FDA announces new safety recommendations for high-dose simvastatin due to Increased risk of muscle injury.

The U.S. Food and Drug Administration today is announcing safety label changes for the cholesterol-lowering medication simvastatin because the highest approved dose–80 milligram (mg)–has been associated with an elevated risk of muscle injury or myopathy, particularly during the first 12 months of use.

The agency is recommending that simvastatin 80 mg be used only in patients who have been taking this dose for 12 months or more and have not experienced any muscle toxicity. It should not be prescribed to new patients. There are also new contraindications and dose limitations for when simvastatin is taken with certain other medications.

Simvastatin is used together with diet and exercise to reduce the amount of “bad cholesterol” (low-density lipoprotein cholesterol or LDL-C) in the blood. In some studies high levels of LDL-C are linked to a higher risk of heart attack, stroke and cardiovascular death. In 2010, about 2.1 million patients in the United States were prescribed a product containing simvastatin 80 mg. This drug, like all statins, has been aggressively marketed and is grossly over prescribed.

“The FDA has completed its review of the safety of high-dose simvastatin and is making label changes to reduce the risk of statin-associated muscle injury,” said Eric Colman, M.D., deputy director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “We want to ensure that patients and health care professionals are aware of the new labeling changes to simvastatin, including the increased risk of myopathy when using the 80 mg dose of simvastatin.”

The changes to the label for simvastatin-containing medications are based on the FDA’s review of the results of the seven-year Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine clinical trial, other clinical trial data, and analyses of adverse events submitted to the FDA’s Adverse Event Reporting System. All showed that patients taking simvastatin 80 mg daily had an increased risk of muscle injury compared to patients taking lower doses of simvastatin or other statin drugs. The risk of muscle injury is highest during the first year of treatment with the 80 mg dose of simvastatin, is often the result of interactions with certain other medicines, and is frequently associated with a genetic predisposition for simvastatin-related muscle injury.

Simvastatin is sold under the brand-name Zocor and as a single-ingredient generic product. It is also sold in combination with ezetimibe as Vytorin and in combination with niacin as Simcor.

The FDA has revised the drug labels for simvastatin and Vytorin to include the new 80 mg dosing restrictions. The agency also revised the labels for simvastatin, Vytorin and Simcor to include new dosing recommendations when these drugs are used with certain medications that interact to increase the level of simvastatin in the body, which can increase the risk for myopathy. Patients who are unable to adequately lower their level of LDL-C on simvastatin 40 mg should not be given the higher 80 mg dose of simvastatin; instead, they should be placed on an alternative LDL-C-lowering treatment(s).

One school of thought is that claims over many years that raised cholesterol is responsible for increased risk of heart disease are fundamentally wrong or have been significantly overstated. There may actually be little or no real scientific basis for the use of anti-cholesterol drugs. All such drugs cause some unwanted side effects, many of them severe. Long term use of statins is a particular concern. Unfortunately pharmaceutical companies are brilliant marketers, study manipulators and enjoy plenty of political power. Combine these facts with prescriber ignorance, overwork, undue reliance on drug representatives for “ongoing education” and a number of intra-professional and general cultural forces and we have a recipe for increasing wealth for pharmaceutical investors while consumers’ real health outcomes decline.

Patients taking simvastatin 80 mg daily have an increased risk of myopathy compared to patients taking lower doses of this drug or other drugs in the same class. This risk appears to be higher during the first year of treatment, is often the result of interactions with certain medicines, and is frequently associated with a genetic predisposition toward simvastatin-related myopathy. Patients with myopathy generally have muscle pain, tenderness or weakness, and an elevation of a muscle enzyme in the blood (creatine kinase, or CK). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure which can be fatal. Rhabdomyolysis is rare; hospitalized rhabdomyolysis occurs in 4.9 people out of every 100,000 people exposed to simvastatin for one full year (the average incidence for hospitalized rhabdomyolysis for atorvastatin, pravastatin, or simvastatin is 4.4 people out of every 100,000 people). (Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-90.)

The new changes to the drug labels for simvastatin-containing medicines are based on FDA’s review of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and other data described in the Agency’s March 2010 Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury.

SEARCH was a seven-year, randomized, double-blind clinical trial comparing the efficacy and safety of simvastatin 80 mg to simvastatin 20 mg, with or without vitamin B12 and folate, in survivors of myocardial infarction.

At the end of the trial, the incidence of major vascular events was 25.7% in the 20-mg group versus 24.5% in the 80-mg group [RR=0.094, 95% CI (0.88, 1.01); p=0.10]. Due in part to greater use of off-study LDL-C lowering medication in the simvastatin 20 mg group versus the 80-mg group, the difference in mean levels of LDL-C between the two treatment groups was 13 mg/dL instead of the expected difference of 20 mg/dL. Nonetheless, the 6% reduction in relative risk for major vascular events observed in SEARCH is consistent with the 13 mg/dL lower level of LDL-C in the 80-mg group.

Fifty-two patients (0.9%) in the 80-mg group versus one patient (0.02%) in the 20-mg group developed myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times the upper limit of normal [ULN]). This was higher than the labeled risk (based on clinical trial data) of 0.53%. Twenty-two patients (0.4%) in the 80-mg group versus no patient in the 20-mg group developed rhabdomyolysis (defined as unexplained muscle weakness or pain with serum CK >40 times ULN). There were no fatalities related to rhabdomyolysis.

The risks for myopathy and rhabdomyolysis with simvastatin 80 mg were highest in the first 12 months of treatment, 5 per 1000 person-years and 2 per 1000 person-years, respectively, and decreased to 1 per 1000 person-years and 0.4 per 1000 person-years after that.

Older age and female sex both increased the risk of myopathy. In SEARCH, the risk of myopathy was approximately doubled in patients taking a calcium channel blocker, in particular diltiazem. Approximately 60% of the cases of myopathy were associated with a genetic variant which affects the coding of the transporter responsible for simvastatin uptake into the liver. This variant increases the plasma concentration of simvastatin, thus increasing the risk of myopathy.

The findings from the SEARCH trial are supported by analyses of the FDA’s Adverse Event Reporting System (AERS) database, which show that the level of reporting of fatal rhabdomyolysis associated with the 80-mg dose of simvastatin has been higher in comparison with lower doses of simvastatin or lower doses of most other statins. In addition, clinical trial data from other long-term statin trials show higher overall rates of myopathy and rhabdomyolysis in patients treated with simvastatin 80 mg versus lower doses of simvastatin or other statins.

For more information from the FDA:

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