Withdrawn Drugs Posed Greater Health Risk for Women Than Men, GAO Says
Between January 1997 and December 2000, FDA or pharmaceutical companies withdrew the following 10 drugs: alosetron hydrochloride (Lotronex, Glaxo Wellcome), astemizole (Hismanal, Janssen), bromfenac sodium (Duract, Wyeth-Ayerst), cisapride monohydrate (Propulsid, Janssen), dexfenfluramine hydrochloride (Redux, Wyeth-Ayerst), fenfluramine hydrochloride (Pondimin, Wyeth-Ayerst), grepafloxacin hydrochloride (Raxar, Glaxo Wellcome), mibefradil dihydrochloride (Posicor, Roche), terfenadine (Seldane, Hoechst Marion Roussel), and troglitazone (Rezulin, Parke-Davis). Most had been available to U.S. patients for less than three years.
In its report (PDF) released February 8, GAO noted that women have a "higher incremental risk" than men of arrhythmia after taking astemizole, cisapride, mibefradil, or terfenadine. The agency speculated that women's higher usage of the appetite suppressants fenfluramine and dexfenfluramine, the antidiabetic agent troglitazone, and the gastrointestinal agent alosetron, compared with men's usage, may have accounted for the greater health risk posed by these drugs.
Astemizole, cisapride, and terfenadine can cause torsades de pointes by prolonging the interval between heart contractions. Compared with men, women have a longer interval between heart contractions, increasing the risk of potentially fatal torsades de pointes, according to literature cited by GAO. Also, male sex hormones lessen the heart's sensitivity to arrhythmia-promoting drugs.
As for the cardiovascular agent mibefradil, the greater health risk may have been caused by physiological differences, GAO found. The drug lowered the heart rate in elderly women and adversely interacted with 26 other agents.
The withdrawal of a drug from the market, GAO stated, does not occur in isolation. A drug such as troglitazone, which caused liver failure and deaths, remained on the market until newer, safer antidiabetic agents became available.
Incorrect use by health care professionals and patients can also lead to withdrawal of a drug. GAO blamed the withdrawal of bromfenac sodium, which caused liver failure, on physicians who continued to have patients take the pain reliever for 10 or more days despite reminders from FDA and the manufacturer to limit use to 9 days. Terfenadine's withdrawal resulted from the antihistamine's use in combination with drug therapies listed as contraindications in the product labeling.
GAO also raised the issue of "off-label" use of drugs, for which investigations of safety and effectiveness may be incomplete or lacking. For example, fenfluramine, indicated for short-term use as a single agent, became part of a popular two-drug long-term weight loss and management program.
The report was prepared at the request of Representative Henry A. Waxman (D-CA) and Senators Tom Harkin (D-IA), Olympia J. Snowe (R-ME), and Barbara A. Mikulski (D-MD). In releasing the report, Waxman said FDA and the pharmaceutical industry must do more to discover sex-related variations in a drug's adverse effects before the product enters the U.S. market.
"This new GAO report calls into question whether FDA and the pharmaceutical industry are following a drug review process that adequately protects women," Waxman said in a prepared statement. "It raises serious questions as to whether the drug companies are including women in clinical trials in adequate numbers and analyzing the data by sex before putting the drug on the market."
Waxman expects GAO to issue an in-depth report on drug withdrawals and women's greater health risk in late April.