Correspondence
Cerivastatin and Reports of Fatal Rhabdomyolysis
N Engl J Med 2002; 346:539-540February 14, 2002
- Article
To the Editor:
Bayer's voluntary withdrawal of cerivastatin from the U.S. market led to questions regarding the safety of all hydroxymethylglutaryl–coenzyme A reductase inhibitors, or statins. Myopathy and the rarer severe rhabdomyolysis are considered adverse events of therapy with this class of drugs.1 Concomitant use of drugs that can increase blood levels of statins can increase the risk of myopathy, as can concomitant use of gemfibrozil.2 We summarize the U.S. reports of fatal rhabdomyolysis associated with all six drugs in this class: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and cerivastatin.
We reviewed reports in the Adverse Event Reporting System of the Food and Drug Administration (FDA). We also examined the number of prescriptions dispensed in the United States since the marketing of each drug began, according to the National Prescription Audit Plus (IMS HEALTH, Fairfield, Conn.). This is a nationally projected audit of retail pharmacies and mail-order houses.
Our results show that fatal rhabdomyolysis is a rare event among statin users, with reporting rates much lower than 1 death per million prescriptions in the case of most statins (Table 1Table 1
Reported Cases of Fatal Rhabdomyolysis and Numbers of Prescriptions for All Statins Dispensed in the United States since These Products Were Launched.). The rate of fatal rhabdomyolysis associated with cerivastatin therapy, however, is 16 to 80 times as high as the rates for any other statin. Some of this difference appears to be related to the known, marked interaction (relative to that of other statins) between cerivastatin and gemfibrozil, which in late 1999 led to the listing on the label of contraindications against the combined use of these agents. The use of this combination was reported in 12 of the 31 deaths. After the exclusion of the 12 cases in which gemfibrozil was used with cerivastatin and the 7 cases in which it was used with lovastatin, the reporting rate of fatal rhabdomyolysis in association with cerivastatin monotherapy is 1.9 per million prescriptions, 10 to 50 times as high as the rates associated with the other statins. Among the 19 deaths associated with cerivastatin in the absence of gemfibrozil therapy, 12 occurred after use of the 0.8-mg dose (which was approved in the United States in July 2000), 6 occurred after use of the 0.4-mg dose, and the dose was not reported in 1 case. This pattern suggests that the event was related to the dose.Because of the underreporting of adverse reactions, the use of reporting rates as proxy measures of risk has limitations. Only about 1 percent of all serious events are directly reported by physicians.3 There is a secular trend of increased reporting to the FDA over the past decade.4 However, the rate of reports of fatal rhabdomyolysis associated with the use of atorvastatin (approved for use within six months before the approval of cerivastatin) was far less than for cerivastatin. Thus, the increased reporting associated with the use of cerivastatin appears to be more than an artifact related to an increased awareness of statin-associated rhabdomyolysis or to secular trends in reporting.
On the basis of the finding of a markedly increased reporting rate of fatal rhabdomyolysis in association with cerivastatin, Bayer, with the concurrence of the FDA, moved to withdraw cerivastatin from the U.S. market. Clinicians should be aware of this labeled but rare event associated with the use of all statins and should warn patients to watch for symptoms of myopathy, such as muscle pain or weakness, which should prompt an immediate consultation with their physician.
(The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement by, the FDA or the U.S. government.)
4 ReferencesJudy A. Staffa, Ph.D., R.Ph.
Jennie Chang, Pharm.D.
Lanh Green, R.Ph., M.P.H.
Food and Drug Administration, Rockville, MD 20857
staffaj@cder.fda. gov 1
Physicians' desk reference. 55th ed. Oradell, N.J.: Medical Economics, 2001.
2
Pierce LR ,Wysowski DK ,Gross TP . Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990;264:71-75
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Scott HD ,Rosenbaum SE ,Waters WJ , et al. Rhode Island physicians' recognition and reporting of adverse drug reactions. R I Med J 1987;70:311-316
Medline4
Kennedy DL, Goldman SA, Lillie RB. Spontaneous reporting in the United States. In: Strom BL, ed. Pharmacoepidemiology. 3rd ed. New York: John Wiley, 2000:151-74.
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