The Food and Drug Administration (FDA) has lowered the maximum daily dosage of the lipid-lowering drug simvastatin (Zocor) from 80 mg to 40 mg for most patients, based on the risks of myopathy and rhabdomyolysis associated with higher doses. Myopathy is unexplained muscle pain and damage; muscle damage is reflected by a serum level of creatine kinase more than 10 times the upper limit of normal. Rhabdomyolysis is a complication of myopathy in which the kidneys are damaged by the contents of the ruptured muscle cells; acute renal failure and even death can result. Although the 80-mg simvastatin tablet won't be taken off the market, the label now indicates that that dose should only be used by those who've been receiving 80 mg a day for at least one year without experiencing complications. Patients newly prescribed simvastatin shouldn't be started at this dosage, and patients currently receiving 40 mg per day or less shouldn't be increased to it. Currently, simvastatin is available in several strengths: 10, 20, 40, and 80 mg. It's also available in combination with ezetimibe, under the trade name Vytorin. The new limit on dosage also applies to the formulation of Vytorin that contains 80 mg of simvastatin.
The FDA's decision is based on a review of data from various clinical trials, most notably the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and reports of adverse effects submitted to the FDA. SEARCH was a seven-year trial that involved more than 12,000 patients who'd had a myocardial infarction and needed statin therapy. The patients in the trial received either 80 mg or 20 mg of simvastatin and were also randomized either to receive vitamin B12 and folate or not to receive them. Although SEARCH found that 80 mg of simvastatin decreased cholesterol more than the 20-mg dose did, and lowered the risk of major vascular events, the higher dose also greatly increased the risks of myopathy and rhabdomyolysis. The incidence of myopathy in those receiving 80 mg was 0.9%, compared with 0.02% in those receiving 20 mg; the incidence of rhabdomyolysis was 0.4% in the 80-mg group, but no one in the 20-mg group developed it. There were no deaths from rhabdomyolysis in SEARCH, but the FDA's adverse effects database does include reports of deaths from high doses of simvastatin. The SEARCH data showed that the risks of myopathy and rhabdomyolysis were highest in the first 12 months of daily therapy with 80 mg of simvastatin; they were also more common in older adults, women, and those concurrently receiving a calcium channel blocker (diltiazem in particular). Another interesting finding of SEARCH was that there appeared to be a genetic variant that contributed to a patient's risk of developing myopathy and rhabdomyolysis. This variation altered the ability of the liver to take up simvastatin for metabolism. When simvastatin isn't taken up by the liver, there's a higher circulating level of the drug, which also increases the risk of adverse effects.
Contraindicated medications. The FDA notes that certain medications may also increase the circulating levels of simvastatin, which would, consequently, increase the patient's risk of myopathy and rhabdomyolysis. The revised label notes these drugs as contraindications:
* itraconazole
* ketoconazole
* posaconazole (new in the triazole antifungal class)
* erythromycin
* clarithromycin
* telithromycin
* HIV protease inhibitors
* nefazodone
* gemfibrozil
* cyclosporine
* danazol
Gemfibrozil, cyclosporine, and danazol were previously contraindicated only in patients taking more than 10 mg of simvastatin.
In addition, patients taking amiodarone, verapamil, or diltiazem shouldn't exceed 10 mg of daily simvastatin, and patients taking amlodipine or ranolazine shouldn't exceed 20 mg of simvastatin per day.
Nurses caring for patients taking simvastatin should confirm that the patient hasn't already been prescribed a drug that's a contraindication to simvastatin use. Nurses should also assess patients taking simvastatin for evidence of myopathy and rhabdomyolysis (unexplained muscle pain, tenderness or weakness, red or dark-colored urine, decreased urine production, or unexplained fatigue). Patient education should include the signs and symptoms of myopathy and rhabdomyolysis and the importance of reporting these findings at once to the prescriber. NPs who treat patients with elevated cholesterol levels shouldn't prescribe the 80-mg daily dosage of simvastatin to new patients or increase any patient to that dosage who currently receives 40 mg or less. If cholesterol counts aren't controlled with lower dosages of simvastatin, another drug may be added or the patient can be switched to another drug entirely.