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PROMETHAZINE Rx-TO-OTC SWITCH SHOULD NOT BE ALLOWED, FDA ADVISORY PANEL RECOMMENDS; PANEL CONCERNED OVER ASSOCIATION WITH SIDS AND PRESCRIBING ABUSE

Executive Summary

FDA should put the brakes on the already-approved Rx-to-OTC switch of promethazine, FDA's Pulmonary-Allergy Drugs Advisory Committee recommended at its July 31 meeting. Asked by FDA whether combination drug products containing promethazine with labeling requirements for short-term use should be marketed OTC for relief of cold symptoms, the advisory committee voted seven to one against allowing the OTC marketing of such products. The committee members concluded that there is a possible relationship between the use of promethazine-containing products and Sudden Infant Death Syndrome (SIDS), and with obstructive apnea. Panel member Barbara Gothe, MD, Case Western Reserve University, summarized the reasoning behind the committee's determination: "I'm not sure what the relationship is between use of promethazine and SIDS. I think the concern has been raised that there might be a relationship, [but] the data is inconclusive." Gothe added: "We don't have the information. I'll have to side with the patients -- there is potential for toxicity or potential risk." FDA approved Wyeth-Ayerst's promethazine-containing products Phenergan VC and Phenergan DM for OTC marketing on Aug. 11, 1988 via supplemental NDAs ("The Pink Sheet" Oct. 24, 1988, T&G-1). One day later, FDA published the tentative final monograph for combination cough/cold products, which allowed promethazine-based combination products to be marketed OTC ("The Pink Sheet" Aug. 15, 1988, p. 6). However, FDA subsequently asked the advisory committee to discuss the Rx-to-OTC switch decision in light of a December 14, 1988 petition from Public Citizen's Health Research Group (HRG) and the University of Maryland's Sudden Infant Death Syndrome Institute. The petition requests a ban on OTC sales of promethazine-containing products because of reported association of SIDS ("The Pink Sheet" Dec. 19, 1988, T&G-14). Wyeth-Ayerst decided to delay the planned June introduction of its OTC Phenergan products in anticipation of the advisory committee meeting and the panel's recommendations. Panel members expressed concern that the population at risk of SIDS, children under two years of age, are being given promethazine-containing products even though prescription labeling contraindicates use in that age group. Office of Epidemiology and Biostatistics Director Gerald Faich, MD, said that, based on IMS America data, overall promethazine use "is estimated to be 11 mil. prescriptions or mentions a year." Of those, 8 mil. are for oral forms, Faich noted, "of those, 800,000, remarkably enough, are in children under the age of two." "Excluding codeine [products], the exposure in the U.S. in 1988 in children under the age of two was 650,000 prescriptions," Faich reported to the committee. This would suggest that "about 9% of all children under the age of two [are] being exposed at any one year to this product," he said. The FDAer and panel members questioned whether OTC availability of promethazine products will increase the exposure of this age group to the ingredient. Wyeth-Ayerst noted that the OTC labeling for the Phenergan syrups will contain the same contraindication for use in children under two as does the current prescription labeling. HRG's petition cited several studies in the literature that associate promethazine use with SIDS, including a 1982 case-control study of children who died of SIDS in Belgium by Kahn et al. Faich explained that the study involved 52 SIDS cases, 36 near misses, and 175 controls. The exposure rates for promethazine and alimemazine "was 23% in SIDS cases, 22% in near misses, [and] 2% in controls," Faich said. He noted that SIDS cases and near misses in children on phenothiazines was "about 13 times the rate of exposure . . . as . . . in controls." Faich suggested that there my have been a selection bias in the study since the investigator had earlier published a study indicating phenothiazines' association with SIDS. Faich informed the advisory committee of other flaws he found with the study. He suggested that the control group was a population "that will have artifically low exposure" to a phenothiazine prior to admission. Faich also noted that it cannot be determined from the study whether 23% of the 52 SIDS cases were exposed to promethazine or alimemazine. "We are lacking other supportive studies in [the] literature, [including] epidemiologic studies," the FDAer said. "I cannot absolutely rule out an association between promethazine and SIDS . . . [however] those studies don't rule it in for me," Faich stated. In a prepared statement in response to the advisory committee recommendation, Wyeth-Ayerst Labs President Marc Deitch, MD, stated: "Thre is no demonstrated risk that use of promethazine is associated with sudden infant death syndrome (SIDS) of infant sleep apnea." Deitch added that "it is extremely important to emphasize that the advisory committee did not find any positive association." Wyeth-Ayerst said that "discussions with the FDA following Monday's advisory committee meeting confirm that the agency is carefully evaluating the committee's findings." The company noted that FDA " will delay OTC availability of promethazine products until the matter can be thoroughly reviewed." Committee member Hendeles also questioned the efficacy of the Phenergan products in treating cold symptoms. "There's no evidence published that the drug is effective for either sneezing or runny noses, " Hendeles maintained. The drug was found to be effective "in uncontrolled studies for allergic rhinitis" at 12.5 to 25 mg doses, and that efficacy was assumed because it was thought that data submitted on chlorpheniramine, an antihistamine, "would be also true for promethazine," he asserted. In 1976, FDA's cough/cold panel recommended an Rx-to-OTC switch for promethazine in the Notice of Proposed Rulemaking for cough/cold combinations. However, in the notice's preamble, FDA said that promethazine should not be marketed OTC because the drug's risk of adverse effects on the central nervous system is not justified in the absence of therapeutic superiority over other antihistamine ingredients.
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