The US FDA has recommended limiting the use of high-dose simvastatin because the cholesterol-lowering drug can elevate the risk of muscle injury. The agency said the 80-mg dose should only be taken by patients who already have been using the medication for 12 months or longer without experiencing the side effects indicative of myopathy.
Simvastatin is sold both as a generic and under the brand-name Zocor and is combined with ezetimibe in Vytorin and with niacin in Simcor. According to the FDA, 2.1 million US patients were prescribed a product containing simvastatin in 2010.
The FDA issued the new recommendations after reviewing data from clinical trials, as well as adverse event reports filed with the agency.
Patients taking 80 mg simvastatin daily have an increased risk of myopathy, characterized by muscle pain and weakness, compared to patients taking a lower dose of the drug or another medication in the same class of statin drugs. The risk of problems was greatest during the first year of use and in patients taking certain other medications, such as calcium-channel blockers. Risk was also elevated in people with a genetic-associated predisposition toward simvastatin-related myopathy.
AVOID NEW PRESCRIPTIONS
“Our overall goal is to get doctors to not start patients on 80 mg of simvastatin,” Eric Colman, MD, deputy director of the FDA Division of Metabolism and Endocrinology, said in a consumer article posted on the FDA website. The most serious form of myopathy — rhabdomyolysis — can cause kidney damage and failure, which can be fatal.
The agency recommended that patients who cannot achieve a desirable blood cholesterol level with 40 mg daily of simvastatin should be switched to a different statin rather than increasing their dose to 80 mg.
“There are alternative statins that may not have the same risk as 80 mg per day of simvastatin,” Larry B. Goldstein, MD, professor of medicine (neurology) and director of the Duke Stroke Center at Duke University, told Neurology Today. “Physicians also need to aware of potential drug interactions that can potentiate statin toxicity.”
Dr. Goldstein served on the steering committee for a study that found that 80 mg per day of atorvastatin reduced the risk of stroke by 16 percent in patients who had a stroke or transient ischemic stroke within the prior six months, and also significantly reduced the chance of heart attack compared to a placebo.
The new labeling changes for simvastatin-containing drugs stem from a FDA review of data from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, a nearly seven-year randomized double-blind clinical trial that compared 80 mg simvastatin to 20 mg of the drug, with or without vitamin B12 and folate, in patients with a history of myocardial infarction. A major vascular event was experienced by 24.5 percent of the 6,000-plus patients taking 80 mg compared to 25.7 percent of those on 20 mg, investigators reported in the November 2010 edition of The Lancet.
But 52 patients (0.9 percent) in the 80-mg study group developed myopathy compared to one patient (0.02 percent) in the 20-mg group, which was higher than the labeled risk of 0.53 percent that was based on clinical trials, the FDA said of the SEARCH results. Myopathy was defined as unexplained muscle weakness or pain with a serum creatine kinase (CK) greater than 10 times the upper limit of normal. (See “SEARCH Data.”)
ADVERSE EVENTS MORE COMMON
The agency said the findings from the SEARCH trial are in line with an analysis it conducted of cases reported to the FDA‘s Adverse Event Reporting System. There were more reported cases of fatal rhabdomyolysis connected to 80-mg simvastatin compared to lower doses of the drug and lower doses of most other statins. The FDA said data collected in other clinical trials also pointed to more problems with the 80-mg dose.
The FDA also updated the list of drugs that should not be taken with simvastatin and those that should only be taken with low-doses of the medication. New to the list of “contraindicated drugs with simvastatin” is posaconazole, an anti-fungal medication. In addition, the blood pressure medication amlodipine and ranolazine, used to treat angina, should not be taken with more than 20 mg of simvastatin.
Paul Twydell, DO, assistant professor of neurology at the University of Rochester in New York, said simvastatin is likely more toxic to muscle tissue because of its tendency toward lactose formation and higher lipophilicity, allowing it to better infiltrate muscle cells.
Dr. Twydell said that muscle aches are reported by about 10 percent of people who take statin drugs, but most cases are not severe and are temporary. “If we look at the other statins out there, there are other options that don‘t have the toxicity profile of simvastatin, but still have a similar lipid-lowering profile,” he told Neurology Today. Among the options: pravastatin, lovastatin, and rosuvastatin.
Dr. Twydell said he thinks it‘s wise to complete a thorough medication list review and get a baseline CK muscle enzyme reading on patients before prescribing any statin therapy so that there is a point of comparison if muscle problems arise.
Dr. Goldstein noted that diagnosing myopathy is not always straightforward. “We‘re dealing in general with elderly patients who commonly have a variety of aches and pains, including muscle pain, but we have to remain appropriately vigilant because this could be due to myopathy in a patient receiving a statin,” he said.
SEARCH STUDY DATA
* 22 patients (0.4 percent) on the simvastatin 80 mg developed rhabdomyolysis compared to none of the patients at the 20-mg dose.
* Rhabdomyolysis was defined as unexplained muscle pain or weakness, with a serum CK of greater than 40 times the upper limit of normal.
* The risks for myopathy and rhabdomyolysis with simvastatin 80 mg were greatest in the first 12 months of treatment, 5 per 1,000 person-years and 2 per 1,000 person-years respectively, and decreased to 1 per 1,000 person years and 0.4 per 1,000 person-years after that.
* Seniors and women had a higher risk. Patients who also took a calcium-channel blocker, in particular diltiazem, had double the risk of myopathy.
* Approximately 60 percent 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 FDA said.