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Executive Summary

A boxed warning describing serious cardiovascular adverse events will be added to the labeling of Janssen's nonsedating antihistamine Hismanal (astemizole), FDA announced in a July 20 press release. The warning states that "rare cases of serious cardiovascular adverse events including death, cardiac arrest, QT prolongation, torsades de pointes and other ventricular arrhythmias have been observed in patients exceeding recommended doses of astemizole." The warning also tells patients not to "exceed the recommended dose of 10 mg" per day. The FDA action follows by two weeks the inclusion of a similar warning in the labeling of Marion Merrell Dow's Seldane ("The Pink Sheet" July 13, p. 9). The Hismanal label change was foreshadowed by the Canadian Health Protection Branch's decision during the week of July 13 to move both Hismanal and Seldane (terfenadine), which are OTCs in Canada, behind pharmacy counters where consumers must ask for the products and can receive pharmacist counseling ("The Pink Sheet" July 20, T&G-14). At the time of the Seldane relabeling, FDA said it would be reviewing adverse drug reaction reporting for all antihistamines. The cardiovascular risks associated with Hismanal appear to be related to overdosing rather than drug interactions of the type seen with Seldane. FDA said that cardiovascular events "have occurred at reported doses [of Hismanal] as low as 20 to 30 mg daily -- two to three times the recommended daily dose." FDA said that there have been 44 adverse cardiovascular events with Hismanal reported worldwide, including 12 cases of ventricular fibrillations, 11 cardiac arrests, eight torsades de pointes, eight QT prolongations and two reports of arrhythmias. A total of nine deaths of patients on the drug have been reported, including three deaths due to deliberate overdoses. While the number of reported deaths worldwide associated with terfenadine is slightly higher (10 deaths), the deaths related to Hismanal overdose have occurred over a shorter period of time. Seldane has been marketed internationally since 1981, while Hismanal was introduced in 1983. Seldane was approved in the U.S. in 1985 and Hismanal in 1988. Janssen said that millions of patients have been treated with Hismanal. Janssen sent out 400,000 "Dear Doctor" letters on July 20 informing physicians of the new warning describing the cardiovascular risks of Hismanal. The letter encourages physicians to advise patients "to adhere to the recommended dose of 10 mg per day." The letter emphasizes that patients should "understand that the dose should not be increased to accelerate or improve efficacy." The company said it will change labeling to "no longer recommend use of larger doses (30 mg, 20 mg) during the first several days of treatment as this may suggest to patients that such doses should be used chronically," the letter states. While Marion Merrell Dow is in the planning stages of direct- to-consumer advertising to inform the public about the risks of drug interactions and overdoses of Seldane, Janssen parent Johnson & Johnson said that it will not launch a similar campaign for Hismanal. MMD also is preparing patient pamphlets to be distributed in physicians' offices and pharmacies. Like MMD, Janssen's prospects for taking the nonsedating antihistamine over the counter in the U.S. may be dramatically diminished by the addition of a boxed warning. At a July 13 round table discussion for trade press, FDA Commissioner Kessler commented that the agency could not clear OTC drugs that have serious or life-threatening adverse reactions even though they may be rare.

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