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ABBOTT's VASOCARD (TERAZOSIN) APPROVAL AS ONCE-A-DAY ANTIHYPERTENSIVE ENDORSED BY FDA ADVISORY CMTE. UNLESS DATA REVIEW SHOWS TUMORIGENICITY

Executive Summary

Abbott's Vasocard (terazosin) should be approved as a once-a-day antihypertensive if further FDA analysis of data establishes that the drug has no tumorigenic potential, FDA's Cardio-Renal Advisory Cmte. unanimously agreed at its March 27 meeting. Based on 17 controlled clinical studies with terazosin, two of which were considered pivotal, the cmte. agreed that the alpha-1 receptor blocker is an effective once-daily antihypertensive. Cmte. reviewer Harry Margolius, MD/PhD, Medical University of South Carolina, commented that "the fact that this drug can be used once a day, and it clearly demonstrated efficacy in some patients once a day, gives it an advantage over available agents." However, the cmte. agreed that the advantage of once-daily dosing would not outweigh the risk of tumorigenicity if that were found to be a characteristic of terazosin. In questions to the cmte., FDA said there was evidence of adrenal medullary tumors in male rats and mammary tumors in female rats. The agency said it would "reach final formal conclusions regarding the meaning of these findings and whether they suggest that terazocin is a weak tumorigen." The cmte. was charged with answering the question: If FDA's "finding suggests at least some tumorigenic potential for man, does terazosin offer any gain as an alternative agent that would cause this risk to be acceptable, assuming it was described in labeling?" Expressing the cmte.'s consensus, cmte. member Bertran Pitt, MD, University of Michigan School of Medicine, said: "I don't feel at all convinced there is a tumor risk, and that's someone else's job to do. But if there were, I would feel far less sanguine about approval of the drug -- given that risk -- for the benefit of the 24-hour" dosing. The cmte. also expressed concern over laboratory data showing that abnormal hematic values were seen in some patients. Margolius suggested that FDA "look at the data and ask hematologists who have thought about antihypertensive drugs . . . for advice" regarding any possible risks of serious adverse reactions such as leukopenia. FDA Office of Drug Research and Review Director Robert Temple, MD, commented that "what we've got here, maybe, is fairly common, very small effects [and] what you're worried about probably is rare large effects." He explained that FDA's "experience has been once you put it in the labeling and sort of flag it for people, there isn't any better way to find out about it then to watch the reports as they come in." The cmte. also recommended a reanalysis of Abbott's data on use of terazocin in combination with diuretics to determine the dose response of combination therapy and postmarketing studies on the lower end of terazosin's dose respone curve, both as monotherapy and as combination therapy. Cmte. Chairman Jeffrey Borer, MD, New York Hospital-Cornell Medical Center, said: "We believe it is appropriate that postmarketing studies should be performed to explore the lower end of the dose response curve both for the drug when used as monotherapy, and perhaps even more importantly, if its going to be used in combination" with thiazide diuretics." Borer noted that one "study shows that 10 mg doesn't cause a significant effect and that the 10 mg dose is less effective than the 5 mg dose, and at least quantitatively, is less than the 2 mg dose, which makes me wonder about any inferences at all that one can draw from these data about dose response."
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