The risk of myopathy and rhabdomyolysis associated with Merck's Zocor (simvastatin) increases in proportion to the dose, revised labeling says.

"The risk of myopathy/rhabdomyolysis is dose-related," the updated Zocor Warnings section states in bolded type.

"The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80 mg."

Zocor is now the only marketed statin that specifies a dose-related effect for myopathy and rhabdomyolysis. Old labeling mentioned a dose-dependent relationship with myopathy but not rhabdomyolysis, and did not cite numbers.

In addition to revamped Warnings section content, the title of the "Skeletal Muscle" subsection has been strengthened by changing it to the "Myopathy/Rhabdomyolysis" subsection.

The revised Warnings section also omits previously included data from the Scandinavian Simvastatin Survival Study (4S), which cited one case of myopathy among 1,399 patients taking 20 mg (daily) Zocor and no cases among 822 patients taking 40 mg for a median duration of 5.4 years.

FDA approved Merck's labeling supplement May 6. Merck said it submitted the sNDA May 15, 2001 as part of its obligation to respond to new postmarketing adverse event signals.

The submission came three months before the withdrawal of Bayer's Baycol (cerivastatin) from the market due to reports of severe and fatal rhabdomyolysis associated with the highest doses (¹ Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 August, 2001., p. 4).

Rhabdomyolysis at the highest dose has been an issue in FDA's review of AstraZeneca's Crestor (² Also see "AstraZeneca Crestor 80 Mg Dose Would Have Low Demand, CEO Suggests" - Pink Sheet, 4 February, 2002., p. 25). Rosuvastatin received an "approvable" letter May 31.

If labeling language similar to Zocor's is not added to labeling for other marketed statins, Zocor could face increased competitive challenges. Bristol said it does not anticipate labeling changes to warnings for Pravachol (pravastatin); Novartis likewise indicated it has no labeling revision plans for Lescol (fluvastatin).

The emphasis on dose-relationship for Zocor could be especially problematic in light of the recent approvals of higher starting doses for Pravachol and Pfizer's Lipitor .

The April 22 supplemental approval for Lipitor adds 20 mg and 40 mg (for patients who require a large reduction in LDL-C) as recommended starting doses; the previous starting dose was 10 mg. FDA revised labeling for Pravachol in December to recommend a starting dose of 40 mg, and also added a new 80 mg dose (³ Also see "Bristol Pravachol 80 Mg Long-Term Safety Data Is Phase IV Commitment" - Pink Sheet, 14 January, 2002., p. 28).

⁴ Revised Zocor labeling retains starting dose recommendations of 20 mg or 40 mg for patients requiring larger LDL-C reductions. However, the new label recommends lower doses of Zocor for patients who are also on drugs that inhibit CYP3A4 and lipid-lowering drugs that can cause myopathy, and adds a bolded warning on concomitant use with those groups of drugs.

The Warnings section also adds the antiarrhythmic amiodarone (Wyeth's Cordarone and generics) as a drug that may increase the risk of myopathy or rhabdomyolysis. "In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone," labeling notes. Amiodarone is not mentioned in the labeling of other statins as potentially increasing myopathy/rhabdomyolysis risk.

Zocor labeling now recommends a 20 mg daily limit of Zocor for patients also using amiodarone or verapamil, and states that "the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (>1 g/day) of niacin."

Patient information has changed as well. In addition to the class labeling instructing patients to report muscle pain, tenderness or weakness, Zocor patients are "advised to inform other physicians prescribing a new medication that they are taking Zocor."

Merck Zocor Rhabdomyolysis Risk Is Dose-Related, Revised Warning Says

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