Based on review of data from a large clinical trial and data from other sources, the FDA ( Food and Drug Administration ) has informed the public about an increased risk of muscle injury in patients taking the highest approved dose of the cholesterol-lowering medication, Zocor ( Simvastatin ) 80 mg, compared to patients taking lower doses of Simvastatin and possibly other statins.

The clinical trial data being reviewed is from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine ( SEARCH ) trial. The Agency is also reviewing data from other clinical trials, observational studies, adverse event reports, and data on prescription use of Simvastatin to better understand the relationship between high-dose Simvastatin use and muscle injury.

The muscle injury, also called myopathy, is a known side effect with all statin medications. Patients with myopathy generally have muscle pain, tenderness or weakness, and an elevation of a muscle enzyme in the blood ( creatine kinase ). The higher the dose of statin used, the greater the risk of developing myopathy. The risk of myopathy is also increased when Simvastatin, especially at the higher doses, is used with certain drugs.

The most serious form of myopathy is called rhabdomyolysis. It occurs when a protein ( myoglobin ) is released as muscle fibers break down. Myoglobin can damage the kidneys. Patients with rhabdomyolysis may have dark or red urine and fatigue, in addition to their muscle symptoms. Damage to the kidneys from rhabdomyolysis can be so severe that patients may develop kidney failure, which can be fatal.

Known risk factors for developing rhabdomyolysis include age ( greater than 65 years ), hypothyroidism, and poor kidney function. Myopathy and rhabdomyolysis are listed as possible side effects in the Simvastatin and other statin drug labels.

The SEARCH trial evaluated over 6.7 years the number of major cardiovascular events ( myocardial infarction, revascularization, and cardiovascular death ) in 6031 patients taking 80 mg of Simvastatin compared to 6033 patients taking 20 mg of Simvastatin. All patients in the study had previously had a myocardial infarction.

Preliminary SEARCH trial results revealed that more patients in the Simvastatin 80 mg group developed myopathy compared to patients in the Simvastatin 20 mg group ( 0.9% compared to 0.02% ). Further, FDA's preliminary analyses of the primary data suggest that 11 ( 0.2% ) of the patients in the Simvastatin 80 mg group developed rhabdomyolysis compared to no patients in the Simvastatin 20 mg group.

In 2008, the Agency alerted the public about an increased risk of developing rhabdomyolysis when doses greater than 20 mg of Simvastatin are given with Amiodarone.
In March 2010, FDA approved a labeling revision for Simvastatin based on interim results from an ongoing clinical trial – the Heart Protection Study 2 (HPS2). The revised label states that patients of Chinese descent should not receive Simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. Further, the revised label recommends caution when such patients are treated with Simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products. The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent ( 0.03% ) taking 40 mg Simvastatin plus cholesterol-modifying doses ( greater than or equal to 1 g/day ) of a Niacin-containing product. It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.

Moreover, FDA has requested that the sponsor of Simvastatin change the product labeling to instruct healthcare professionals to avoid prescribing Simvastatin doses greater than 40 mg daily when patients are taking the medication Diltiazem, due to an increased risk for myopathy.

A 2010 review of prescription drug use data conducted by FDA found that, despite dose limitations and drug-drug interaction precautions included in the Simvastatin drug label, patients are continuing to be prescribed higher doses of Simvastatin with other medications that are known to increase the risk for rhabdomyolysis.

It is important for healthcare professionals to consider the potential risks and known benefits of Simvastatin compared to other cholesterol-lowering therapies when deciding to use Simvastatin. Healthcare professionals should also carefully review patients' medications for potential drug-drug interactions before prescribing or dispensing Simvastatin.

Simvastatin dose limitations

These limitations apply to all patients taking Simvastatin.

A) Do not use Simvastatin with these medications: Itraconazole, Ketoconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease inhibitors, Nefazodone;

B) Do not use more than 10 mg of Simvastatin with these medications: Gemfibrozil, Cyclosporine, Danazol;

C) Do not use more than 20 mg of Simvastatin with these medications: Amiodarone, Verapamil;

D) Do not use more than 40 mg of Simvastatin with this medication: Diltiazem.

Source: FDA, 2010

XagenaMedicine2010


Link: Xapedia - Medical Encyclopedia