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SCHERING-PLOUGH's CLARITIN AND PFIZER's REACTINE HUMAN CARCINOGENICITY "NOT LIKELY" -- ADVISORY CMTE.; OTC DOXYLAMINE SHOULD CARRY CANCER WARNING

Executive Summary

Schering-Plough's Claritin (loratadine) and Pfizer's Reactine (cetirizine) are "not likely" to be carcinogenic in humans, FDA's Pulmonary and Allergy Drugs Advisory Committee voted at its June 13-14 meeting. Committee member Barbara Gothe, MD, Case Western Reserve University Hospital, said that available data led her to conclude that the possibility of greater cancer risk from the drugs "is not excluded for anyone, but is not likely." The committee agreed in a 5-1 vote. FDA asked the committee to evaluate rodent carcinogenicity data for the two antihistamines and to determine the data's implications for human use of the drugs. The committee was not asked to discuss efficacy or any other safety aspects of the compounds ("The Pink Sheet" June 17, p. 2). A third antihistamine discussed at the meeting was OTC doxylamine, an ingredient in Pfizer's Unisom and Procter & Gamble's Nyquil. The committee voted 5-1 that doxylamine also is "not likely" to be carcinogenic in humans. They recommended by a 5-1 vote, however, that it carry a warning label to inform consumers of the existence of rodent studies suggesting a possible tumorigenic effect. The committee's vote on the rodent carcinogenicity data may clear the way for further FDA action on the pending NDA applications, but it could mean that the products will have labels carrying some mention of the carcinogenicity findings. Pfizer filed its Reactine NDA in June 1988. Claritin was making its second appearance before the committee; it was recommended for approval in October 1987. Office of Drug Evaluation I Deputy Director and Office of OTC Drugs acting Director Paula Botstein, MD, introduced the subject to the committee. Compared to methapyrilene, which is a "gangbuster hepatic carcinogen which [FDA] pulled rapidly from the OTC market in the 70s" and diphenhydramine, chlorpheniramine and various other antihistamines that "don't appear to be carcinogens," cetirizine and loratadine are "middling rodent carcinogens," Botstein commented. "We have not made a final determination whether these two drugs can be approved for marketing; partly, we want to wait until we see what has happened with this committee," Botstein pointed out. Efficacy was not a subject at the June 13-14 meeting. If it were, Botstein quipped, the committee would have had "to move into [the] Ramada Inn [where the meeting took place] for a week or two." The deputy director asked the committee to make certain assumptions about the products. Botstein called cetirizine a "sedating, first generation antihistamine" and suggested that loratadine was sedating at high doses and less sedating at lower doses. "Neither," she asserted, "has an obvious niche or special patient population or warrants approval for an unusual population." Committee member Les Hendeles, University of Florida, agreed. "These three drugs are not unique in any respect," he said. "On the other hand, there's absolutely no evidence that predicts that the animal studies really are in any way consistent with how patients take the drug." Asked by FDA's Pulmonary Products Group Leader Eileen Leonard, MD, what degree of cancer risk would be acceptable for these products, Hendeles responded, "I don't think any risk is worth it for a runny nose." The committee voted 6-0 that any increased cancer risks from these products would be unacceptable. Carcinogenicity data presented by Schering VP-Drug Safety and Drug Metabolism Hugh Black showed loratadine-treated male mice had a positive trend toward increased liver adenomas. While the mice did not demonstrate a significant increase in liver carcinoma alone, a combined analysis of liver adenoma and carcinoma incidence in male mice treated with loratadine was significant. The incidence of combined adenoma and carcinoma was also higher than control in male and female rats at high doses of loratadine. Black concluded that "the tumorigenic effect of loratadine in rodents only occurs at exposure with high sustained levels of drug and there is probably a threshold below which neither tumorigenesis nor physiological alterations occur." Black suggested that the formation of benign tumors in mice can be explained by the fact that loratadine is a liver microsomal enzyme inducer. He compared its induction activity to that of phenobarbitol, a potent hepatic enzyme inducer, which has been found to have no carcinogenic potential. FDA's analysis of the data found that "loratadine showed activity in male mice based on increases in hepatocellular adenoma and carcinoma combined," FDA toxicologist Alan Taylor, PhD, reported. In addition, he noted that "the rat findings, which [FDA] found to be equivocal, were generally within the range of historical control data, but [the data] were supportive of an effect in the liver." The agency's main criticism of the Schering studies was that the maximum tolerated dose was not used in the mice studies. "They used a dose of 40 mg/kg per day . . . it should have been two-to- five times higher than that," said Taylor. "We do have concerns that if the studies had been done at higher doses and for a longer duration that [Schering] may have seen more adenomas and possible carcinomas." Pfizer Senior Associate Director responsible for preclinical research Joseph Catuogno, PhD, presented cetirizine data to the committee that showed a similar increase in hepatocellular adenomas in male mice at