SMITHKLINE BEECHAM’s OTC CIMETIDINE EFFICACY DATA FOR TREATING HEARTBURN IS INADEQUATE BUT PRODUCT IS SAFE FOR OTC USE, FDA ADVISORY COMMITTEE CONCLUDES

Efficacy data for the over-the-counter use of SmithKline Beecham's cimetidine are inadequate, FDA's Nonprescription Drugs and Gastrointestinal Drugs Advisory Committee concluded on Sept. 9. The joint panel was unanimous (16-0) in concluding 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 for subsequent episodes. Expressing a common sentiment of committee members regarding cimetidine efficacy, OTC advisory committee member Maria Chanco Turner, MD, National Institutes of Health, charged: "There really doesn't seem to be much of a difference between antacids and cimetidine...so I really don't see the advantage" of cimetidine from the study results. "It seems to boil down to 15 minutes," she added. Submitted to FDA in December 1991, the 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 immediate relief of initial and subsequent heartburn episodes for up to two weeks. 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, 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 that was 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 patients taking cimetidine 200 mg experienced relief 82% of the time followed by 78%, 66% and 58% of the time for cimetidine 100 mg, antacid and placebo, respectively. 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 followed by cimetidine 100 mg dropping to 73%, 66% for antacid and 58% for placebo. In the third major trial, study B19, patients were randomized to receive 100, 200 and 300 mg of cimetidine and 28 mEq of antacid for the two week trial. 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 most significant relief of symptoms followed by cimetidine 100 mg. Patients in the 300 mg treatment group inexplicably demonstrated "meaningless superiority," in both duration and relief endpoint analysis, underperforming the other two cimetidine groups. SmithKline Beecham will seek a meeting with FDA in the next few weeks to discuss reanalyzing efficacy data for the H[2] antagonist, the company indicated. The agency has indicated a willingness to meet with SmithKline to talk about reanalyzing the data, the company said. SmithKline also noted that, if deemed necessary by FDA, the firm is willing to conduct additional studies on the efficacy of cimetidine 100 or 200 mg in treating heartburn. Currently, no additional studies are under way. Despite the difficulty SmithKline had in developing a study to establish the efficacy of heartburn relief, the company was applauded by G-I advisory committee member Vay Liang Wong Go, MD, UCLA School of Medicine, who said that "the sponsors have done really a pioneering kind of job at reaching the issue. The design may not be perfect," he said, "but they really have done something that I'm pleased to see for the first time in OTC drugs." Likewise, G-I Advisory Committee Chairman Rosemarie Fisher, MD, Yale University, agreed that the "sponsor should be congratulated on this difficult study." Despite determining that the cimetidine is not effective, the committees unanimously decided that the drug could be safely marketed as an OTC remedy for heartburn. Ironically, safety issues had been considered potential stumbling blocks to switching cimetidine OTC, primarily due to its drug/drug interaction profile. Ultimately, though, committee members felt that drug-drug interaction concerns were not insurmountable and could potentially be handled through labeling. Drug-drug interactions with theophylline, phenytoin, warfarin and lidocaine should be highlighted on a potential label for OTC cimetidine advising people taking these drugs not to use cimetidine OTC as a heartburn remedy, Gastro committee member Helen Shields, MD, Harvard Medical School, recommended. Proposed labeling submitted by SmithKline for OTC cimetidine states: "Persons taking asthma medication, blood thinning medication, or seizure medication will be advised to consult their physician prior to taking cimetidine," SmithKline VP-Regulatory Affairs and Product Professional Services Robert Powell, PhD, told the committees. OTC committee Chairman Randy Juhl, PhD, University of Pittsburgh School of Pharmacy, summarized committee discussions of the variables pertaining to drug interactions on the label by saying that the "important thing is being able to have consumers self-identify that they fall into one of those categories, whether it's taken from a disease point of view or a drug point of view." He added that "a sophisticated use study to define the way people self-identify" with warnings on OTC labels would be helpful. Based on the discussion of drug-drug interactions, the advisory committees unanimously decided that the "potential for drug interaction for cimetidine raises special safety concerns for OTC use." The committees were split on whether the safety concerns would "depend on how often [cimetidine] would be used." The committees also indicated that a study on cimetidine's effects on the elderly should be conducted. As for other special populations, SmithKline's proposed labeling for cimetidine states that "use during pregnancy or lactation will be advised against and persons with kidney disease will be advised not to use cimetidine except under the supervision of a physician," SB's Powell told the committees. Similarly, "use in children under the age of 16 will require supervision by a physician," Powell said of proposed labeling. Despite labeling concerns, the committees voted 10-4 that cimetidine "can be adequately labeled for OTC use in terms of who should take it, the safe dose and dose duration, warnings about adverse reactions, drug interactions, and information as to when a health professional should be consulted." The committees decided unanimously that cimetidine has an "adverse reaction profile that is acceptable for OTC use." The groups also voted 12-1 that cimetidine would be safe for use without the oversight of a health professional.