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This article was originally published in The Tan Sheet

Executive Summary

PROCTER & GAMBLE REQUESTS ANTIDIARRHEAL MONOGRAPH DELAY until FDA can review the results of an ongoing clinical study being conducted by P&G to support the efficacy of pediatric doses of Pepto-Bismol (bismuth subsalicylate) as an antidiarrheal. In a Sept. 9 letter to the agency, P&G argued that "if the antidiarrheal monograph finalizes without provision for continued labeling of bismuth subsalicylate drugs for use in children, people continuing to use this drug for children will have no guidance on appropriate dose levels, resulting in the potential for misdosing." "Once data from the clinical study confirm the efficacy of the children's dosing regimens," the company continued, "restoring children's dosing to the product labeling is likely to cause further consumer confusion." P&G added that Pepto-Bismol is currently used to treat diarrhea in over 20% of U.S. children aged three to 12 years. At the request of FDA, P&G has been conducting a multicenter, double-blind, placebo-controlled clinical study predominantly in Central and South America to confirm the efficacy of low-dose bismuth subsalicylate dosing for children three to 12 years old with acute nonspecific diarrhea. FDA gave P&G the go-ahead to proceed with the study at a November 1992 OTC "feedback" meeting at which the agency urged P&G to limit the study to three to six year olds and extrapolate the results to other age groups. P&G promised FDA that results of the study would be provided in "early 1994," with the final study report expected to be available in June. "At present, recruitment is restricted by lack of diarrhea outbreaks" in the study area, P&G told the agency, adding that "we anticipate that sufficient subjects will be recruited during the fall and winter seasons to provide FDA with a final study report [in] approximately June 1994." "If the agency should decide that it must finalize the monograph before completing review of the clinical study results, we request that action on bismuth subsalicylate children's dose labeling be explicitly deferred," P&G wrote. "In this case," the firm suggested that FDA explain in the preamble to the antidiarrheal final monograph "that labeling of bismuth subsalicylate-containing products with children's dose regimens may continue pending completion of FDA review of the children's clinical study results." To support its request, P&G pointed to past cases of FDA issuing final monographs "covering some ingredients or indications, while leaving open the sections about which new questions have been raised." These situations included benzoyl peroxide being excluded from the topical acne products final monograph pending a review of safety data, doxylamine succinate being excluded from the antihistamine final monograph pending review of bioassay data, and live yeast cell derivative for relief of hemorrhoids being excluded from the anorectal products final monograph pending review of efficacy data. Bismuth subsalicylate was listed in Category III (data insufficient to permit classification) in the 1986 tentative final monograph for OTC antidiarrheals. In July 1991, FDA's Gastrointestinal Drugs Advisory Committee recommended that the ingredient be placed in Category I (safe and effective) for the treatment of diarrhea in adults, but did not endorse use of the ingredient in pediatric populations based on a statistical extrapolation of the adult data. At the request of FDA, P&G then convened an outside scientific panel to discuss the pediatric dosing issue. The panel concluded that basing bismuth subsalicylate dosing for the six-to-12-year- old population on a statistical extrapolation from the adult dose is "rational and supportable," but suggested that extrapolating a dosage for three-to-six-year-olds based on adult dosing could lead to use of a dose too low to be effective. FDA has received several requests to defer action on certain ingredients in the antidiarrheal final monograph. FDA denied a request by the Nonprescription Drug Manufacturers Association to postpone acting on attapulgite in the antidiarrheal monograph ("The Tan Sheet" Oct. 4, p. 1). FDA told NDMA that "although your letter cites several precedents in which the agency deferred particular ingredients" from final monographs, "it should be noted that in all those cases, data on these ingredients were pending before the agency. This is not the case with attapulgite."





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