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
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.
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
Patricia A. Howard, PharmD, FCCP, BCPS, is a Professor and Vice Chair
of Pharmacy Practice, University of Kansas Medical Center, School of Pharmacy,
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
- Pasternak RC. J Am Coll Cardiol. 2002;40:567-572.
- Zocor [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.;