NEJM: FDA weighs in on change to simvastatin's label

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Statins are a widely administered class of drug indicated to treat dyslipidemia. While this drug class has been shown to lower LDL cholesterol levels and reduce major adverse cardiovascular events, do these benefits outweigh the potential risks that often include myopathy or muscle injury?

This is the question Amy Egan, MD, MPH, and Eric Colman, MD, of the FDA’s office of the division of Metabolism and Endocrinology Products, Office of New Drugs, Center for Drug Evaluation and Research in Silver Springs, Md., addressed in their June 15 perspective published in the New England Journal of Medicine.

The commentary comes on the heels of the FDA's decision to change the label on the popular cholesterol-lowering medication simvastatin after it was found that the 80 mg dose of the drug was associated with an elevated risk of myopathy, particularly during the first 12 months.

The FDA’s decision was based on a review of the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial and its Adverse Event Reporting System (AERS).

The SEARCH trial showed that myopathy developed in 52 patients within the 80 mg dose group and only one patient in the 20 mg dose group. Rhabdomyolysis occurred in 22 patients within the 80 mg group and no patients administered the 20 mg dosage.

However, while the authors noted that simvastatin is particularly prone to drug-drug interactions, it is not only simvastatin containing drugs that have this risk. In fact, Egan and Colman noted that "all statins are associated with myopathy, ranging in severity from asymptomatic increases in creatine kinase to muscle aches or weakness to fatal rhabdomyolysis."

They also hypothesized that the increased risk for myopathy found with the 80 mg dose of simvastatin could be due to the concomitant use of medications such as amiodarone, diltiazem and amlodipine.

The FDA found that the incidence of myopathy was three times higher with the 80 mg dose of simvastatin compared to lower doses of rosuvastatin and atorvastatin. The agency has recommended that the 80 mg dose of simvastatin be used only in patients who have been taking the medication for 12 months or more who have no signs of significant muscle toxicity. The FDA said that the CV benefits of the drug outweigh the low absolute risk of myopathy. Patients who need their LDL cholesterol level lowered can be administered a 40 mg dosage of the drug, the FDA noted.

On the flipside, a recent meta-analysis that evaluated more than 90,000 patients showed that for every 39 mg per deciliter that statin drugs lowered LDL cholesterol levels, the risk of major adverse cardiovascular events was reduced 25 percent.

Egan and Colman also noted that average LDL cholesterol-lowering effects for the highest doses of approved statins are 63 percent for rosuvastatin (40 mg), 57 percent for atorvastatin (80 mg), 46 percent for simvastatin (80 mg), 41 percent for pitavastatin (4 mg), 40 percent for lovastatin (80 mg), 34 percent for pravastatin (80 mg) and 31 percent for fluvastatin (80 mg).

The FDA has changed the labeling on higher doses of simvastatin (Zocor) and ezetimibe and simvastatin (Vytorin). Egan and Colman said that the FDA will continue to monitor prescription-use data for these drugs to determine “whether the safety-labeling changes and the communication outreach are having their intended effects of limiting new initiation of high-dose simvastatin therapy and guiding appropriate use of concomitant medications with simvastatin.”

The authors concluded that the FDA will take further regulatory action if the current actions are deemed unfit.