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Executive Summary

FDA is keeping the door ajar for the possible future monograph switch of the antihistamine promethazine to OTC status, the agency indicated in its final monograph for OTC Antihistamine Drug Products published in the Dec. 9 Federal Register. The monograph, however, continues to exclude promethazine for use as a single-ingredient in OTC antihistamine products. If "promethazine is considered a monograph condition for use in OTC cough-cold combination drug products, the agency will reconsider its potential OTC use as a single ingredient antihistamine for the temporary relief of runny nose and sneezing associated with the common cold," FDA states. FDA said it will make its final determination on promethazine "after all the data and information have been reviewed and evaluated." Any reconsideration of promethazine's status as an antihistamine, the agency adds, "will be done in a future Federal Register notice in which the agency discusses the use of antihistamines for relief of the symptoms of the common cold or discusses the use of cough-cold combination drug products." The ingredient was recommended as Category I by the OTC Cough/Cold Products review panel but was placed in Category III in a January 1985 tentative final monograph due to concerns about a possible association with tardive dyskinesia. In August 1988, FDA proposed promethazine as a Category I OTC ingredient in combination cough/cold products, which would only be used on a short-term basis, but did not change its position on use of the product as a single-ingredient OTC anti-allergy product due to concerns with long-term use. Following a July 1989 review by FDA's Pulmonary-Allergy Drugs Advisory Committee that was called to address a possible association of promethazine with sudden infant death syndrome (SIDS), FDA reversed its position on the Rx-to-OTC switch. Wyeth- Ayerst later petitioned FDA to reconsider, declaring that the advisory committee ruling was based on "inappropriate and irrelevant issues." The potential side effects issues that have hindered a promethazine switch may become moot if FDA decides to do away with the use of all antihistamines in cough/cold combination products. FDA has reported that it is reconsidering whether to allow cough/cold claims for OTC antihistamine ingredients. The Antihistamine Drug Products final rule does not address the issue of antihistamine claims for symptoms of the common cold. OTC Monograph Review Staff Director William Gilbertson told an industry conference in November that FDA would defer the issue pending review by the OTC advisory committee at its second meeting in March 1993 ("The Pink Sheet" Nov. 23, p. 18). OTC antihistamine cough/cold claims were the subject of an April hearing before the Government Operations/Intergovernmental Relations Subcommittee. At that time, Center for Drug Evaluation and Research Director Carl Peck, MD, told the subcommittee that "there has been no change" in the status of the indication. He indicated, however, that FDA was reviewing that position ("The Pink Sheet" April 13, p. 6). The deferment of the common cold indication is one of "six significant changes" from the TFM identified in the Dec. 9 notice. Another change is the inclusion of diphenhydramine citrate as a monograph ingredient, the only ingredient added since the TFM. Diphenhydramine HCl was included in the tentative final monograph published in January 1985. Because the two salts are equivalent, FDA said, it is including diphenhydramine citrate as a monograph ingredient, noting that 76 mg of the citrate salt is equivalent to 50 mg of the HCl salt. In December 1989, FDA said it would include the citrate salt in the final monograph in response to petitions filed by Miles, Bristol-Myers and Rich-Vicks ("The Pink Sheet" Jan. 1, 1990, T&G-7). Other changes made in response to comments include allowing the option of using "temporarily relieves" or "for the temporary relief of" in the indications section. FDA also has reworded the warning statement against use of antihistamines in patients with "breathing problems" to eliminate the word "asthma." FDA is deferring action on the status of the ingredient doxylamine due to carcinogenicity concerns. Doxylamine was a Category I antihistamine in the tentative final monograph. A National Center for Toxicological Research study in rodents, however, showed a carcinogenic effect of doxylamine. FDA's Pulmonary-Allergy Drugs Advisory Committee voted in June 1991 that doxylamine is "not likely" to be a human carcinogen but proposed a consumer warning label ("The Pink Sheet" June 24, 1991, p. 7). FDA rejected a request to include an indication of "post-nasal drip" in the final monograph, the agency noted. "The agency suggests that any party interested in studying the use of an antihistamine for this claim meet with the agency to discuss an appropriate protocol before beginning the study," the notice states. The agency also rejected suggested indications for "sinus congestion" and allergic itching.

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