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SYNTEX CARDENE (NICARDIPINE) LABELING SHOULD ADDRESS LARGE PEAK/TROUGH DIFFERENCES, COMMITTEE SAYS; CARDENE IS APPROVABLE FOR HYPERTENSION -- FDA

Executive Summary

Labeling for Syntex' Cardene (nicardipine) should indicate that the three-times-daily calcium channel blocker has large swings in antihypertensive effects at peak and trough, FDA's Cardio-Renal Drugs Advisory Committee recommended at its Nov. 3 meeting. Suggesting how labeling might be drafted to advise physicians of an appropriate dosing course to avoid problem related to the wide swing of effects, committee reviewer Carl Leier, MD, Ohio State University, said: "My view would be to suggest that pressures be taken somewhere between seven and eight hours after dosing. One should add the proviso that if doses have to be advanced to get an effective trough pressure, caution should be taken relative to the peak effect of this paarticular drug, and if side effects occur at peak effect ]pressure should[ be taken at that time as well to show that the patient does not have a pressure of 80 over 60 or 80 over 50." At the opening of the meeting, Cardio-Renal Drug Products Division Director Raymond Lipicky noted that the division has recommended that nicardipine be approved for hypertension. The committee focused its discussion on the labeling of dosing information and adverse reaction data. During the review, FDA Office of Drug Evaluation I Director Robert Temple, MD, noted that the agency was considering placing the information about peak/trough effects in the indications section. "My notes to myself say that the indications section, but this isn't a final thought, should include some notation pointing out to people that there's a wide difference between peak and trough and that its important to measure through values to be sure you're getting what you wanted to get," Temple said. The committee did not specifically address whether the peak/trough data should go in the indications section, but suggested that the dosage and administration section give the physician advice about how to monitor for dosing problems. Committee member Milton Packer, MD, Mount Sinai Medical Center, New York, also recommened that labeling state "that the reason one does this is because much of the antihypertensive efficacy is lost at the end of the interval." After subtracting placebo effects, trough/peak ratios in the firm's studies ranged between 24 and 44%. In support of the t.i.d. regimen, the firm presented two pivotal studies with dosages ranging from 10 mg to 40 mg. In one of the trials, 273 patients were randomized to receive either placebo, nicardipine 10 mg, 20 mg, 30 mg, or 40 mg t.i.d. for a period of six weeks. At peak, diastolic blood pressure was reduced by 7.8% in the 10 mg group, 13.9% in the 20 mg group, 16.1% in the 30 mg group and 18.7% in the 40 mg group, compared to trough reductions of 3.9%, 6.2%, 6.5% and 7.5%, respectively. Systolic blood pressure reductions were: 9% at peak and 5% at trough for the 10 mg dose; 13.8% at peak v. 8.2% at trough with 20 mg; 18% at peak v. 10.5% trough at 30 mg. and 19.8% peak v. 12.8% trough at 40 mg. Although several committee members noted that nicardipine would probably be better with shorter dosing intervals, the committee agreed that the drug should be approved on the basis of improvements over placebo. The committee also noted that most adverse reactions, with the exception of pedal edema, did not appear to be dose related. Discussing the adverse reaction information that should be included in labeling, Leier suggested that labeling should highlight those reactions that are clinically significant and run a tabular listing v. placebo of common events. "My listing ]of events worth distinguishing outside a list[ would be: pedal edema; the hypotensive vasodilatory phenomena, under which I would include . . . ]dizziness, headache and flushing[; I'd put the angina possibility as a complication of hypotension, and even suggest that myocardial infarction could be a result; and then tachycardia, which appears to be reflex in origin with palpitations," Leier said.
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