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CIMETIDINE OTC SWITCH SLATED FOR SEPTEMBER ADVISORY COMMITTEE REVIEW

This article was originally published in The Tan Sheet

Executive Summary

CIMETIDINE OTC SWITCH SLATED FOR SEPTEMBER ADVISORY COMMITTEE REVIEW at FDA by a joint session of the agency's OTC Drugs Advisory Committee and Gastrointestinal Drugs Advisory Committee. FDA is looking at the possibility of a two-day meeting immediately after the Labor Day holiday (Sept. 7-8) to discuss SmithKline Beecham's NDA to support OTC marketing of the active ingredient currently marketed as the anti-ulcer prescription product Tagamet. The expected advisory committee review will come about 21 months after SB filed its NDA for the switch in December 1991. The probable first indication for an OTC version will be for treatment of episodic and nocturnal heartburn. A favorable September review would give SB a shot at getting the OTC version to market before generic competition develops. The patent for the prescription product expires in May 1994. SmithKline has had cimetidine OTC projects under way since the mid-1980s but was stymied by dosing issues and finding the right OTC indication. Those questions may be less troublesome to the company at this point. SmithKline Beecham has published favorable comparative results on a 200 mg chewable dose of cimetidine and alginic acid compared to 400 mg of cimetidine. Alginic acid is already an inactive ingredient in SB's Gaviscon, which was picked up in the August 1992 OTC deal with Marion Merrell Dow. The heartburn indication may be easier to approach after the firm's March 1991 approval for a prescription claim for GERD (gastroesophageal reflux disease). The other companies attempting H[2] antagonist switches (J&J-Merck, Glaxo and Lilly and Whitehall) also are believed to be looking at a similar indication. The looming difficulty for a Tagamet switch may be cimetidine's large drug/drug interaction profile and the number of widely-used products with which the drug has shown interactions. Tagamet's current prescription labeling notes that due to an effect on certain microsomal systems, Tagamet "has been reported to reduce hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline and metronidazole, thereby delaying elimination and increasing blood levels of these drugs." Tagamet labeling also warns that "clinically significant effects have been reported with the warfarin anticoagulants" and suggests "close monitoring" of patients taking both drugs. In addition, the labeling points out that "interaction with phenytoin, lidocaine and theophylline has also been reported to produce adverse clinical effects." Ironically, it is the agency's recent experience with SB's other newly adopted switch project -- MMD's Seldane -- that creates the particular sensitivity at FDA to the interaction issue. The agency's request for relabeling of the antihistamine in July 1992 due to interaction with ketoconazole and erythromycin creates a heightened awareness of the interaction issue. One OTC switch issue that already may have been resolved is the potential for H[2] blockers to increase blood alcohol levels in patients. The topic was the subject of a March 12 meeting of FDA's Gastrointestinal Drugs Advisory Committee, which voted that H[2] blocker interaction with alcohol is "not clinically significant" ("The Tan Sheet" March 22, p. 4). Although the committee did not find the increases to be clinically significant, a majority agreed that increased blood levels were "consistently" demonstrated in patients who had taken three of the ulcer drugs: Tagamet, Axid and Zantac. While a cimetidine review in September is very likely, it is not clear whether other H[2]-antagonist applications are far enough along to be included in the advisory committee review. A switch application for the J&J-Merck candidate famotidine (Pepcid) was filed in January 1993. That application is believed to be next behind the cimetidine application followed by the Lilly and Whitehall program for Axid and Glaxo's program for Zantac (ranitidine).
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