the highest dose. There was "no increase in malignant tumors," he added. "We believe the species-specific pharmacodynamic responses by cetirizine have no apparent relevance for human safety," he said. He showed that rodents had different metabolic reactions to the drug and argued that the dog model, which showed no hepatotoxicity, was more relevant. Pfizer also stressed the extensive human use of cetirizine, including 1,826 patients in U.S. clinical trials and 915 in foreign trials. Over 3 mil. prescriptions of cetirizine were written last year overseas, the company said. In addition, cetirizine is a metabolite of hydroxyzine (Pfizer's Atarax), which has been used for over 30 years, Pfizer said. Hydroxyzine was also the subject of an epidemiological study which showed no increased cancer risk, Pfizer added. As with Schering's data, FDA expressed concern that Pfizer had not used the maximum tolerated dose in animal trials. "They [may have] designed their study to look at minimum effect on the liver and not to maximize tumor induction," Taylor said. However, he added, "The cetirizine bioassay was cleared with the agency" at the time it was performed. Committee member Harold Nelson, MD, National Jewish Center for Immunology and Respiratory Medicine, concluded that cetirizine was the least likely of the three drugs to be carcinogenic. If the other two are "unlikely," he said, cetirizine is "very unlikely." When the committee concluded that available data could not clearly determine human risk, they were asked what additional data they would like to see. The committee voted to "suggest . . . refinement of the current rodent bioassays" to determine the mechanism involved in producing the adenomas. They also said "that perhaps case control studies could be done" and "if possible a human in vitro technique should be pursued." Several committee members also said that "prospective epidemiological studies" may be the only way to reach a definitive answer. The committee was not asked to specify whether new studies would be needed for approval. The committee decided not to vote on a question which asked "should the agency require repetition of animal carcinogenicity studies at the maximum tolerated dose for marketed antihistamines for which carcinogenicity studies were done at lower levels?" In a statement issued following the meeting, Schering-Plough said that it is "confident that FDA can proceed expeditiously to complete its review of the loratadine NDA." A two-year rodent study, presented by National Center for Toxicological Research's Carlton Jackson, PhD, found that maximum tolerated doses of doxylamine increased the combined incidence of liver adenoma and carcinoma in male rats. The incidence of adenoma or carcinoma alone was not significantly increased. In female rats, high doses of doxylamine increased liver hypertrophy, liver degeneration, bone osteoporosis and chronic liver inflammation but did not increase the incidence of adenoma or carcinoma. In the studies, maximum doses of doxylamine caused a high incidence of liver and thyroid follicular adenoma in both male and female mice. The incidence of liver adenoma in male mice was 54.4% and in the females, 20%. Jackson noted that there was also an increase in liver hypertrophy and liver necrosis in female mice receiving high doses of doxylamine. Procter & Gamble's Richardson-Vicks Toxicology Section Head Julie Skare, PhD, argued that the small number of liver tumors found in doxylamine-treated rats was "well within the range of historical controls." She also pointed out that liver adenomas are "very common" in the strain of mice used in the NCTR studies. "The incidence ranges from 0-44% in males and 0-18% in females" under normal conditions. Skare further asserted that doxylamine is a hepatic enzyme inducer in rodents similar to phenobarbitol. "There is a relationship between liver microsomal enzyme inducer and the production of liver tumors in rodents," Skare explained; however, "epidemiological evidence is lacking for an increased cancer risk in humans treated chronically with phenobarbitol." Using the phenobarbitol analogy, she remarked that "the possibility of an increased human cancer risk for doxylamine must be considered remote." The committee agreed that doxylamine should remain available OTC, but should carry a warning that alerts consumers to the existence of the rodent data. "I think it's unlikely that these drugs have [carcinogenic] potential," Hendeles said, "but I don't think this information should be filed away somewhere without the American public being aware of it." He suggested that a warning label would be the most useful "mechanism" for making the information available. Botstein, who took over as acting OTC Office director on June 17, asked about the meaningfulness of the label statement to consumers. "Given the difficulty everybody in this room has coming to grips with this data," Botstein said, "how do you expect the consumer" to understand a warning label? Hendeles asked if FDA policy would allow such a warning. FDAer Leonard answered that "I would rather hear what you think we should do rather than second- guess what our actions will be." The one dissenting vote on the OTC doxylamine question was cast by consumer representative Mary Garcia. She argued that the products should only be available by prescription, so doctors can "use [their] professional judgment . . . Let the physician make that decision." She added, "we have taken Nyquil at home . . . but now I would rather choose something else."
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