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DIPHENHYDRAMINE IS MONOGRAPH INGREDIENT IN FINAL RULE FOR OTC ANTIEMETIC PRODUCTS; BISMUTH SUBSALICYLATE STATUS DEPENDS ON OVERINDULGENCE MONOGRAPH

Executive Summary

Diphenhydramine is a Category I OTC ingredient in the final monograph for antiemetic drug products, the first final rule to clear the ingredient for use in a class of OTC products. The monograph, published in the April 30 Federal Register, upgrades diphenhydramine from the tentative final monograph (TFM) classification as a Category III ingredient. FDA explained that although the efficacy of diphenhydramine for use as an antiemetic in motion sickness was not in question, it had concluded in the TFM that "additional evidence was needed to establish that the sedative effects of diphenhydramine hydrochloride are not significantly different from those of dimenhydrinate." FDA said no new data was submitted in response to the antiemetic TFM, published in July 1979, but since that time the agency has placed diphenhydramine as a Category I ingredient in the OTC antitussive tentative final monograph and has proposed diphenhydramine as a Category I ingredient in the TFM for OTC antihistamine drug products. In addition, FDA approved Parke-Davis' supplemental NDA for diphenhydramine (Benylin) as an OTC antitussive. "Accordingly, FDA concludes that the risks presented by diphenhydramine hydrochloride for use as an antiemetic are not sufficient to warrant continued restriction to prescription status, provided that adequate warnings concerning the side effect of drowsiness are included in the labeling," the agency stated. Through its OTC feedback procedure, FDA has also classified diphenhydramine as a Category I nighttime sleep-aid ingredient. The antiemetic final monograph contains three additional ingredients generally recognized as safe and effective for OTC use as antiemetic drugs: cyclizine hydrochloride, dimenhydrinate, and meclizine hydrochloride. FDA noted that bismuth subsalicylate, the active ingredient in Norwich-Eaton's Pepto-Bismol, is not being included in the monograph at this time "pending review of data submitted to the rulemaking on OTC drug products for relief of symptoms associated with overindulgence in alcohol and food." FDA said the Miscellaneous Internal Drug Products Panel recommended Category I status for bismuth subsalicylate for the relief of upset stomach due to overindulgence in the combination of food and drink. If the agency concurs with the panel, "the antiemetic final monograph will be amended to included the nausea claim," FDA said. The final rule notes that one response to the TFM cited five studies to support the effectiveness of bismuth subsalicylate in treating nausea of gastrointestinal origin. FDA said three of the five studies relate to use of bismuth subsalicylate in treating symptoms associated with overindulgence in food and alcohol and the other two studies provide data on use of the ingredient for treating nausea associated with diarrhea. The latter two studies "do not provide sufficient evidence to demonstrate effectiveness" of bismuth subsalicylate for the proposed indication, FDA concluded. In other changes to the TFM, FDA has revised the drowsiness and alcohol warnings for antiemetics containing antihistamines to reflect differences in the degree of drowsiness that ingredients may induce. Products containing diphenhydramine or dimenhydrinate will include the warning: "May cause marked drowsiness." Labeling for other ingredients will include the warning: "May cause drowsiness." The warnings section will also state: "Alcohol, sedatives, and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages while taking this product. Do not take this product if you are taking sedatives or tranquilizers, without first consulting your doctor. Use caution when driving a motor vehicle or operating machinery." The indication for antiemetic products has been revised to add dizziness to the treatment claim. Thus, the indication states: "For the prevention and treatment of the nausea, vomiting, or dizziness associated with motion sickness." FDA noted that scopolamine hydrobromide and phosphorated carbohydrate, which were listed as Category III ingredients in the TFM, are not included in the final monograph. The agency said no additional data was submitted to support a recognition of safety and efficacy for scopolamine hydrobromide and the data submitted to support reclassification of phosphorated carbohydrate was insufficient to demonstrate efficacy. However, FDA noted that one manufacturer of phosphorated carbohydrate is conducting additional studies to prove the efficacy of the ingredient and "the results will be submitted to the agency in the near future."
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