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LILLY's PINDAC (PINACIDIL) ANTIHYPERTENSIVE IS RECOMMENDED FOR APPROVAL BY FDA CMTE. WITH THE STIPULATION FOR USE IN COMBINATION WITH DIURETICS

Executive Summary

Lilly's Pindac (pinacidil) should be approved for hypertension with the stipulation that it only be used concomitantly with diuretics, FDA's Cardio-Renal Drugs Advisory Committee recommended at its May 28 meeting. FDA Cardio-Renal Drug Products Division Director Raymond Lipicky, MD, said he would make an approvable recommendation but only with the realization "that some people on the committee have some serious reservations about the dosing interval alone [and] that the approvable vote would result in an action that would say that pinacidil should not be used alone, it should be used with a diuretic." The committee concluded from a review of Lilly's clinical data that concomitant diuretic therapy is necessary because of the high incidence of edema seen in patients treated with pinacidil alone. The panel also said that an appropriate dose regimen had not been established for pinacidil. The panel did not specify a precise dose schedule for pinacidil, but did suggest a general range taken from the doses used in the trials. The dosing range used in the trials was 12.5 to 75 mg b.i.d. The committee generally agreed that a dose of 12.5 or 25 mg b.i.d. was the most effective regimen because doses above 25 mg did not seem to increase effectiveness. Panel member Saulo Klahr, MD, Washington University School of Medicine, commented that "we should be somewhere between 12.5 and 25 mg." Responding to an FDA question regarding the proper dose range for pinacidil, Committee Chairman Jeffrey Borer, MD, New York Hospital-Cornell Medical Center stated that for pinacidil monotherapy doses "we agree that 37.5 [mg] is above what one would want to give because of the effectiveness versus the side effect issue." He noted that 12.5 mg is known to be effective, but "we really don't know what the relationship is in terms of dose response for effectiveness between 12.5 and 25." Borer added that it was "difficult to make a decision" about an appropriate dose and "perhaps we cannot go further than that with the data we have." The limits of a dosing range for pinacidil in combination with a diuretic also could not be precisely determined. "There's not even a suggestion of the dose response curve throughout the range that we've seen once we have a diuretic, so there really is no information that we have that would suggest that someone should receive more than 12.5 mg b.i.d. if the drug is given in association with a diuretic," said Borer. Commenting on the incidence rate of edema in both fixed and titrated dose studies, Lilly Associate Clinical Pharmacologist Michael Goldberg, MD/PhD, said that with dosing of up to "50 mg plus a day in combination with [a] diuretic, either starting together fixed dose fashion or [with] titration . . . edema clearly seems to be the adverse event which limits your dose." The incidence of edema for pinacidil alone at 25 mg was 23.5%, at 37.5 mg it was 45.2%, and at 50 mg the rate was 30%. Administration of pinacidil with a diuretic had edema rates of 7.7% at 25 mg and 17.7% at 37.5 mg. The committee, concerned with the fact that pinacidil has a half-life of four hours, asked Lilly whether the product had sustained release characteristics. Borer stated that the data "indicate that within the formulation there is a component that peaks earlier than another component." But the chairman added that "the correlation between plasma concentration and antihypertensive effect [isn't] clear yet" and should the panel want to investigate further "perhaps it would be desirable to have some additional data." According to FDA, clinical trials suggested that pinacidil causes T wave morphology changes. The panel agreed that such EKG abnormalities could indicate a risk for post myocardial infarction patients. Borer commented that for pinacidil labeling "a strong cautionary note might be more appropriate than specific recommendations." The question of whether pinacidil has an effect on blood lipids and whether sponsors should be permitted to promote such findings was brought before the committee. "We don't know whether this has any clinical beneficial effect at all; therefore we really can't say anything about promotion," concluded Borer. Lilly licensed pinacidil from Leo, a Danish company. Pinacidil was approved in Denmark in February 1987. In addition to the U.S., approval for pinacidil is currently pending in several European countries.
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