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Executive Summary

FDA approval of Lilly's Decabid (indecainide) and Knoll's Rythmol (propafenone) should be limited to life-threatening arrhythmias based on the results of the Cardiac Arrhythmia Suppression Trial (CAST), FDA's Cardio-Renal Drugs Advisory Committee concluded at its Oct. 5 meeting. In a seven-to-three vote, the committee agreed that "as a consequence of CAST, the listed indication 'ventricular arrhythmias that are symptomatic' needs to be deleted from the labeling of pafenone and indecainide," leaving only life-threatening ventricular arrhythmias, Committee Chairman Craig Pratt, MD, Baylor College of Medicine, said in summation. FDA modified the labeling for Riker's Tambocor (flecainide) and Bristol-Myers' Enkaid (encainide) in April after preliminary results from the CAST study showed that the two Class 1C anti-arrhythmics had mortality rates more than twice that of placebo in patients with asymptomatic or mildly symptomatic arrhythmias who had survived a myocardial infarction ("The Pink Sheet" May 1, p. 10). The results of CAST were published in the Aug. 10 issue of the New England Journal of Medicine. Of the 1,455 patients in the CAST study randomly assigned to receive flecainide, encainide or matching placebo, there were 56 deaths or cardiac arrests in the encainide/flecainide group versus 22 deaths in the placebo group. In the two drug groups, 33 patients died from arrhythmias or cardiac arrest compared to nine deaths in the placebo group. The committee unanimously agreed that in light of the CAST data, FDA's decision to restrict labeling was warranted; however, the group split (5-5) on whether the labeling of flecainide and encainide should explicitly discourage all uses of the drugs in any ventricular arrhythmias other than life-threatening. The committee's decision on Decabid and Rythmol supports FDA's intention to withhold the symptomatic arrhythmia indication from 1C anti-arrhythmics. "Our plan was to not give a claim of symptomatic arrhythmia to either of those two drugs, because there is not enough data to rule out the possibility" of results similar to the CAST study," FDA Office of Drug Evaluation I Director Robert Temple, MD, told the committee. FDA gave Rythmol "approvable" status in March for the suppression of ventricular arrhythmias; an NDA is pending for Decabid. In November 1988, the Cardio-Renal Drugs Advisory Committee unanimously recommended indecainide for approval in the treatment of life-threatening and non-life-threatening cardiac arrhythmias ("The Pink Sheet" Nov. 7, T&G-4). Also based on the CAST study results, the committee recommended that all 1A and 1B anti-arrhythmic drug labeling should be "limited to life-threatening arrhythmia and symptomatic arrhythmias" and "share the statement that no benefit with respect to mortality has been shown for any anti-arrhythmic drug." Labeling for 1A anti-arrhythmics -- quinidine; disopyramide (Searle's Norpace); procainamide (Parke-Davis' Procan SR) -- and 1B anti-arrhythmics -- lidocaine, tocainide (Merck's Tonocard), mexiletine (Boehringer Ingelheim's Mexitil) -- should also include results from CAST in some form, the committee determined. "Everyone was concerned about the plethora of 'Dear Doctor' letters that followed CAST from pharmaceutical manufacturers [of anti-arrhythmics other than flecainide and encainide] who maintained that their drug should be strongly considered in the CAST patient population," asserted committee member Milton packer, MD, Mount Sinai Medical Center, New York.

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