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H[2] BLOCKER INTERACTION WITH ALCOHOL IS NOT CLINICALLY SIGNIFICANT, FDA ADVISORY COMMITTEE CONCLUDES MARCH 12; ISSUE MAY BE REVISITED, AGENCY INDICATES

Executive Summary

H[2] blockers' interaction with alcohol has not been shown to be clinically significant, FDA's Gastrointestinal Drugs Advisory Committee concluded at its March 12 meeting. Committee member Arvey Rogers, MD, University of Miami, said that "based on the data that has been presented to us...there is no apparent clinical or social significance" to the elevations of blood alcohol levels for patients who have taken an approved H[2] antagonist -- SmithKline Beecham's Tagamet (cimetidine), Glaxo's Zantac (ranitidine), Merck's Pepcid (famotidine) or Lilly's Axid (nizatidine). By a vote of five to one, the committee agreed with Rogers. An additional four members voted by proxy that there was no significant effect. A majority of the committee did agree, however, that increased blood alcohol levels were "consistently" demonstrated with patients who had taken three of the ulcer drugs: Axid, Tagamet and Zantac. "Even the sponsors' own studies have demonstrated significance," committee member Ralph D'Agostino, PhD, Boston University, said. "It is at a very low level [.15 g/kg of alcohol] and it is under very strict conditions: fed healthy male nondrinkers" who were tested in the morning. Several members noted that there were more data available for Zantac and Tagamet than for Axid. While a majority of the committee felt that Merck's Pepcid had not been "consistently" shown to interact with alcohol, the group voted unanimously that no H[2] blocker, including Pepcid, had been shown conclusively to have no effect on blood alcohol levels. The committee considered possible labeling statements to incorporate the data, although no consensus emerged. On the basis of the discussion, FDA Gastrointestinal and Coagulation Drug Products Division Director Steven Fredd, MD, said: "I don't sense at this point any urgency about" changing the label. "I really get a sense of discomfort from the committee of making a labeling change at this time," Fredd said. "I also get a sense of discomfort at saying" that no labeling change will ever be warranted. Fredd suggested that the committee could address the labeling issue again "perhaps a year from now." In the meantime, he said, FDA "will work...to try to get data to help answer" the committee's questions. The committee asked for data comparing drug to placebo within individuals of various ages to determine if there were any people for whom an H[2] blocker could cause a clinically significant change in psychomotor performance. Committee member Helen Shields, MD, Beth Israel Hospital (Boston), expressed concern that there may be "unusual and rare patients" for whom the slight increase in alcohol concentrations "might make a difference." Shields was the one committee member who voted that the interaction is clinically significant. Representatives of Glaxo and SmithKline Beecham told the committee that they would be willing to perform a psychomotor study if it meant that no labeling change would be made at this time. A representative from Merck demurred, noting the company's position that Pepcid already has been shown not to have the effects seen with other H[2] blockers. While the committee discussion focused on the alcohol interaction data as strictly a prescription labeling issue, FDA will also have to consider possible consumer labeling for the H[2] blockers. OTC switch applications are pending for cimetidine and famotidine, and both Glaxo and Lilly are pursuing OTC versions of their products. Two "FDA invited speakers," Mt. Sinai School of Medicine researchers Thomas Gentry, PhD, and Enrique Baraona, MD, appeared before the committee to present the case for an effect of H[2] blockers on alcohol absorption. The researchers maintained that the ulcer drugs interfere with "first-pass metabolism" of alcohol, a process by which up to 30% of orally ingested alcohol is metabolized before it enters the bloodstream. Baraona presented data showing that ranitidine, cimetidine and nizatidine -- but not famotidine -- can block alcohol dehydrogenase, the enzyme responsible for first-pass metabolism, in vitro. He also presented data showing that alcohol's bioavailability is increased in subjects treated with H[2] blockers, excluding famotidine, compared to placebo. The drug-alcohol interaction "should be considered rather like a frequent side effect," Baraona maintained. "Patients treated with some H[2] antagonists should be warned of the possibility of developing unexpected impairment," he said. H[2] blocker manufacturers made two presentations to the committee: Merck discussed studies of Pepcid, while SmithKline Beecham and Glaxo appeared jointly to discuss Zantac, Tagamet and Axid. Merck Gastrointestinal Research Director Thomas Simon reviewed in vitro evidence that Pepcid does not block alcohol dehydrogenase and presented results from a total of 12 in vivo studies including four funded by Merck. The 12 studies, which compared Pepcid and some or all of the other H[2] blockers to placebo, "consistently show...that famotidine is without an effect on blood alcohol concentrations," Simon said. "There have been variable effects demonstrated in some studies for cimetidine, ranitidine and nizatidine," he added. Glaxo and SmithKline Beecham disputed Merck's conclusion that Pepcid differs from other H[2] blockers in its effect on alcohol. "All H[2] receptor antagonists can cause small increases" in blood alcohol "under certain circumstances," SmithKline Beecham VP-Gastroenterology Robert Palmer, MD, maintained. Palmer presented results from a study sponsored by SmithKline Beecham examining famotidine for evidence of an effect on first- pass metabolism. The 24-patient trial showed a 23% increase in maximum alcohol absorption compared to placebo, Palmer said. "A comprehensive review of the literature and our own studies indicate that cimetidine and other H[2] receptor antagonists as well as other commonly used over-the-counter and prescription medications cause small increases in the absorption of alcohol," Palmer said. "However, the increases are small absolutely. The amounts of additional alcohol absorbed in subjects taking one or two drinks is about four tablespoons of beer or about one-and-a-half teaspoons of liquor." "The resulting increases in blood alcohol concentrations... are well under the limits of concern" and have shown "no documented changes in psychomotor function," Palmer continued. "We do not believe that the effect is important clinically." He concluded that "the primary concern of physicians should be with alcohol and discouraging its use." Glaxo Group Research's John Wood, MD, reviewed 33 studies of Zantac and alcohol. Three of five low-dose studies (.15 g/kg) showed "a statistically significant small increment in blood alcohol concentrations." Echoing Palmer's conclusions, Wood said that "this change, seen only at low blood alcohol concentrations, is without clinical significance." One higher-dose study, by Dipadova et al., published in the Jan. 1, 1992 issue of the Journal of the American Medical Association, "caused us great concern," Wood said. The study, which included Gentry and Baraona as co-investigators, evaluated a dose of .3 g/kg alcohol in 20 men taking Zantac, Tagamet or Pepcid. The study found a significant increase in blood alcohol concentrations for Zantac and Tagamet treated patients, but no effect for Pepcid patients. "There were six studies that failed in the case of ranitidine to reproduce the findings in the Dipadova study," Wood said.

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