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PROCTER & GAMBLE DOXYLAMINE CLINICAL STUDY RESULTS EXPECTED IN JANUARY 1994

This article was originally published in The Tan Sheet

Executive Summary

PROCTER & GAMBLE DOXYLAMINE CLINICAL STUDY RESULTS EXPECTED IN JANUARY 1994, P&G Toxicology Section Head Julie Skare, PhD, told FDA's Nonprescription Drugs Advisory Committee on June 28. Skare said that the study, which is currently in progress, "will provide data addressing the potential for hepatic enzyme inductions in humans at therapeutic doses of doxylamine." At the June 28 meeting, the OTC advisory committee decided that a warning label for doxylamine-containing products is not warranted based on rodent tumorigenicity data (see preceding story). Skare explained that, because only animal data are currently available, P&G is conducting the study to provide "additional data to characterize the human response to therapeutic doses of doxylamine." The rodent studies showed a tumorigenic response using doxylamine doses much higher than the human therapeutic dose. "If the [clinical] results indicate that doxylamine is not an enzyme inducer in humans, this would provide further data to indicate that the human response to doxylamine is different from rodents," Skare said. She maintained that "the weight of the evidence indicates that doxylamine does not present a cancer risk to humans." The objectives of the P&G study, as outlined by Skare, are to "determine if doxylamine affects mixed function oxidase activity, to determine if doxylamine alters thyroid function, and to determine the plasma pharmacokinetic profile of doxylamine upon multiple dose oral administration." The open label, placebo-controlled, parallel design study is being conducted on 48 healthy male subjects randomly assigned to one of three treatment groups. One group is receiving 12.5 mg doxylamine (the maximum dose allowed by FDA in the tentative final monograph for antihistamines) four times daily for 17 days. The second group is receiving 30 mg phenobarbital four times daily for 17 days, and the third group is receiving placebo. Phenobarbital is known to induce cytochrome P450 mixed function oxidase enzymes. Some members of the advisory committee voiced concern over the study design. Noting that only males between the ages of 18 and 40 are included in the study, Alan Sinaiko, MD, University of Minnesota Medical School, said he did not understand why the company "eliminated women . . . individuals less than 18 years of age . . . [and] geriatric patients." If "this study shows that there's no statistical significance" between doxylamine and enzyme induction, Sinaiko continued, "I assume . . . you're going to say it's safe" for all populations. In reply, Skare said she did not intend "to characterize this study as the be-all, end-all study. We feel it's a reasonable next step to take" in response to the animal studies indicating that doxylamine is an enzyme inducer. She also noted that women were not included in the study because the rodent data "don't indicate any sex difference" in enzyme induction and "to avoid any possibility of the menstrual" cycle. Skare added that P&G is conducting animal studies on doxylamine and "would follow that up with additional clinical studies" if the animal study results warrant it. Apprising the OTC advisory committee of the ongoing P&G clinical study was part of a larger presentation by the Nonprescription Drug Manufacturers Association, which maintained that the available evidence does not support a warning on the labels of doxylamine-containing products. NDMA Senior VP-Science and Technology William Soller, PhD, argued to the committee that "FDA's consistent and long-standing policy has been to require warnings only when they are scientifically documented clinically significant and important to the safe and effective use of the products by average consumers." The "animal bioassay data on doxylamine do not meet this standard," Soller said. The NDMA official also noted that a warning statement for doxylamine "would represent a major precedent-setting break in FDA's policy," which, he maintained, is "inappropriate in this instance." As part of the NDMA contingent, Richard Merrill, special counsel at Covington & Burling and former FDA chief counsel, maintained that "to require a warning or other disclosure regarding the rodent bioassay on doxylamine would be a sharp and complete reversal" of FDA's "conservative policy with respect to OTC drug warnings." After the OTC advisory committee made its recommendation against requiring a warning statement for doxylamine-containing products, NDMA issued a statement applauding the decision.
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