NEJM: FDA Officials Explain the New Simvastatin Label Reply

(Updated with comments from Joe Ross and Steve Nissen)– In a perspective published in the New England Journal of Medicine, two FDA officials, Amy Egan and Eric Colman, explain in some detail the recent changes made by the FDA regarding simvastatin. They note that in the SEARCH trial myopathy developed in 52 (0.9%) patients in the 80 mg group compared to only 1 (0.02%) patient in the 20 mg group. There were 22 cases of rhabdomyolysis in the high dose group compared to no cases in the low dose group. Further, patients at high risk usually developed myopathy early in the course of treatment.

In addition, because simvastatin is “particularly prone to drug-drug interactions,” the risk of myopathy is increased in patients taking high dose simvastatin who are also taking other drugs, including several commonly used cardiovascular drugs including amiodarone, verapamil, diltiazem, amlodipine, and ranolazine.

Finally, the FDA authors summarize data from adverse event reports from all the statins, noting that rates of fatal rhabdomyolysis have been higher with simvastatin 80 mg than with atorvastatin 80 mg or rosuvastatin 40 mg.

Joe Ross provided the following comment to CardioBrief:

It’s reassuring to see the FDA make use of the authority they were granted by FDAAA to act on safety concerns raised about medications that have already been approved and marketed, using both clinical trial data and adverse event data to systematically examine whether the safety concern is real and sufficiently burdensome to act on. In the case of simvastatin, while the absolute risk is low, the medication is so commonly prescribed and there are so many alternatives to therapy available that limiting the use of 80mg among patients makes good sense from a public health standp

Steve Nissen provided the following comment to CardioBrief:

Once again, the FDA was asleep at the switch. Most lipid experts have known for many years  that the 80mg dosage of simvastatin carried a 7-10 fold high risk of myopathy compared with lower dosages of simvastatin or other statins. In the NEJM commentary, Drs. Egan and Colman state that “Recently, concerns have been raised about a disproportionate increase in the risk of myopathy with high dose simvastatin.” It all depends on what you consider recent. We warned of this risk in an editorial in JAMA in 2004 and the SEARCH Trial confirmed these concerns in 2008. Now, 7 years later, after about 70 deaths due to rhabdomyolysis, FDA has chosen to act. Too little, too late.

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