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DOXYLAMINE TUMORIGENICITY LABEL WARNING IS NOT ADVISED

This article was originally published in The Tan Sheet

Executive Summary

DOXYLAMINE TUMORIGENICITY LABEL WARNING IS NOT ADVISED given the limitations of such a consumer warning based on animal study results, FDA's Nonprescription Drugs Advisory Committee unanimously concluded on June 28. Responding to an FDA query about whether OTCs containing doxylamine should bear warnings that the ingredient has been found to induce tumors in rodents, committee member Marcus Reidenberg, MD, Cornell Medical Center, declared: "With regard to a specific warning label and the narrow options that that encompasses, I really don't see that there is a specific thing to warn against." Committee member Maria Chanco Turner, MD, National Institutes of Health, concurred, adding that "if everything [people] do or take is a risk," then the public "just will not pay attention" to warnings. FDA "should probably save the warnings for when we really know that it will make a difference" and when there is a greater risk, Turner said. Pointing out problems with a potential warning statement for doxylamine-containing products, consultant Paul Roberts, MD, the committee's industry liaison, argued that "to say it causes tumors in animals and let it go at that without a very full discussion" of the animal data "seems to fall short" of completely informing the consumer. "I just don't think that if you want to inform and allow a reasonable statement that you can do it on the space" of a product label, he maintained. The Nonprescription Drug Advisory Committee's decision represents a turnaround from recommendations made by FDA's Pulmonary-Allergy Drugs Advisory Committee in June 1991. In light of an April 1991 National Center for Toxicological Research report that found doxylamine to be a rodent carcinogen, the Pulmonary-Allergy Drugs Advisory Committee had recommended that FDA require some cautionary statement informing consumers of the existence of the animal tumorigenicity data. After the meeting, FDA invited comments on a potential warning statement for doxylamine-containing OTC products, but never issued a Federal Register notice proposing such a statement. Doxylamine is found in a number of OTC products including Pfizer's Unisom and Procter & Gamble's NyQuil line. Instead of requiring a label warning on doxylamine-containing products, the OTC advisory committee decided to urge FDA "to write a fully descriptive article for the [agency's consumer magazine] FDA Consumer on the subject," Reidenberg summed up. Asked by Office of OTC Drug Evaluation Director Michael Weintraub, MD, about what information and terminology should be included in such an article, Committee Chairperson Randy Juhl, PhD, University of Pittsburgh, replied that several phrases suggested by FDA for use in a potential label warning "have relevance." These terms include: "found to produce tumors in laboratory animals"; "in animals given 'large' oral doses"; "relevance to humans is unknown"; "no data demonstrate the occurrence of tumors in humans"; and "consult a health professional/physician." Roberts suggested that the article also should emphasize that the lab animals were administered higher doses of doxylamine than the human therapeutic dose. Committee member Alan Sinaiko, MD, University of Minnesota Medical School, added that "something should be said" in the article "about differentiating the use [of doxylamine] in children and adults." More generally, Reidenberg advised that the article should include a summary of the animal tumorigenicity data presented to the committee by FDA Division of Oncology and Pulmonary Drugs Supervisory Pharmacologist Alan Taylor, PhD. Taylor reported that doxylamine induced hepatocellular adenoma and thyroid follicular cell adenoma in male and female mice, hepatocellular adenoma and carcinoma in male rats, and a low incidence of rare pineal gland tumors in rats. Outlining the animal study findings that argue "against the potential for relevance to humans," Taylor pointed out: that "only benign tumors were observed" in the rodents; that doxylamine is "considered negative overall in genotoxicity studies"; that mouse liver is a "questionable endpoint" for human carcinogenic risk assessment because "mouse liver is the most common target for tumors in mouse carcinogenicity studies"; that increases in benign liver tumors "may be species-specific"; and that thyroid tumors in mice "probably reflect an indirect mechanism related to alterations in hormone balance secondary to induction of liver microsomal enzymes and may not be relevant to humans." However, Taylor also suggested that several elements of the animal trials may be relevant to humans, including: that "increases were observed in the multiplicity of tumors; that there is a clear dose-related increase in the incidence of male mice with adenomas and mice with multiple adenomas"; and that "mechanisms associated with liver tumors in rodents are not understood" and irrelevance for human risk has not been demonstrated. Despite the unanimous vote against a doxylamine label warning, some committee members expressed concern that an article in the FDA Consumer magazine may not be an adequate method of informing the public. Consumer representative Lorie Rice, University of California- San Francisco, argued that "FDA, or popular magazines or the industry itself can't provide the type of information that the consumer wants and needs." To withhold information on product labeling that "this drug might cause tumors in animals" is "really a disservice" and "patronizing," Rice maintained. "To say [the warning] might scare people is also to say that people don't have the intelligence to seek the type of information that they need and they deserve," she asserted. Reidenberg countered that he did not "know how many people [would] pay attention if it was on the label." Publishing an article, on the other hand, is a "much broader approach" than labeling, Reidenberg explained. "The writers of the nonprofessional media will at least read the FDA Consumer and share in the responsibility to inform consumers more fully about the aspects of over-the-counter drugs. . . . We need a much broader approach in this society to either labeling or nothing," he said. Even if consumers are not apprised of the animal data, Reidenberg concluded, doxylamine "is safe and effective for this particular use" and the "risk of carcinogenesis, if it exists at all, is too small to be measured." FDA Monograph Review Staff Director William Gilbertson told the committee that FDA also is "looking for . . . assistance" on labeling for benzoyl peroxide. Gilbertson said that proposed labeling for benzoyl peroxide, which was provided to committee members for review, "is moving through the FDA for the moment" and is "still in the final stages of agency clearance." At a May Food & Drug Law Institute meeting, Gilbertson said the proposed labeling would advise individuals that benzoyl peroxide "is a tumor promoter and they should avoid use of it in the presence of sunlight or else use it with a sunscreen if they have to go out into the sun" ("The Tan Sheet" May 24, p. 3). In April 1992, FDA's Dermatologic Drugs Advisory Committee recommended that benzoyl peroxide be allowed to remain in OTC medications, but that a label warning be developed to inform consumers that animal studies have observed a tumorigenic effect.
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