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PROMETHAZINE OTC SWITCH VETO BY FDA ADVISORY COMMITTEE

Executive Summary

PROMETHAZINE OTC SWITCH VETO BY FDA ADVISORY COMMITTEE was based on "inappropriate and irrelevant issues" and "should not be considered" in the agency's final determination on whether to allow nonprescription marketing of the cough-cold ingredient, Wyeth-Ayerst maintains in a May 29 petition to the agency. The petition responds to FDA's Nov. 28 Federal Register notice reopening the administrative record of the Cough-Cold Tentative Final Monograph to allow further comment after halting the Rx-to-OTC switch for promethazine. The Wyeth-Ayerst petition argues that FDA's Pulmonary-Allergy Drugs Advisory Committee, which advised the agency not to allow OTC availability for promethazine at a July 31, 1989 meeting, "was unduly influenced" by "inappropriate and irrelevant issues." Wyeth-Ayerst points as an example to doubts expressed by several committee members over promethazine's effectiveness at the proposed OTC dosage, 6.25 mg. The advisory panel been charged with examining promethazine safety only and had been instructed to "assume effectiveness" by FDA, Wyeth stated. FDA first okayed an Rx-to-OTC switch for promethazine in August 1988 in the tentative final monograph for cough-cold combinations and via supplemental NDA's granted the same month for Wyeth-Ayerst's Phenergan products. The switch was cancelled after the Pulmonary-Allergy committee voted against the move and concluded that a possible link exists between promethazine and sudden infant death syndrome ("The Pink Sheet" Aug. 7, p. 10 and Sept. 4, 1989 p. 5). The review was prompted by a petition alleging a promethazine/SIDS link from Public Citizen's Health Research Group and the University of Maryland's SIDS Institute. The issue of promethazine effectiveness was raised during the advisory committee's deliberations by committee member Leslie Hendeles, University of Florida. Hendeles' statements were "not correct" the petition asserts, pointing out that promethazine has "already been subject to multiple reviews for effectiveness under both the DESI and OTC reviews,...[and] also had been approved for effectiveness at the doses in question under new drug applications for prescription use, and then again for over-the-counter use." Wyeth states that the committee "did not consider FDA's view of promethazine effectiveness...but only Dr. Hendeles' view of the ingredient...This makes its consideration of the effectiveness issue even more impermissible as a basis for any final decision by FDA." FDA should ignore the advisory committee's advice because "in both scientific and procedural contexts, the committee failed completely to provide FDA with a fair and objective response to the issues the agency had referred to it for recommendations," Wyeth asserts. The manufacturer also alleges that the committee's consideration of the SIDS issue was improperly stacked against its drug. As framed by the committee chair, the question put to the committee for a vote was whether a link between promethazine and SIDS was "possible," begging the question of "whether the data was sufficiently reliable to support the alleged association," the petition points out. * Wyeth's May 29 submission includes information, gathered from FDA records, on adverse reactions reported with other OTC and prescription cough-cold combinations, intended to show that "promethazine is not qualitatively more hazardous than other ingredients that are routinely available." Focusing on sedative-associated, "CNS-type" side-effects such as breathing difficulty, apnea, extrapyramidal associations and convulsions, the company points out that promethazine-containing products have had numerically fewer reports of these effects than other popular cough-cold ingredients: from 1969-1988 products containing brompheniramine (Dimetapp) had 98 mentions for this class of side effects; tripolidine (Actifed) had 182; diphenhydramine (Benadryl) had 174; while promethazines had 73. No associations of promethazine with a SIDS case appears in the material gathered by Wyeth. Wyeth-Ayerst also feels that HRG in its testimony confused the safety issue by stressing promethazine's status as a phenothiazine. Other drugs in the phenothiazine class have been linked to extrapyramidal reactions such as tardive dyskinesia (Parkinson's-like involuntary movements). Promethazine is only "technically" classified as a phenothiazine and its "chemical and pharmacological properties show it to be far more akin to other antihistamines," Wyeth maintains. The firm calls the drug's link to tardive dyskinesia "theoretical" and says that unlike other phenothiazenes, promethazine "has no antipsychotic action" and has a weak dopamine receptor affinity. "Promethazine's primary activity is as an antihistamine," the petition maintains.
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