The muscle injury, also called myopathy, is a known side effect with all statin medications. According to the FDA, the risk of myopathy is also increased when Zocor, especially at the higher doses, is used with certain drugs. Those drugs include Amiodarone, niacin and diltiazem.
The most serious form of myopathy is called rhabdomyolysis. According to the FDA, it occurs when the protein myoglobin is released as muscle fibers break down. Myoglobin can damage the kidneys as they filter blood out of the body. 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.
According to the FDA, known risk factors for developing rhabdomyolysis include age (> 65 years), low thyroid hormone levels (hypothyroidism), and poor kidney function. Myopathy and rhabdomyolysis are listed as possible side effects in the simvastatin and other statin drug labels.
The agency's warning was based on its review of data from a large clinical trial called the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, as well as data from other clinical trials, observational studies, adverse event reports, and data. The SEARCH trial evaluated over 6.7 years the number of major cardiovascular events (heart attack, revascularization, and cardiovascular death) in 6031 patients taking 80 mg of Zocor compared to 6033 patients taking 20 mg of the medication. All patients in the study had previously had a heart attack.
Of the study patients given the highest dose of Zocor, 52 (.09 percent) developed myopathy, while only one patient (.02 percent) in the 20 mg dose group did so. The FDA's preliminary analyses of the primary data suggest that 11 (0.02%) of the patients in the simvastatin 80 mg group developed rhabdomyolysis compared to no patients in the simvastatin 20 mg group.
The emerging research found that the simvastatin both hinders the ability of specialized immune cells, called macrophages, to kill pathogens and also enhances molecule—cytokine—production, which prompts and maintains inflammation.
The researchers conducted experiments on human cells and mice, using human macrophages derived from blood samples of healthy donors and murine (mouse) macrophages, said Science Daily. Macrophages were incubated with Staphlococcus aureus, a bacteria generally found on the skin and in the body’s upper airways, said Science Daily. When the infection took hold, the team analyzed the bactericidal response of macrophages treated with simvastatin, said Science Daily.
Treated macrophages responded with significant impairment when attempts were made to remove the bacteria and related cell debris, said Science Daily. Similar impairment was also seen when attempts were made to kill ingested bacteria, versus the same attempts on untreated cells, said Science Daily. The cells that were treated also produced higher amounts of cytokines, the molecule that prompts cell inflammation, said Science Daily, which noted that the experiments caused similar results when conducted on mice.
Zocor, Simlup, Simcard, and Simvacor are all brand names for simvastatin medications. Vytorin is a combination of the Zocor and Zetia.
Recently, the makers of the controversial cholesterol-lowering drug Vytorin—Merck & Company and Schering-Plough Corporation—agreed to settle allegations that they delayed the release of negative information derived from a study of the drug, reported Reuters. Merck and Schering-Plough will pay $5.4 million to 35 states and the District of Columbia, said Reuters, which explained that the two sell Vytorin via a joint venture and also sell Zetia, a “related” drug and a component of Vytorin.
Vytorin, a combination of the Zocor and Zetia, has been under the microscope since the ENHANCE study, which found the drug was no better than a cheaper, generic statin in preventing clogged arteries, was released in January 2008. Merck and Schering-Plough delayed releasing ENHANCE for more than a year; the trial was actually completed in 2006. The state attorneys general allege that before the drug makers released any of the negative study results, both Merck and Schering-Plough conducted intense marketing of Vytorin through direct-to-consumer (DTC) advertising, Reuters pointed out.
The ENHANCE controversy spawned well over 100 lawsuits alleging Merck and Schering-Plough were fraudulent by withholding the study results for so long. Investigations into the ENHANCE debacle and Vytorin marketing are also being conducted in Congress, by the U.S. Justice Department, and several state attorneys general. Also, in August, the drug makers agreed to pay $41.5 million to settle class-action lawsuits filed by consumers who used Vytorin and Zetia.
Amiodarone is an ingredient in Wyeth's Cordarone and is also sold generically. Simvastatin is an ingredient in Merck & Co's Zocor and Abbott Laboratories Inc's Simcor, and is sold generically. It also a component of Merck and Schering-Plough Corp's Vytorin.
Simvastatin is a statin, a class of drugs which already carries a risk of rhabdomyolysis. However, the FDA said today that the risk of developing rhabdomyolysis is more pronounced when simvastatin is combined with Amiodarone than it is with other statin medications.
Rhabdomyolysis
According to today's FDA warning, the risk of developing rhabdomyolysis is dose-related and increases when a dose of simvastatin greater than 20 mg per day is given with Amiodarone. The agency said that healthcare professionals, who prescribe simvastatin or simvastatin-containing medications (Simcor, Zocor, Vytorin), should be aware that patients taking Amiodarone should not take more than 20 mg per day of simvastatin.
Patients starting therapy with simvastatin, or who have had their dose of simvastatin increased, should contact their doctor immediately if they experience symptoms of unexplained muscle injury, such as muscle cramps, pain, tenderness, stiffness or spasm.
The FDA said it is working with the manufacturer of Cordarone (Amiodarone) to modify prescribing information to warn of an increased risk of rhabdomyolysis when Amiodarone is taken with simvastatin doses exceeding 20 mg daily. In 2002, the labeling of simvastatin was changed to include similar information.