FDA Removes Rezulin From the U.S. Market
By William T. Elliott, MD, FACP
The fda has asked parke-davis/warner-lambert, the manufacturer of the anti-diabetes drug troglitazone (Rezulin), to remove the drug from the U.S. market. This drastic action occurred after an extensive safety review of the drug, and introduction of two alternative drugs into the U.S. market. The company has agreed to the FDA’s request. Several other countries in Europe had already removed troglitazone from the market, but the FDA only took this action after the two "safer glitazones," rosiglitazone (Avandia) and pioglitazone (Actos) were approved. Reports of severe liver toxicity associated with troglitazone began filtering into the FDA in 1997. The FDA’s first action was to require stricter labeling and close monitoring of liver function tests in patients taking the drug. Despite this, there have been 90 confirmed cases of liver failure associated with troglitazone of which 63 patients died. Now, with safer alternatives on the market, the agency felt they could no longer justify the continued risk of the drug.
Janssen Pharmaceuticals also announced in late March that it will stop marketing cisapride (Propulsid), its pro-motility drug used to treat gastroesophageal reflux disease. The drug is associated with nearly 350 reports of heart rhythm abnormalities including 80 deaths. Most of these events occurred in patients who were taking other medications that might cause drug interactions, or who suffered from underlying conditions known to increase the risk of heart arrhythmias. Janssen will continue to distribute the drug until July 14, 2000, a date chosen to provide adequate time for patients and physicians to make alternative treatment decisions.
The American College of Cardiology (ACC) issued a clinical alert in mid-March regarding results of a study to be published in the April 19 issue of the Journal of the American Medical Association. The alert urges physicians to reevaluate patients being treated with the alpha-adrenergic blocker doxazosin (Cardura) following the sudden termination of the doxazosin arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) by the National Heart, Lung, and Blood Institute. According to early releases of the data, patients taking doxazosin had 25% more cardiovascular problems and were twice as likely to be hospitalized for heart failure than patients using the diuretic chorthalidone. Whether these findings are applicable to all alpha-blockers is unknown. The ACC says it will be publishing guidelines on the use of alpha-blockers in the near future.
The Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS) was also halted early in mid March, but for a different reason. Researchers found that the survival in the active treatment arm was superior to treatment with placebo. COPERNICUS is a study of more than 2000 patients with advanced heart failure, evaluating the effects of the beta-blocker carvedilol (Coreg). Although the final numbers are not available, the authors of the study suggested that the benefit was greater than that in other beta-blocker trials, which have shown at most a 34% mortality reduction. The target dose of carvedilol in COPERNICUS was 25 mg b.i.d. A recent study from Sweden evaluated the benefit of long- acting metoprolol in patients with chronic symptomatic heart failure. Nearly 4000 patients from 14 countries were randomly assigned to receive metoprolol or placebo in addition to standard therapy for heart failure. Metoprolol use resulted in reduction in all-cause hospitalization and total mortality of 19%, and reduction in death or heart transplant by 32%. Patient’s functional status symptoms were improved in the active treatment arm of the study (JAMA 2000;283:1295-1302). Metoprolol is currently being compared to carvedilol for patients with heart failure in the COMET trial.
Alosetron (Lotronex—Glaxo Wellcome), an antagonist of the type 3 serotonin receptor, was recently approved by the FDA for the treatment of irritable bowel syndrome (IBS) in women (see next article). A new study in nearly 650 women with diarrhea-predominant or alternating diarrhea-constipation IBS showed the drug to be significantly more effective than placebo in relieving symptoms. The alosetron-treated patients experienced decreased urgency, reduced stool frequency, and improved stool consistency, confirming earlier studies on which the drug’s approval was based (Lancet 2000;355:1030-1031, 1035-1040).
Research into the treatment of premenstrual dysphoric syndrome is focusing increasingly on manipulation of the neurotransmitter serotonin. Vitamin B6 has been used as an over-the-counter remedy for years. Its major role in the brain is to modulate levels of serotonin. Recently, selective serotonin reuptake inhibitors (SSRIs) have been used successfully in this role. A new study looks at the SSRI sertraline (Zoloft) in 243 women in a randomized double-blind, placebo-controlled trial. Treatment with sertraline resulted in substantial improvements in psychosocial functioning and quality of life within two menstrual cycles (J Clin Psychiatry 2000;61:101-109). This is the largest study to date of the use of SSRIs and for the treatment of premenstrual dysphoric syndrome.
Magnets have become a commonplace therapy for the treatment of musculoskeletal pain syndrome including low back pain. A new report from JAMA suggests bipolar magnets are no more effective than placebo in relieving chronic low back pain. Twenty patients wore either a bipolar magnet over the area of pain for six hours per day, three days per week for one week, with a one-week washout period between the two treatment weeks. No statistically significant differences were noted in the pain relief effect between real and sham magnets over the study period (JAMA 2000;283:1322-1325).
In what is sure to be a no-holds-barred brawl, with the rights to the world’s most popular medication at stake, Andrx Corporation announced at the end of March that the FDA has given tentative approval to the company for its generic formulation of Astra Zeneca’s omeprazole (Prilosec). The official launch of a generic omeprazole cannot occur until Astra Zeneca’s patent expires on April 5, 2001, and the company is pulling out all stops to extend the patent on its $3.5 billion per year drug. Most drug companies hold multiple patents on their lucrative drugs and omeprazole is no exception, so it is unlikely that a generic will be available this time next year.
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