LILLY's DECABID (INDECAINIDE) SHOULD BE APPROVED

LILLY's DECABID (INDECAINIDE) SHOULD BE APPROVED for treatment of life-threatening and non life-threatening cardiac arrhythmias, FDA's Cardio-Renal Drugs Advisory Committee unanimously agreed at its Nov. 3-4 meeting in Bethesda, Maryland. By an 8-0 vote, the panel recommended approval of indecainide for sustained ventricular tachycardia, ventricular fibrillation, non-sustained ventricular and chronic benign ventricular premature contractions.

"I think that one thing we have all been very impressed about is that this is the first time we are really seeing symptomatic reduction in palpitations and improving quality of life," committee member Milton Packer, MD, Mt. Sinai Medical Center, remarked. "And it is important to realize that it is not the improvement in the well being of the patient that was as telling as was the reduction in palpitations."

Lilly's NDA submission included five clinical trials covering a data base of 792 patients. In one of the two pivotal studies 124 patients were randomized to an immediate release (q.i.d.) formulation of indecainide and tested against placebo. Lilly subsequently conducted a parallel trial in which 170 patients received a b.i.d. version.

The company plans to market only the two-a-day formulation of the 1C antiarrhythmic. Of the total patient data base, 27% were treated with the sustained release product and 73% with the other. The three other studies evaluated 479 indecainide patients against then-available therapies -- the 1A anti-arrhythmic drugs procainamide, quinidine and disopyramide. Subsequent retrospective studies were done comparing indecainide to two 1C drugs, Riker's Tambocor (flecainide) and Bristol-Myers' Enkaid (encainide), which became available after Lilly's clinical program began.

Approximately 70% of all patients receiving indecainide responded to a daily dose of 200 mg or less, Lilly reported, adding that increasing the dosage to 300 mg per day resulted in a 90% response. The company is recommending a daily dose of 100-2-- mg per day.

Among the adverse reactions noted by the committee were dizziness, pro-arrhythmias and congestive heart failure, all of which appeared to be dose-related. Instances of dizziness, which is considered a relatively minor side effect, were reported in 18% of patients on the 200 mg dose, 12% on 150 mg, 9% on 100 mg versus 8% on placebo. Pro-arrhythmias were reported in 14.8% of the indecainide group compared to 7.7% in the comparator group. Worsening heart failure was observed in 3.9% of the indecainide patients compared to 3.2% in the comparator group.

A key concern of the committee focused on the relationship between low ejection fraction and development of more severe heart failure and/or pro-arrhythmias. "I find it difficult to say that there is a clear benefit over risk in patients with an ejection fraction less than 30%," Committee Chairman Craig Pratt, MD, Baylor College of Medicine stated.

However, the committee agreed that while the sponsor's data indicated a relationship between low ejection fraction and incidence of heart failure/pro-arrhythmia, the issue could be resolved in the labeling. "I think there is enough data on the table to write a very reasonable label," new committee member Edward Pritchett, MD, Duke University Medical Center, said. "I would also say that I kind of liked the presentation here today which, except for the numbing number of slides, was quite a nice package."