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Executive Summary

Labeling for oral anti-anginal nitrate products with no chronic-use trials should be changed to reflect the existing data, i.e., the drug should be indicated only for single or short-term use, FDA's Cardiovascular & Renal Drugs Advisory Committee recommended at its June 3-4 meeting. Committee guest Milton Packer, MD, Columbia Presbyterian Hospital, suggested that revised labeling also should state that sublingual nitroglycerin is the "treatment of choice" for "acute anginal attack." He commented: "It wouldn't be tremendously favorable labeling, but it isn't a tremendously favorable database." The recommendation for changed labeling resulted from renewed concerns about tolerance to oral anti-anginal agents. A question to the committee explains: "Several oral formulations of anti- anginal nitrates are now on the market with no clinical data to show that they are superior to placebo in any chronic regimen. The only study of a chronic regimen showed it to be statistically indistinguishable from placebo." That negative study, performed using an unidentified sustained-release oral isosorbide dinitrate formulation, suggests that the approved twice-a-day regimen for the drug "must not be a reasonable [chronic] regimen" and is the reason the agency brought the issue to the committee, FDA Cardio-Renal Drug Products Division Director Raymond Lipicky, MD, explained. "We have the one [sustained-release] ISDN which has this rather negative result, and it seems harsh to penalize it more than the other products about which we have only total ignorance," FDA Medical Reviewer Robert Fenichel, MD, commented. Currently marketed sustained-release products include Wyeth-Ayerst's Isordil, Zeneca's Sorbitrate and Reed & Carnrick's Dilatrate. The agency plans to "go back through the sublingual, the oral, the chewable, the sustained-release [dosages] for both nitroglycerin and isosorbide and make sure" that adequate data exist, Lipicky told the group. The drugs were approved by FDA under DESI (Drug Efficacy Study Implementation) review when "the emphasis on having really good data [was] not as high" and nitrate tolerance as "a major clinical problem was not as well defined," Lipicky said. Anti-anginal nitrate drug labeling was revised to address tolerance problems in 1989. To explore further the issue of nitrate tolerance, the committee examined data from trials on three oral isosorbide-5- mononitrate products: Schering-Plough's Imdur and Schwarz Pharma's Monoket, both pending at FDA, and Wyeth-Ayerst's approved product Ismo. For Imdur and Monoket, "at low doses on an intermittent regimen, it appears as though tolerance can make the lower doses not clinically useful and that higher doses seem to make them clinically viable," Lipicky reported. Imdur at 60 mg once a day, the dose at which it is marketed worldwide, " 42 days [to be] ineffective," committee chair Craig Pratt, MD, Baylor College of Medicine, concluded. The 42-day Imdur trial presented to the committee evaluated doses of 30, 60, 120 and 240 mg. "From this data I wouldn't trust it to be an effective anti-anginal" at 60 mg, Lipicky agreed. Committee member Lloyd Fisher, PhD, University of Washington, also stressed the importance of longer-term data, noting that in a study of Monoket a suspicious "initial drop" in efficacy leveled off in the first and second week of the trial. Lipicky said Ismo was an "exception" -- efficacy did not increase with increased dose as it seemed to do with the other two drugs. In a 21-day study of Ismo 20, 40 and 60 mg b.i.d, "you have more of a problem with high doses than low doses," Lipicky observed. Ismo is approved at 20 mg twice a day.

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