HEALTH NEWS

Study Title:

FDA Warns Not to Take High-Dose Zocor

Study Abstract

FDA News Release:

The U.S. Food and Drug Administration (FDA) is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication, simvastatin (80 mg) because of increased risk of muscle damage. Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy). Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. In addition to these new limitations, FDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.

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).1

FDA has revised the drug labels for simvastatin and Vytorin to include the new dosing restriction for the 80-mg dose. The labels for simvastatin, Vytorin, and Simcor were also revised to include new dosing recommendations when these drugs are used with certain medicines that interact with simvastatin to increase the level of simvastatin in the body. Increasing the levels of simvastatin in the body can increase the risk for myopathy (see Simvastatin Dose Limitations below).

In March 2010, FDA announced it was reviewing the safety of simvastatin in the Agency's Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury1

Additional Information for Patients

Patients currently taking 80-mg simvastatin-containing medicines should:

Not stop taking their medicine unless told to by their healthcare professional.
Review their medical history with their healthcare professional, the currently prescribed dose of simvastatin, and a list of their other current medications to determine if the medicines they are taking are appropriate. Know that certain medications should never be taken with simvastatin (see Simvastatin Dose Limitations below).
Immediately contact their healthcare professional if they experience muscle pain, tenderness or weakness, dark or red colored urine, or unexplained tiredness.
Talk to their healthcare professional about any questions or concerns they have about simvastatin-containing medicines.
Report side effects from the use of simvastatin-containing medicines to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.

Additional Information for Healthcare Professionals

FDA recommends that healthcare professionals should:

Maintain patients on simvastatin 80 mg only if they have been taking this dose for 12 or more months without evidence of muscle toxicity.
Not start new patients on simvastatin 80 mg.
Place patients who do not meet their LDL cholesterol (LDL-C) goal on simvastatin 40 mg on alternative LDL-C lowering treatment(s) that provides greater LDL-C lowering (see Relative LDL-lowering Efficacy of Statin and Statin-based Therapies below).
Follow the recommendations in the simvastatin-containing medicines labels regarding drugs that may increase the risk for muscle injury when used with simvastatin (see Simvastatin Dose Limitations below).
Switch patients who need to be initiated on a drug that interacts with simvastatin to an alternative statin with less potential for the drug-drug interaction.
Report adverse events involving simvastatin-containing medicines to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.

Data Summary

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 injury2.

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.

Simvastatin Dose Limitations

When used with simvastatin, the following medications can raise the levels of simvastatin in the body and increase the risk of myopathy. Taking no more than the recommended dose of simvastatin with these medications will help keep simvastatin levels in the body at a safer level.

Press Release from ABC News:

The U.S. Food and Drug Administration has recommended limiting high doses of a widely prescribed cholesterol-lowering drug called simvastatin -- commonly known as Zocor -- after
reviewing the results of a clinical trial that found a higher risk of muscle damage compared to patients taking lower doses of the statin. The use of the 80-mg dose of Zocor, the highest
approved dose of the drug, can harm muscles and potentially cause deadly kidney damage, the U.S. Food and Drug Administration warned Wednesday.

The new recommendation applies only to what the FDA estimates to be 2 million Americans who in 2010 were prescribed 80 milligram doses of simvastatin in one form or another -- whether as Zocor or its generic equivalent, or in the combination statin drugs Vytorin and Simcor.

The most common side effects of Zocor include muscle pain, tenderness and weakness. While rare, more serious side effects include muscle damage that can lead to liver disease and kidney failure. Five out of every 100,000 people taking Zocor for a year experienced the effects, according to the FDA.

Statins, including Zocor, have been shown to dramatically lower bad cholesterol in patients with heart disease and diabetes. But many doctors say they've known long before this warning of its potential dangers. And, some said, an FDA recommendation for a warning label is a necessary next step.

"It's about time," said Lynn Willis, professor of the department of pharmacology at Indiana University School of Medicine in Indianapolis. "I'm of the view that the muscle pain induced by Zocor occurs with much greater frequency than we would think."

Dr. Steven Nissen, chairman of the department of cardiovascular medicine at Cleveland Clinic referenced an editorial he wrote for the Journal of the American Medical Association in 2004 citing potential dangers of the high dose medication.

"It takes the FDA a long time to make these decisions," said Nissen. "Unfortunately it takes time to sort through the evidence."

Many doctors said they already switch to other kinds of statins, including Crestor and Lipitor, if a patient requires a higher dose. The drugs were not among those shown to raise the risk of muscle damage.

"The more we study drugs in a systematic fashion and conduct surveillance, the more we find out," said Dr. John McPherson, a clinical cardiologist at Vanderbilt University Medical Center in Nashville, Tenn.

McPherson is among many researchers at Vanderbilt who are looking into specific genes that can show if a patient is at risk for complications from Zocor before they are even put on the drug.

Many heart patients at Vanderbilt University Medical Center now undergo genetic tests before they are prescribed any kind of heart medications, including statins.

"An abnormal copy of the gene can affect how we metabolize drugs," said Dr. Russell A. Wilke, director of genomics and cardiometobolic risk at Vanderbilt University Medical Center. "We are using genetic tests to reduce the frequency of statin-related side effects.

"We can know at the point of prescribing," Wilke said

Study Information

FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury.
FDA Announcement
2011 June