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Executive Summary

MARION MERRELL DOW SELDANE RELABELING DISCUSSIONS are underway with FDA to address drug interactions related to use of the non- sedating antihistamine (terfenadine) with certain anti-infective products. FDA met with MMD representatives on June 26 to discuss the adverse event profile for terfenadine. MMD acknowledges that it is involved in talks with FDA; the company declines to comment on the extent of adverse events or prospective labeling changes for Seldane. * Seldane's labeling has already undergone one significant revision for adverse effects two years ago. That relabeling revolved around reports of cardiovascular side effects ("The Pink Sheet" Aug. 27, 1990, T&G-1). The current discussions are believed to stem from similar concerns. The 1990 relabeling was accompanied by a "Dear Doctor" letter, which characterized the events described in the revised labeling as "extremely rare" and said that similar "rare cardiovascular events have been reported in patients taking first and other second generation anti-histamine drugs, particularly in overdoses." The current discussions indicate a further review of the frequency and/or severity of the cardiovascular side effects with Seldane. FDA is said to be looking more closely at the interaction between terfenadine and ketoconazole (Janssen's Nizoral) and whether that interaction may extend to other anti-infectives. The 1990 changes specifically addressed the terfenadine/ketoconazole interaction: "Patients with impaired hepatic function (alcoholic cirrhosis, hepatitis) or on ketoconazole or troleandomycin (Roerig's Tao) therapy, or having conditions leading to QT prolongation (e.g., hypokalemia, congenital QT syndrome) may experience QT prolongation and/or ventricular tachycardia at the recommended dose." The Precautions section of the present Seldane label recommends against concurrent use of terfenadine with ketoconazole or troleandomycin. "Concurrent use of other macrolides should be approached with caution," labeling notes. MMD also rewrote Seldane's Overdosage section to state: "At overdoses of 600 mg/day (300 mg b.i.d.) there may be prolongation of the QT interval. At 900 mg or more there have been rare incidents of ventricular arrhythmia (torsades de pointes or fibrillation). Seizures and syncope have been reported." If the agency changes its perception of the terfenadine/ketoconazole interaction, it is reasonable to expect the agency to ask for Nizoral labeling revisions as well. Current Nizoral labeling recommends against the concomitant use of terfenadine, stating that "preliminary evidence shows that ketoconazole inhibits the metabolism of terfenadine, resulting in an increased plasma concentration of terfenadine and a delay in the elimination of its acid metabolite. Increased plasma concentration of terfenadine or its acid metabolite may result in prolonged QT intervals. Cases of torsades de pointes and other ventricular dysrhythmias have been reported in patients taking terfenadine concurrently with ketoconazole." Because of Seldane's broad usage and wide consumer visibility, FDA is approaching the relabeling with particular caution. The agency may be ready to ask for patient labeling for the product to highlight the potential drug interactions. The MMD product is the top selling Rx antihistamine; in 1991, it was among the top dozen Rx products in the U.S. by dollar sales. * The timing of the recent discussion with FDA may be awkward for MMD as it approaches a decision on a partner for the development of an OTC version of the antihistamine. Earlier this year, MMD indicated that it would choose an OTC partner by the middle of this year. Following the FDA concern about side effects in 1990, MMD's initial effort at an Rx-to-OTC switch was derailed. In April of this year, however, MMD said it planned to resubmit the OTC application by the end of the second quarter ("The Pink Sheet" April 6, p. 16). The company has not yet submitted that re- application.

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