergo metabolism by the CYP3A4 isoenzyme. However, CYP3A4 metabolism accounts for approximately only 20% of atorvastatin¡¯s metabolism and the overall use of lovastatin is relatively low. Thus, it is not surprising that simvastatin has emerged as the statin most frequently associated with interactions involving CYP3A4 inhibitors such as amiodarone. Although somewhat controversial, another contributing factor may be simvastatin¡¯s high lipid solubility, which enhances the drug¡¯s penetration into muscle tissue.

A continued interaction

The FDA first warned of a possible interaction between simvastatin and amiodarone in 2002. However, despite this warning and revised prescribing information, the FDA continues to receive reports of this interaction, particularly with simvastatin doses ¡Ý20 mg daily.

There are several probable explanations for the increasing awareness of this drug interaction. Simvastatin use has increased due to generic availability, which prompted many third party insurance providers and hospital formularies to designate simvastatin as their preferred statin. The 2004 ATP III Update supported the option of more aggressive LDL lowering in high-risk patients, thus exposing more patients to higher statin doses. The clear relationship between simvastatin dose and muscle toxicity has been demonstrated through analysis of data from 41,050 patients in the simvastatin clinical trials database. Among patients receiving simvastatin daily, the incidence of myopathy was 0.02% for 20 mg, 0.08% for 40 mg and 0.53% for 80 mg.

In patients for whom amiodarone is the antiarrhythmic of choice and statin therapy is indicated, several strategies may be employed to minimize the risk for severe muscle toxicity. Most importantly, when used in combination with amiodarone, simvastatin doses should not exceed 20 mg daily as outlined in the 2008 FDA advisory. This recommendation applies to all medications that have a simvastatin component such as simvastatin/extended-release niacin (Simcor, Abbott) or ezetimibe/simvastatin (Vytorin, Merck/Schering Plough). In fact, the risk is likely greater with these combination drugs because the additional lipid-lowering agents also carry an independent risk for myotoxicity. A second option for amiodarone patients is to choose a different statin that is not primarily metabolized via the CYP3A4 pathway such as fluvastatin, pravastatin or rosuvastatin (Crestor, AstraZeneca). This strategy may be preferred for many patients who are receiving multiple other medications that also affect CYP3A4 activity. Additionally, this may be the most appropriate alternative for patients requiring LDL reductions beyond that typically reached with simvastatin 20 mg daily. For example, many high-risk patients may require LDL reductions in excess of 50%. This degree of LDL lowering can usually be reached with a potent noninteracting statin such as rosuvastatin in daily doses of 10 mg to 40 mg. Conversely, the use of simvastatin would likely require doses of at least 40 mg to 80 mg daily and in some cases combination drug therapy, thus greatly increasing the risk for severe muscle toxicity.

In most patients, statins are well tolerated and the risks for severe muscle toxicity and rhabdomyolysis are low. However, many factors affect the overall risk, including comorbidities, the individual statin used, statin daily dose and concomitant therapy with potentially interacting drugs. The risk appears to be significantly increased when simvastatin doses greater than 20 mg daily are used in patients receiving other drugs that inhibit the CYP3A4 isoenzyme, such as amiodarone. When the need for aggressive lipid lowering necessitates the use of higher simvastatin doses, an alternative regimen should be considered.

Patricia A. Howard, PharmD, FCCP, BCPS, is a Professor and Vice Chair of Pharmacy Practice, University of Kansas Medical Center, School of Pharmacy, Kansas City.

Rhonda Cooper-DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainsville, is Cardiology Today¡¯s regular Pharmacology Consult columnist and a member of the CHD and Prevention section of Cardiology Today¡¯s editorial board.

For more information:

  • Bottorff MB. Am J Cardiol. 2006;97:27C-31C.
  • FDA.gov/medwatch/safety/2008/safety08.htm#Simvastatin. Accessed June 2, 2009.
  • Pasternak RC. J Am Coll Cardiol. 2002;40:567-572.
  • Zocor [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2008.