CIMETIDINE DRUG INTERACTIONS COULD BE HANDLED IN LABELING

CIMETIDINE DRUG INTERACTIONS COULD BE HANDLED IN LABELING, Gastrointestinal Drugs Advisory Committee member Helen Shields, MD, Harvard Medical School, indicated at a Sept. 9 joint meeting of the G-I and Nonprescription Drugs Advisory Committees. Discussing potential components of a label for OTC cimetidine, Shields said: "I would restrict its use so that people who are specifically on theophylline, warfarin, phenytoin, [and] lidocaine would not be advised to use this drug over-the-counter." In proposed labeling submitted by SmithKline for OTC cimetidine to treat heartburn, "persons taking asthma medication, blood thinning medication, or seizure medication will be advised to consult their physician prior to taking cimetidine," according to SmithKline VP-Regulatory Affairs and Product Professional Services Robert Powell, PhD. Committee member Louis Cantilena, MD/PhD, Uniformed Services University of the Health Sciences, suggested that "asthma" might be too broad a term and would not prevent all potential cimetidine/theophylline interactions because "there are other uses for theophylline," such as chronic obstructive pulmonary disease. Patients who take theophylline for COPD may therefore not respond to the warning directed to asthma patients, he indicated. Another committee member, Thomas Petty, MD, Presbyterian St. Luke's Medical Center, Denver also supported a specific warning for theophylline, saying: "I would be very, very concerned about using cimetidine at all in anybody" taking theophylline. Nonprescription committee Chairman Randy Juhl, PhD, University of Pittsburgh School of Pharmacy, said 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. The FDA advisory committees voted 10-4 that cimetidine could "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 advisory committees also voted 12-1 that cimetidine would be safe for use without the oversight of a health professional. SmithKline VP-Clinical R&D Robert Palmer, MD, responded that "even for patients taking theophylline, warfarin or phenytoin, clinical interactions are unlikely because the effects of cimetidine are clearly dose related. Even at four prescription doses" of cimetidine, "clinical events due to this [theophylline] interaction are uncommon." Moreover, "at OTC doses," Palmer maintained that "the interaction was . . . really quite minor." Prescription labeling for cimetidine warns that cimetidine "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." Rx labeling also states that "interaction with phenytoin, lidocaine and theophylline has also been reported to produce adverse clinical effects." Committee member Lorie Rice, University of California-San Francisco School of Pharmacy, recommended that labeling should state that "anyone who is taking any other medication should contact their physician prior to taking" cimetidine because she was not convinced that theophylline, warfarin, phenytoin and lidocaine are the only drugs that should be included in a warning. Another committee member, Maria Chanco Turner, MD, National Institutes of Health, agreed with Rice that a potential OTC cimetidine label should caution that "if you are taking any other systemic medication to consult with your pharmacist or your doctor." Most pharmacists have a "computerized [drug] interaction screen" they can use to advise consumers, she added. FDA Office of OTC Drug Evaluation Director Michael Weintraub, MD, pointed out that a final regulation issued by FDA in August requires that all OTC antacid products carry a statement warning consumers to consult with their physicians before they take antacids if they are also taking any prescription drug ("The Tan Sheet" Aug. 30, p. 6). 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." SmithKIine's Palmer had emphasized in a presentation to the advisory committees that "clinically significant drug interactions are extremely unlikely with the use of low-dose, intermittent, short-term OTC cimetidine" because "most drugs have wide therapeutic windows." FDA Medical Reviewer Kathy Robie-Suh, MD/PhD, asserted, however, that "proposed labeling appears inadequate" to inform "consumers about possible drug interactions." Another labeling issue discussed by the panel was whether there should be a label warning against use of cimetidine in the elderly population. Committee member Marcus Reidenberg, MD, New York Hospital-Cornell Medical Center, asked SmithKline: "What fraction of your [study] population were above 70 or 75 [years old] so you can be confident that there's no reason to have a" warning against use by the elderly?" After Palmer indicated that there were few subjects over 75, Cantilena asserted that the company was "proposing, in essence, unrestricted use in the elderly [and] no special labeling for the elderly." Reidenberg concluded that he "would be reluctant" to allow elderly people to use cimetidine without consulting first with their physicians. Juhl added: "I'd like to see that study [on cimetidine's effects on the elderly] be done." In addition to the warning against use with asthma, seizure and blood thinning medications, SmithKIine's proposed labeling for cimetidine also provides 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," Powell explained. "Similarly," he continued, "use in children under the age of 16 will require supervision by a physician." FDA reviewer Robie-Suh pointed out that SmithKline should "be concerned" about use of cimetidine by pregnant women despite the warning since about 50% of pregnant women experience heartburn regularly.