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OTC CIMETIDINE EFFICACY FOR TREATING HEARTBURN NOT PROVEN

This article was originally published in The Tan Sheet

Executive Summary

OTC CIMETIDINE EFFICACY FOR TREATING HEARTBURN NOT PROVEN by SmithKline Beecham's clinical trial data, FDA's Nonprescription Drugs and Gastrointestinal Drugs Advisory Committees unanimously agreed at a Sept. 9 meeting. The joint panel concluded in a 16-0 vote that SmithKline Beecham's clinical trials to support the Rx- to-OTC switch of cimetidine (Tagamet) were unable to demonstrate that the H[2] antagonist relieved heartburn symptoms. The unanimous vote was recorded in response to a two-part question posed by FDA: "Have controlled clinical trials shown that patients with heartburn get relief from cimetidine during its initial use, and is there relief if cimetidine is taken for subsequent episodes?" In voting, however, committee members did not distinguish between cimetidine's efficacy for initial use and the drug's effectiveness in treating subsequent episodes. Expressing a common sentiment among the committee members regarding the OTC cimetidine efficacy data, Maria Chanco Turner, MD, National Institutes of Health, observed that "there really doesn't seem to be much of a difference between [the efficacy of] antacids [in the trials] and cimetidine . . . so I really don't see the advantage" of cimetidine. "It seems to boil down to 15 minutes" improvement in onset of action, she said. Submitted to FDA in December 1991, SmithKline Beecham's NDA for OTC cimetidine attempted to show that cimetidine in a low dose of 100 mg or 200 mg taken up to four times daily could provide quick relief of initial and subsequent heartburn episodes for up to two weeks. Cimetidine is currently marketed as a prescription drug for the treatment of erosive gastroesophageal reflux disease (1,600 mg daily in divided doses for up to 12 weeks), duodenal ulcer (300 mg q.i.d. for acute healing), gastric ulcer, pathological hypersecretory conditions and gastrointestinal bleeding in critically ill patients. Despite determining that the clinical trial data did not demonstrate the drug's effectiveness in treating heartburn, the committees unanimously decided that cimetidine is safe enough to be marketed as an over-the-counter heartburn remedy. The safety issues had been considered a potential stumbling block to a cimetidine Rx-to-OTC switch primarily due to the drug's large drug-drug interaction profile. Ultimately, though, committee members felt that drug-drug interaction concerns were not insurmountable and could potentially be handled through labeling. Some members of the committee, however, refused to acknowledge that adequate labeling could be devised for cimetidine because efficacy of the drug has not yet been supported by the data. "If we agree that there has not been any demonstrated efficacy of this compound, then labeling is a moot issue," maintained George Dukes, PharmD, University of Maryland School of Pharmacy. Asked by FDA to vote on whether "the trials approximate, with respect to patient population and conditions of drug use, an OTC setting," the committee members determined that certain trials did while others did not. For instance, in a 10-4 vote with two abstentions, the committees decided that studies B04 and B05 adequately simulated OTC use conditions. However, the panel found that study B19 did not approximate an OTC setting. As described by SmithKline Beecham Clinical R&D Group Director Carl Friedman, MD, study B04 was a double-blind randomized two- week trial designed to monitor the efficacy of 100 mg and 200 mg cimetidine, 14 mEq antacid and placebo in treating heartburn in 374 patients. Three endpoints were identified: the time to onset of relief, duration of relief for up to six hours, and a composite endpoint which is the percentage of successfully treated episodes. The composite endpoint combines onset of relief within an hour and duration of relief for six hours. In study B04, 50% of the test subjects taking cimetidine 200 mg experienced relief 82% of the time; 50% of the subjects taking cimetidine 100 mg experienced relief 78% of the time. The relief rate for 50% of antacid subjects was 66%; and 50% of placebo subjects experienced relief from heartburn episodes 58% of the time. Study B05 was identical in design to study B04 except that 346 patients were monitored for one week. In this study, as in study B04, 50% of the Patients taking cimetidine 200 mg experienced relief 82% of the time, while half of the cimetidine 100 mg subjects experienced relief 73% of the time. The relief rate was 60% for antacid subjects and 58% for placebo subjects. In the third major trial presented by SmithKline Beecham -- study B19 -- patients were randomized to receive 100, 200 and 300 mg of cimetidine and 28 mEq of antacid for two weeks. Symptoms were assessed individually at fixed 30-minute intervals with severity assessed on a four-point scale. This study excluded placebo responders through a run-in trial. Patients receiving cimetidine 200 mg received the greatest relief of symptoms followed by cimetidine 100 mg. The 300 mg treatment underperformed the other two cimetidine groups. FDA and the committee members primarily focused their questions on SmithKline's study methodology and statistical analyses of the data. The advisory committees' conclusions on cimetidine do not bode well for other companies seeking OTC heartburn indications for their H[2] antagonists. Also pending at FDA is J&J-Merck's application for a famotidine (Pepcid) Rx-to-OTC switch. Lilly and Whitehall's nizatidine (Axid) OTC switch project is still in clinical trials. Glaxo, which recently formed a joint venture with Warner-Lambert to develop and market an OTC version of ranitidine (Zantac) in the U.S., said it plans to file an Rx-to-OTC switch application for the drug in late 1994 for the treatment of episodic heartburn and dyspepsia ("The Tan Sheet" Aug. 2, p. 4).
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