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Executive Summary

Janssen's Hismanal (astemizole) labeling is carrying a new warning about drug interactions with antibiotic and antifungal agents. The new labeling for the prescription nonsedating antihistamine Hismanal includes the following boxed warning: "concomitant administration of astemizole (Hismanal) with ketoconazole tablets, itraconazole or erythromycin is contraindicated," FDA stated in an Oct. 28 press release. The new labeling changes may further disrupt prescription nonsedating antihistamine sales. Janssen experienced a 10%-15% decline in U.S. Hismanal sales in the third quarter; worldwide sales of Marion Merrell Dow's Seldane (terfenadine) were off 7% ("The Pink Sheet" Oct. 26, p. 10 and p. 14). Both products were relabeled in July for cardiovascular adverse events. On July 7, FDA announced that Seldane would be contraindicated for use with erythromycin or ketoconazole due to a number of serious cardiovascular events, including death, experienced by patients using the drugs concomitantly ("The Pink Sheet" July 13, p. 9). The itraconazole warning was not added until approval of Janssen's Sporanox in September ("The Pink Sheet" Sept. 21, T&G- 1). Janssen also markets the itraconazole product Nizoral. FDA also announced in July that similar cardiovascular events had been reported with large doses of Hismanal and that the labeling would be changed to warn against overdosing ("The Pink Sheet" July 27, p. 3). Only recently did the agency become aware of a potential problem of drug interactions with Hismanal. The agency said that it "recently received reports of serious arrhythmias in two patients who took Hismanal with erythromycin, or erythromycin plus ketoconazole, alerting FDA to a possible interaction between Hismanal and these drugs." The press release adds that "subsequently, Janssen submitted preliminary information indicating that blood levels of Hismanal are greatly increased in patients taking ketoconazole." Janssen said it began pharmacokinetic studies of Hismanal and ketoconazole shortly after the Seldane drug interactions were announced. New Hismanal labeling notes that "there have been two reports to date of syncope with torsades de pointes requiring hospitalization in patients taking combinations of Hismanal 10 mg daily with erythromycin. In each case the QT intervals were prolonged beyond 650 milliseconds at the time of the event. One patient also received ketoconazole and the other patient also had hypokalemia." The labeling states that the recently-generated pharmacokinetic data "indicated that oral ketoconazole significantly inhibits the metabolism of astemizole, resulting in elevated plasma levels of astemizole." On Oct. 26, Janssen sent "Dear Doctor" letters to 600,000 physicians informing them of the new warnings for Hismanal. In addition to the explanations of ketoconazole's effect on Hismanal metabolism, the letter discusses the in vitro effects of itraconazole. "Itraconazole (Sporanox), a new Janssen antifungal, is chemically similar to ketoconazole and also has an effect in vitro, although less pronounced, on the biotransformation system responsible for the metabolism of astemizole." The "Dear Doctor" letter adds that "to date, we have not received any reports of serious cardiovascular reactions in patients taking Hismanal with itraconazole or with ketoconazole alone." The precautions section of the new Hismanal labeling recommends against the use of the drug with other antifungal agents that bear a clinical similarity to ketoconazole, including fluconazole (Pfizer's Diflucan), metronidazole (Searle's Flagyl) and miconazole I.V. (Janssen's Monistat). Labeling also cautions against "concomitant use of astemizole with other macrolide antibiotics," including troleandromycin (Roerig's Tao), azithromycin (Pfizer's Zithromax) and clarithromycin (Abbott's Biaxin). J&J said that while Janssen plans to emphasize the drug interaction potential and cardiovascular risks of Hismanal to physicians through its field sales force, it has no plans for dissemination of the information to consumers. MMD has been working since July on a patient information program, which would include direct-to-consumer advertising and patient pamphlets. Final Seldane labeling was cleared only several weeks ago, and MMD is in discussions with FDA's advertising division over wording of the consumer information material.

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