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Executive Summary

BOOTS MANOPLAX INCREASED MORTALITY TO BE SUBJECT OF FDA CMTE. MEETING in June, Boots said in an April 23 "Dear Doctor" letter advising physicians not to use the 100 mg dose of the congestive heart failure treatment. An interim analysis of the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) study testing the effect of Manoplax (flosequinan) on mortality in severe congestive heart failure patients found "a significantly increased risk of death compared to those not receiving the drug," Boots said in the "Dear Doctor" letter. "These findings will be discussed publicly in June at an advisory committee meeting to be held by the FDA's Division of Cardio-Renal Drug Products," Boots told physicians. A meeting of the Cardiovascular and Renal Drugs Advisory Committee is tentatively scheduled for June 3-4. FDA is not certain that it will be able to prepare for the meeting on such short notice; however, the agency does intend to hold the meeting "soon." "Until further analyses are available, we recommend that the 100 mg dose not be used," the "Dear Doctor" letter states. In product labeling, 100 mg is the recommended starting and maintenance dose for patients not on other therapies. "Patients receiving 100 mg/day should have their dose lowered to either 75 or 50 mg/day," the "Dear Doctor" letter states. The 75 mg group in the PROFILE study did not show a trend towards increased mortality, the letter notes. There was no 50 mg treatment arm. Physicians are advised in the letter that more information will be forthcoming. "The interim PROFILE results have not yet been completely analyzed," the letter states. "In particular, it is not known whether the adverse effects seen with the 100 mg dose were seen predominantly in some subset of the overall population rather than in all patients." In the PROFILE study, "the relative risk [of mortality] seen in the 100 mg group (1.51) is similar to the relative risk indicated -- on the basis of much less data -- in the current labeling," the letter states. "The results of further analyses may generate specific new recommendations regarding the dosage and administration of flosequinan," Boots said. "We expect to send you a subsequent letter within 14 days providing these results and recommendations." Labeling changes for Manoplax in the U.S. will probably await further analysis of the PROFILE data and the outcome of the advisory committee. The committee may also be asked to determine if there is enough efficacy data at lower doses of Manoplax to justify continued marketing given that Boots' first round of Phase III clinical trials, reported in October 1989, failed to show clear efficacy. Manoplax has been shown to be hemodynamically effective at the lower doses, PROFILE investigator Milton Packer, MD, Columbia, maintained. The 75 mg dose has shown the same magnitude of effect as the 100 mg dose and has been studied in clinical trials, he said. In the U.K., 50 mg is the most common dose, Boots said, with only about 20% of patients receiving the 100 mg strength. FDA publicized the "Dear Doctor" letter in an April 26 press release. The letter "is being sent by overnight mail to selected cardiologists and internists," FDA said. "A mailgram, detailing the same information, is being sent to [all] pharmacists, hospital pharmacies and primary care physicians." FDA "recommended that at the present time doctors stop using a 100 mg per day dose of" Manoplax; "both the 75 mg and 50 mg doses may still be used." Manoplax has been on the market in the U.S. for only a few weeks, having been approved by FDA on Dec. 30 ("The Pink Sheet" Jan. 4, p. 15) and launched by Boots in late March. Warner-Lambert copromotes the product in the U.S. Manoplax is also marketed in the U.K., where it was launched by Boots in September. The company sent a similar letter to physicians in the U.K. PROFILE was expected to enroll a total of 3,500 patients and be completed in 1995. The interim analysis came after 2,300 patients had completed enrollment. The PROFILE investigators are considering adding a 50 mg arm to the trial and plan to pursue the 75 mg arm to completion. In October 1991, FDA's Cardiovascular and Renal Drugs Advisory Committee recommended approval for Manoplax for patients intolerant to angiotensin-converting enzyme (ACE) inhibitors ("The Pink Sheet" Oct. 28, 1991, p. 17). The group rejected a first-line indication for the drug based on a meta-analysis of clinical trials that showed a relative risk of mortality in the Manoplax group of 1.46. Members who voted against recommending approval altogether argued that FDA should await results from the PROFILE study. FDA ultimately approved Manoplax for patients intolerant to other therapies and as add-on therapy with ACE inhibitors for patients who remained symptomatic on an ACE inhibitor alone. Manoplax is currently marketed as 50 mg, 75 mg and 100 mg tablets. Boots also received approval for 125 mg tablets, but chose not to market that strength. Boots has "every confidence in the future prospects for Manoplax," the company said April 26.

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