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RIKER's TAMBOCOR (FLECAINIDE) RECOMMENDED FOR APPROVAL FOR NEW SVT USE BY CARDIO-RENAL ADVISORY COMMITTEE; SAFETY ISSUES PROMPT RESTRICTIVE LABELING

Executive Summary

Riker's Tambocor was recommended for approval for a new indication, the treatment of patients with supraventricular tachycardia (SVT) without structural heart disease, by a five-to-two vote of FDA's Cardio-Renal Drugs Advisory Committee Oct. 6. The committee restricted the indication to SVT patients with structural heart disease because of safety issues raised by clinical data, including one fatality out of 225 patients reviewed in safety studies. As a result, the committee voted in favor of a restrictive caveat. "There will be no recommendation for its use in [patients with structural heart disease], but there will be no prohibition against its use [in that group]," Committee Chairman Craig Pratt, MD, Baylor University, said. "We will [make] some statement of the possible increased risk [for patients with structural heart disease, and that the] risk-benefit has not been established." Safety concerns were also voiced by committee members in light of the National Heart, Lung & Blood Institute's Cardiac Arrhythmia Suppression Trial (CAST), which revealed a 2.5-fold increased risk over placebo of non-fatal cardiac arrest or mortality for patients on Bristol-Myers' Enkaid (encainide) and Tambocor ("The Pink Sheet" May 1, p. 11). Both Enkaid and Tambocor were initially indicated for "the treatment of documented life-threatening arrhythmias, such as sustained ventricular tachycardia" and "treatment of patients with symptomatic nonsustained ventricular tachycardia and frequent premature ventricular complexes." The latter indication was dropped last April in response to the CAST study findings. Tambocor was approved in 1985, and the company filed a supplemental NDA for the additional indication earlier this year. Riker presented a safety study reviewing 109 paroxysmal supraventricular tachycardia (PSVT) patients in addition to 117 paroxysmal atrial fibrillation (PAF) subjects. Four individuals in the PSVT and 11 in the PAF group experienced adverse cardiac events. The PAF group suffered one fatality classified as a "proarrhythmic" event, Case Western Reserve's Albert Waldo, MD, reported. One PAF patient developed wide QRS complex tachycardia; both had structural heart disease. Acknowledging its reservations about the "modest" size of the available databases, the committee agreed to recommend cautionary labeling language suggested by FDA Office of Evaluation I Director Robert Temple. "Even if one is comfortable approving the drug for supraventricular arrhythmias in people without structural heart disease, it is fair to say in the labeling that the assurance that there isn't any increased mortality [in patients without structural heart disease] is based on a database of modest size," Temple said. "We can describe what the database is, and [that it] does not rule out some possible increase [in adverse effects versus placebo], even in people without structural heart disease." In addition, the panel voted to adopt Temple's recommendation that "the drug should be reserved for people in whom the symptoms are seriously debilitating." Pratt opposed the restrictive provision on the grounds that it puts "too much practicing medicine in the labeling." In a discussion of a pivotal efficacy study, University of Utah School of Medicine's Jeffrey Anderson, MD, said that data from 34 PSVT subjects and 48 PAF patients from a double-blind, placebo-controlled, randomized cross-over study showed that the drug delays the onset of first attacks "five-fold" over placebo. The number of patients arrhythmia-free are increased about four-fold for PAF and five-fold for PSVT," he pointed out. Anderson suggested that "therapy is best initiated at a dose of 50 mg b.i.d., for both of these arrhythmias. For PAF, increased efficacy occurred usually on a dose of 100 mg b.i.d. In our study, the maximum recommended dose evaluated was 400 mg a day."

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