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MARION MERRELL DOW's CARDIZEM INJECTABLE FOR PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA AND ATRIAL FIBRILLATION/FLUTTER GAINS APPROVAL RECOMMENDATION

Executive Summary

Marion Merrell Dow's injectable Cardizem (diltiazem) for the treatment of paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation/flutter was unanimously recommended for approval by FDA's Cardiovascular and Renal Drugs Advisory Committee at its June 6 meeting. Committee reviewer Edward Pritchett, MD, Duke University Medical Center, stated that he was convinced of I.V. diltiazem's efficacy in suppressing PSVT by "the fact that the arrhythmia was eliminated" and because there was "relief of symptoms." The original NDA for Cardizem injectable (NDA 20-027), which is a new dosage form for a new indication, was submitted to FDA in October 1989. Cardizem is currently available in immediate-release tablets for treating angina and sustained-release capsules (twice- daily) for hypertension. A once-daily dosage for hypertension, Cardizem CD, was recommended for approval by the committee in March. The company has predicted that Cardizem injectable will be launched during the first half of 1992, and hopes that it will generate $ 100 mil. in sales within three years of marketing ("The Pink Sheet" April 29, p. 6). Marion Merrell Dow Senior Director for Clinical Research (Kansas City) Joel Covinsky presented the results from four double-blind, parallel, placebo-controlled trials of I.V. diltiazem: two dose-response trials and two Phase III trials, one in patients with induced PSVT and the other in patients with spontaneous PSVT. Patients entered in the trials had SA node reentry, AV node reentry, or reciprocating tachycardias involving the accessory pathway. Covinsky explained that patients had to have a ventricular response greater than 120 beats per minute during a 15-minute observation period. In the PSVT-induced trial, 54 patients were randomized to placebo or an initial dose of .25 mg/kg of I.V. diltiazem. The initial dose of diltiazem given over two minutes "converted 71% of the patients to a normal sinus rhythm," Covinsky said. The median time to conversion was 2.3 minutes. The seven patients who did not respond went on to receive .35 mg/kg of diltiazem, after which "57% converted to a normal sinus rhythm," Covinsky noted, "giving us an overall 86% response rate in this trial." Nonresponders in the placebo group could go into an open-label arm. The overall response rate including the open- label arm was 90%. "That's 48 of 54 patients that converted to a normal sinus rhythm," the researcher said. Results were similar in the spontaneous PSVT trial in which 36 patients were randomized to placebo or diltiazem. An overall response rate of approximately 88% was seen in the double-blind portion of that trial. In support of the atrial fibrillation/atrial flutter indication, Covinsky presented the results from five double-blind, placebo-controlled trials: two dose-response studies, two Phase III efficacy trials, and a trial in patients with Class III/IV congestive heart failure. Response rate was defined as a 20% reduction in ventricular rate or slowing of the rate to 100 beats per minute. Summarizing results of the studies, Covinsky said that "bolus doses of I.V. Cardizem reduces the ventricular response in 82% of the patients with atrial fib and atrial flutter." He added that "the median time to response was three minutes [and] if a second dose of I.V. diltiazem is necessary, the response rate goes up to about 95%." Marion Merrell Dow is recommending that I.V. diltiazem be administered at an initial dose of 20 mg followed by a second dose of 25 mg, if the first dose does not work. Committee reviewer Pritchett noted that the proposed labeling points out that patients of small stature should be dosed on a mg/kg basis. Committee members expressed some concerns about the new dosage form that they want included in the labeling. During a discussion on the occurrence of atrial fibrillation/flutter in some PSVT patients taking I.V. diltiazem, several members said that the labeling should state that patients be carefully monitored when the drug is administered. Committee member Jeremy Ruskin, MD, Massachusetts General Hospital, said that it "might suffice to say that it ought to be done under monitored conditions." He added that "there ought to be some caveat about the potential for adverse effects with calcium blockage in people with..... pre- excitation [Wolff-Parkinson-White syndrome]." Pritchett said he does not believe atrial fibrillation to be a diltiazem- specific problem, since "PSVT converts to AF in about 30% of patients followed long-term." Several committee members also were concerned about the possibility of I.V. diltiazem being used with beta blockers. Committee member Peter Kowey, MD, Lankenau Hospital, Philadelphia, said that "we don't know what the additive effect of this drug would be in a systemic way with a beta blocker that's already been administered." A company representative noted that the proposed labeling suggests a contraindication with I.V. beta blockers and a precaution for concomitant use with oral beta blockers.
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