Muscle Injury From Use of Simvastatin (ZOCOR) with Amiodarone (CORDARONE)

The Food and Drug Administration (FDA) issued a safety alert Aug. 8 warning healthcare professionals of the risk of severe muscle injury, rhabdomyolysis, which can lead to kidney failure or death.

In 2002, the FDA requested that manufacturer Merck and Co. change the labeling of its cholesterol-lowering drug simvastatin (ZOCOR) to reflect an increased risk of severe muscle injury when taken at a dose greater than 20 milligrams a day along with the anti-arrhythmic drug amiodarone (CORDARONE). Despite this warning, many clinicians continue to prescribe this combination, and cases of life-threatening adverse reactions from the use of these two drugs together continue to be reported to the FDA. 

Statins are cholesterol-lowering drugs, some of which have been shown to reduce the risk of heart attacks, strokes and deaths from vascular disease, especially in highrisk patients. They lower cholesterol levels in the blood by inhibiting a key enzyme in the synthesis of cholesterol and by increasing the clearance of cholesterol from the blood. Simvastatin, first approved by the FDA in 1991, is one of several statins available today. It is currently approved to treat elevated levels of cholesterol in the blood and to reduce the risk of cardio- vascular events (such as heart attacks), including death.

As a class, all statins have the potential to cause myopathy – muscle injury leading to weakness or pain. Statins also can cause a more severe form of muscle damage called rhabdomyolysis, the widespread breakdown of muscle, which can cause kidney failure and, in some cases, death. Almost all patients with rhabdomyolysis require hospitalization and administration of intravenous fluids. This is generally a rare side effect, but the risk increases with higher doses of statins, and when taken with use of other drugs that either inhibit the metabolism of statins (such as amiodarone) or directly cause muscle injury.

Simvastatin is broken down primarily by a liver enzyme called cytochrome P450 3A4 (CYP3A4). This enzyme is inhibited by many drugs, including amiodarone. Thus, when a patient is taking amiodarone, blood levels of simvastatin can increase, raising the risk of muscle damage.

In a large, randomized clinical trial of simvastatin recently published in The New England Journal of Medicine, patients taking high-dose simvastatin (80 milligrams a day) had an eightfold higher rate of myopathy within the first year when taking amiodarone concomitantly (6.5 percent) com- pared to those not taking amiodarone (0.8 percent).

In addition to increasing the rate of myopathy, simultaneous use of amiodarone with high-dose simvastatin has been associated with rhabdomyolysis in many cases reported in medical literature or to the FDA. The Summer 2008 FDA Drug Safety Newsletter reports 52 new cases of rhabdomyolysis (leading to one death) associated with concurrent amiodarone and simvastatin use since the agency’s original safety alert in 2002.

What You Can Do

Statin users who notice new weakness or pain in their arms or legs should let their physician know so that they can be assessed for statin-induced myopathy or rhabdomyolysis. 

Patients taking simvastatin at a dose greater than 20 milligrams a day in combination with amiodarone should let their physician know that this combination puts them at high risk of muscle injury. There are other statins that do not appear to interact with amiodarone, such as pravastatin (PRAVACHOL) or fluvastatin (LESCOL, LESCOL XL), and physicians should consider switching their patients to one of these if amiodarone use must be continued.