CHICAGO—Patients taking the lipid-lowering medications atorvastatin, pravastatin, and simvastatin to reduce cholesterol levels have a relatively low risk of developing rhabdomyolysis, (a disorder that causes the breakdown of muscle), according to a new study in the December 1 issue of JAMA. However, older patients with diabetes mellitus taking combined statin-fibrate therapy appear to be at an increased risk for rhabdomyolysis. And patients who were taking cerivastatin combined with fibrates had a significantly higher risk of about one in 10 treated patients each year. Cerivastatin was removed from the U.S. market in 2001 because of high reporting of rhabdomyolysis in association with its use. The study to be published in the December 1 issue of JAMA is being released early online today because of its relevance to current events.

Disorders of muscle are among the most discussed adverse effects associated with the use of lipid-lowering agents (statins), according to background information in the article. Fibric acid derivatives (fibrates) have also been associated with primary muscle injury, especially when used in combination with a statin.

David J. Graham, M.D., M.P.H., from the Food and Drug Administration, and colleagues, analyzed claims data from 11 managed care health plans across the United States for patients on statins alone (monotherapy) or combined statin-fibrate therapy between January 1, 1998 and June 30, 2001.

"In 252,460 patients treated with lipid-lowering agents, 24 cases of hospitalized rhabdomyolysis occurred during treatment," the researchers report. All patients with rhabdomyolysis were taking statins at daily dosages within the dose-range recommended in product labeling. "Compared with statin monotherapy, fibrate use was associated with a 5.5-fold increase in risk and the combined use of a statin and fibrate increased risk by additional 2-fold vs. fibrate alone," the authors found. "The risk of rhabdomyolysis with cerivastatin monotherapy was 10-fold greater than with other statins, and in combination with a fibrate, was increased more than 1,400-fold."

CHICAGO—A review of the published literature and of internal company documents from the manufacturer of cerivastatin, a cholesterol lowering drug removed from the market in 2001, suggests that information about serious adverse effects of this medication was known to the company within months after this drug was launched, and that company analyses showing substantially increased risk of rhabdomyolysis were apparently not published or disseminated to physicians and patients. The article, released early online today because of its relevance to current events, is to be published in the December 1 issue of JAMA.

According to background information in the article, "For medicines that are effective, prompt approval provides rapid access to the health benefits of new drugs. At the same time, U.S. patients are increasingly the first to receive new medications, some of which are subsequently discovered to have serious adverse effects. As a result, the challenge of early detection is increasingly borne by the U.S. postmarketing systems."

Bruce M. Psaty, M.D., Ph.D., from the University of Washington, Seattle, and colleagues conducted a search of the published medical literature and reviewed internal company documents that have become part of the public record during a trial in Nueces County, Texas. The information gathered was used to review the association between the use of cerivastatin sodium (a statin drug removed from the market in 2001) and the risk of rhabdomyolysis (a disorder involving damage to muscle tissue) to illustrate the operation and limitations of the current U.S. postmarketing safety-surveillance system.

"Soon after marketing [of cerivastatin], spontaneous reports identified cases of rhabdomyolysis, an uncommon condition in which the breakdown of skeletal muscle cell causes pain, weakness, and in some cases, renal failure and death," the authors report. "Many but not all of them occurred in cerivastatin users who also took gemfibrozil (a fibrate, another type of drug used to help lower cholesterol). "In the published literature, cerivastatin was associated with much larger risks of rhabdomyolysis than other statins."..."In internal company documents, multiple case reports suggested a drug-drug interaction within approximately 100 days of the launch [of cerivastatin] in 1998; however the company did not add a contraindication [warning] about the concomitant use of cerivastatin and gemfibrozil to the package insert for more than 18 months," the authors note. "Despite limited data, the asymmetry between the information available to the company and the information available to patients and physicians seems striking."

"This history of cerivastatin illustrates a flaw in the current U.S. system for SADR (suspected adverse drug reactions) reporting and monitoring. When serious adverse effects such as rhabdomyolysis appear after marketing, defects in the safety-surveillance system can, depending in part on the response of the pharmaceutical company, pose a threat to the health of the public," the authors write. "To balance the interests of patients and industry, decisions about label changes, new studies, suspension of sales, or withdrawal of drugs might best be made by an outside group of disinterested reviewers."

CHICAGO—In an editorial in the December 1 issue, JAMA Editor-in-Chief, Catherine D. DeAngelis, M.D., M.P.H., Executive Deputy Editor, Phil B. Fontanarosa, M.D., and Deputy Editor Drummond Rennie, M.D., write "Physicians and patients expect that when medications are prescribed correctly for labeled indications and are used as directed, these medications generally will have beneficial effects and will not cause significant harm. This confidence in pharmaceutical products reflects trust in the effectiveness and integrity of the drug approval and monitoring process. However, the current approval process for drugs and biological agents in the United States has come under intense scrutiny, most notably because of concerns about influence from industry." The editorial, to be published in the December 1 issue of JAMA, is being released early online today because of its relevance to current events.

"To improve the necessary measures to monitor the safety of marketed drugs, the drug approval process must be decoupled from the postmarketing safety and surveillance system. It is unreasonable to expect that the same agency that was responsible for approval of drug licensing and labeling would also be committed to actively seek evidence to prove itself wrong (i.e., that the decision to approve the product was subsequently shown to be incorrect.) One option worth strong consideration, as others have suggested, is to establish an independent drug safety board or independent agency for drug safety, specifically to oversee postmarketing surveillance for drugs and devices." ..."Above all, the agency must be completely independent of influence from the pharmaceutical industry, biotechnology firms, and medical device manufacturers."

LEADING CHOLESTEROL - LOWERING DRUGS LARGELY SAFE FROM SIDE EFFECT MUSCLE DISORDER, THOUGH COMBINING THERAPIES CAN BE DANGEROUS FOR OLDER DIABETICS