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Executive Summary

Topical nitroglycerin 2% formulations are "effective" and are no longer considered "conditionally-approved" DESI drugs, FDA announced in a Sept. 2 Federal Register notice. Under the agency action, FDA is "revoking the temporary exemption for single-entity coronary vasodilator drug products containing nitroglycerin in topical ointment form." The products affected by the announcement include Marion's Nitro-Bid ointment, Parke-Davis' Nitrostat ointment, Wharton Labs' Nitrong ointment, Kremers-Urban's Nitrol ointment, and Byk Gulden's nitroglycerin ointment. The decision to make topical nitroglycerin ointments DESI-effective leaves only the transdermal patch form of nitrate products still in the regulatory limbo of DESI "conditionally approved" status. Clinical data to support final approval of transdermal patches are being compiled by Searle, Ciba-Geigy and Key. FDA ruled on buccal nitroglycerin products in July 1985 and on controlled release oral nitroglycerin in September 1984. According to FDA's approved labeling, nitroglycerin ointment "is indicated for the treatment and prevention of angina pectoris due to coronary artery disease." The labeling adds: "Controlled clinical trials have demonstrated that this form of nitroglycerin is effective in improving exercise tolerance in patients with exertional angina pectoris. Double-blind, placebo controlled trials have shown significant improvement in exercise time until chest pain for up to 6 hours after single application of various doses of nitroglycerin ointment (mean doses ranged from 5 to 36 mg) to a 36 inches area of trunk." The "Indication" section of the approved labeling in the Federal Register notice is part of a general outline for labeling of 2% nitroglycerin topical products. FDA notes, however, that "the labeling should be considered a guideline, to be adjusted to reflect individual product differences." FDA said that six studies using exercise testing provided substantial evidence of effectiveness of 2% nitroglycerin ointment for use in angina. The studies, provided by Marion, Wharton Labs, and Kremers-Urban, were double-blind, placebo-controlled crossover trials involving a total of 135 patients with angina pectoris. Companies marketing nitroglycerin ointment products under conditional approvals are required by FDA to submit a supplemental NDA covering revised labeling that complies with FDA's DESI effectiveness notice, as well as complete container labeling, by Nov. 1 (sixty days after the date of publication). In addition, holders of conditionally approved ANDAs are required within 180 days to supplement their applications "to provide acceptable in vitro dissolution tests and in vivo bioavailability/bioequivalence studies on the drug product in accord" with new bioavailability requirements. FDA said that studies are "currently underway" intended to "establish the absolute and relative bioavailability of nitroglycerin ointment." The agency explained that the products accepted as standards were done so because of the availability of "acceptable clinical efficacy data." FDA said that manufacturers submitting new applications or holding applications for conditionally approved products "will be required to match these standards by performing bioavailability/bioequivalence studies (blood level versus time for parent drug and major metabolites)."

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