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Executive Summary

Nitroglycerin controlled-release oral caps and tabs must carry strengthened label precautions concerning drug tolerance as a condition for continued marketing as DESI effective drugs, FDA stipulated in a Sept. 7 Federal Register notice. The labeling revisions are included in an FDA notice announcing the products' upgrading to effective under the DESI review. The controlled-release oral form is the third dosage form of nitroglycerin to clear the DESI review program. Both I.V. and sublingual forms of nitroglycerin have also been approved, but three other dosage formulations remain subject to final FDA decisions on efficacy -- ointment, controlled-release buccal tabs and transdermal patches. FDA based its determination that the controlled-release oral formulations are effective in the prevention of angina pectoris on data submitted by two firms, Marion and Wharton Labs, a division of U.S. Ethicals. FDA's "general outline" for revised labeling for the products extends the tolerance precautions contained in current labeling. The current labeling states: "Tolerance to this drug and cross-tolerance to other nitrates and nitrites may occur." The revised labeling for controlled-release nitroglycerin oral caps and tabs adds that "tolerance to the vascular and antianginal effects of nitrates has been demonstrated in clinical trials, experience through occupational exposure, and in isolated tissue experiments in the laboratory." Although it notes that "the relative importance of these observations to the routine, clinical use of nitroglycerin are not known," the labeling advises physicians against abrupt withdrawal of nitroglycerin therapy."It seems prudent to gradually withdraw patients from nitroglycerin when the therapy is being terminated, rather than stopping the drug abruptly." The agency also said that it will require bioavailability data for the products. Noting that studies are currently underway to establish "absolute and relative bioavailability for oral nitroglycerin," FDA said mfrs. "will be required to match these standards by performing bioavailability/bioequivalence studies." According to the labeling, clinical trials involving angina patients found that "sustained therapy with some nitrate preparations resulted in significantly less and shorter duration of improvement in exercise time on stress testing than did acute therapy." The labeling notes, however, that a study of 18 angina patients showed "significantly better" treadmill performances among patients receiving "repetitive doses of oral nitroglycerin" than those on placebo "after two weeks of therapy." In addition, the labeling cites the occurrence of tolerance and physicial dependence to nitroglycerin by industrial workers continuously exposed to nitroglycerin. "Physical dependence also occurs since chest pain, acute myocardial infarction and even sudden death have occurred during temporary withdrawal of nitroglycerin from the workers," it says. Chart omitted.

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