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DuPONT’s ETHMOZINE APPROVED FOR TREATING LIFE-THREATENING ARRHYTHMIAS

Executive Summary

DuPONT's ETHMOZINE APPROVED FOR TREATING LIFE-THREATENING ARRHYTHMIAS on June 19. The antiarrhythmic agent was approved after almost three years of review by FDA the NDA was filed in September 1987. Ethmozine (moricizine) was given a "1B" classification denoting a new chemical entity with a modest therapeutic gain over existing therapies. DuPont had been seeking approval of Ethmozine for patients with life-threatening arrhythmias as well as symptomatic ventricular arrhythmias. At its Jan. 27, 1989 meeting, FDA's Cardio-Renal Drugs Advisory Committee recommended conditional approval for the drug ("The Pink Sheet" Jan. 30, 1989, T&G-11). FDA's approval letter for Ethmozine states: "As you know, the pharmacokinetics of moricizine are very complex and, as yet, the relationship of moricizine and its known metabolites to the pharmacodynamic effects of the drug are not known." The letter continued: "It is our understanding that you intend to pursue vigorously further elucidation of the pharmacokinetic/pharmacodynamic relationships of moricizine, including identification of additional metabolites and assessment of their activity and attempting to describe the relationship of antiarrhythmic and electrophysiologic effects to dose and to plasma concentration of metabolites." The advisory committee's conditions for approval were that FDA fully analyze the National Institutes of Health's Cardiac Arrhythmia Pilot Study (CAPS), and that the firm conduct a postmarketing trial that would clarify the safety and efficacy of Ethmozine in patients with sustained ventricular tachycardia. The CAPS trial involved 502 patients post-acute myocardial infarction who were randomized to receive either Ethmozine, encainide (Enkaid), flecainide (Tambocor), imipramine (Tofranil) or placebo. In a comparison of 98 patients on Ethmozine versus 100 patients on placebo, the results show that approximately 66% of the patients on Ethmozine and 37% of patients on placebo meet the efficacy criteria of achieving greater than or equal to 70% suppression in the frequency of ventricular premature contractions. Ethmozine is still being studied in NIH's Cardiac Arrhythmia Suppression Trial (CAST). Two other antiarrhythmics, Enkaid and Tambocor, were removed from the trial when the drugs were found to have mortality rates more than twice that of placebo in patients with asymptomatic or mildly symptomatic arrhythmias who had survived a myocardial infarction. There was no similar concern about Ethmozine's effects ("The Pink Sheet" May 1, p. 10). Subsequently, FDA changed the labeling for the two Class IC antiarrhythmics to restrict their use to life-threatening arrhythmias. Two recently approved Class IC antiarrhythmics Knoll's Rythmol (propafenone) and Lilly's Decabid (indecainide HCl) are indicated only for use in treating life-threatening arrhythmias ("The Pink Sheet" Jan. 8, p. 10). The restricted indication was recommended by the Cardio-Renal Drugs Advisory Committee at its Oct. 5, 1989 meeting. DuPont said that Ethmozine has not been classified according to its mechanism of action. DuPont plans to hold a press conference on Ethmozine's approval on June 26 in Washington, D.C. In a June 20 release on the media briefing, the firm notes that Ethmozine is the first FDA approval of a Soviet drug licensed to a U.S. company. The briefing will address the "difference between Ethmozine and all other drugs in this therapeutic category" and include an update by NIH representatives on the ongoing CAST trial.
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