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Executive Summary

BERLEX BETAPACE (SOTALOL) LAUNCH SET FOR JANUARY, when the company will begin detailing the antiarrhythmic to cardiologists and electrophysiologists with its 300-person sales force, Berlex said Nov. 5. The firm is planning a professional education program to accompany advertising and promotion to physicians. Sotalol was approved by FDA on Oct. 30 ("The Pink Sheet" Nov. 2, T&G-1). "Oral Betapace is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life- threatening," approved labeling states. "Because of the proarrhythmic effects of Betapace...its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided." Betapace is contraindicated in "patients with bronchial asthma, sinus bradycardia, second and third degree A-V block, unless a functioning pacemaker is present, congenital or acquired long Q-T syndromes, cardiogenic shock, uncontrolled congestive heart failure, and previous evidence of hypersensitivity to Betapace," labeling states. FDA announced the approval of Betapace in a Nov. 5 press release. The agency estimates that life-threatening ventricular arrhythmias affect about 150,000 patients per year. Betapace "is the first antiarrhythmic agent approved in the U.S. that possesses both Class II and Class III antiarrhythmic properties," Berex said. Betapace was designated a "priority" review by FDA. Labeling includes multiple references to the National Heart, Lung & Blood Institute's ESVEM trial, which showed that sotalol was superior to six other antiarrhythmics in preventing recurrent life-threatening arrhythmias ("The Pink Sheet" April 20, p. 5). FDA approved Betapace about six months after the results of ESVEM (the Electrophysiology Study Versus Electrocardiographic Monitoring for Selection of Antiarrhythmic Therapy of Ventricular Tachyarrhythmias) were announced. The Betapace NDA was first submitted in June 1988 and resubmitted on Sept. 13, 1991. The warnings section of labeling includes mention of the Cardiac Arrhythmia Suppression Trial (CAST), which showed an increased mortality for two Class I antiarrhythmics, flecainide (3M's Tambocor) and encainide (Bristol-Myers Squibb's Enkaid), used to treat non-life-threatening conditions. "Betapace is devoid of Class I effects, and in a large (n = 1,456) controlled trial in patients with a recent myocardial infarction, who did not necessarily have ventricular arrhythmias, Betapace did not produce increased mortality at doses up to 320 mg/day," labeling states. "On the other hand," labeling continues, "in the large post-infarction study using a non-titrated dose of 320 mg once daily and in a second small randomized trial in high risk post-infarction patients treated with high doses...there have been suggestions of an excess of early sudden deaths." "Overall in clinical trials with sotalol, 4.3% of 3,257 patients experienced a new or worsened ventricular arrhythmia," labeling states. "Additionally, in approximately 1% of patients, deaths were considered possibly drug-related; such cases, although difficult to evaluate, may have been associated with pro- arrhythmic events." Other side effects seen with sotalol include labored breathing,worsening of existing congestive heart failure, fatigue and excessive slowing of the heart rate, although none were seen in incidences of greater than 3%. The total discontinuation rate due to adverse events was 17%. Labeling cautions against possible drug interactions with other anti-arrhythmics, calcium channel blockers, catecholamine-depleting drugs, insulin, beta-agonists, clonidine and "drugs prolonging the QT interval," including Marion Merrell Dow's Seldane and Janssen's Hismanal prescription antihistamines. The recommended initial dose of Betapace is 80 mg twice daily. "This dose may be increased, if necessary, after appropriate evaluation to 240 or 320 mg/day," labeling advises. Higher doses should be prescribed only "when the potential benefit outweighs the increased risk of adverse events, in particular pro- arrhythmia." The dosing interval should be increased in patients with impaired renal function, labeling states. Berlex will market Betapace in bottles and unit dose cartons of 100 tablets in strengths of 80, 160 and 240 mg. Berlex currently markets the Quinaglute brand of the anti-arrhythmic quinidine.

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