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Executive Summary

FDA is upgrading isosorbide dinitrate from DESI "less than effective" status to "effective" for the prophylaxis, treatment and management of angina pectoris, the agency announced in an Aug. 3 Federal Register notice. Under the new FDA-approved labeling, the Federal Register notice reports, isosorbide dinitrate is "indicated for the treatment and prevention of angina pectoris." The labeling notes that "all dosage forms" of the drug, including sublingual, chewable, oral and controlled release forms, improved exercise tolerance in clinicals and "may therefore be used prophylactically to decrease frequency and severity of anginal attacks." Isosorbide dinitrate can also be expected to "decrease the need for sublingual nitroglycerin," the new labeling states. Isosorbide dinitrate is the first major category of single entity coronary vasodilators to clear the DESI review program. Although I.V. and sublingual forms of nitroglycerin have been apporved, dipyridamole, the other nitrates -- pentaerythritol tetranitrate and erythrityl tetranitrate -- and the topical/transdermal and oral forms of nitroglycerin are still subject to final FDA decisions on efficacy. In addition, the labeling notes that "in controlled clinical trials chewable and sublingual isosorbide dinitrate were effective in relieving an acute attack of angina pectoris." However, the labeling indicates that sublingual nitroglycerin should be the treatment of choice for aborting acute angina attacks. "Because of the more rapid relief of chest pain with sublingual nitroglycerin," the labeling states, chewable and sublingual forms of isosorbide dinitrate "should be limited to patients intolerant or unresponsive to sublingual nitroglycerin." Tolerance Precaution Expanded In Revised Labeling Since 1972, isosorbide dinitrate has been classified by FDA as "probably effective" for the treatment and prevention of anginal attacks when administered sublingually and "possibly effective" for management, prophylaxis, or treatment of anginal attacks when administered orally. FDA based its decision on data submitted by Wyeth and Ives (for Isordil), Stuart (for Sorbitrate), and Reed & Carnrick (for Dilatrate). The agency noted that the submitted data "consisted of published and unpublished clinical studies utilizing or relating to (1) exercise testing, (2) hemodynamic measurements, and (3) tolerance from isosorbide dinitrate therapy in angina pectoris." While "the weight of evidence substantiates that isosorbide dinitrate is effective as a single drug entity," the agency observed, "the conglomerate data also strongly suggest that tolerance to the anti-anginal effects can occur." The new labeling expands the current tolerance precaution. The new precaution reads: "Tolerance to the vascular and anti-anginal effects of isosorbide dinitrate or nitroglycerin has been demonstrated in clinical trials, experience through occupational exposure, and in isolated tissue experiments in the laboratory." Noting that one clinical trial showed reduced activity over one week with the same dose and that nitrate withdrawal often leads to a rebound in hemodynamic effects, the labeling adds that the "relative importance of these observations to the routine clinical use of isosorbide dinitrate is not known. However, it seems prudent to gradually withdraw patients from isosorbide dinitrate when the therapy is being terminated, rather than stopping the drug immediately." FDA is giving isosorbide dinitrate mfrs. until Oct. 2, 1984 to file NDA supplements with the revised labeling and updated information on product components, composition and production. In addition, firms will have until Jan. 30, 1985 to submit in vivo bioavailability/bioequivalence data studies using absolute and relative bioavailability standards for each major dosage form of isosorbide dinitrate established by FDA.

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