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This article was originally published in The Tan Sheet

Executive Summary

LIDOCAINE RODENT CARCINOGENICITY STUDIES do not show a link to cancer in humans, FDA's Anesthetic & Life Support Advisory Committee concluded at an Aug. 23 meeting. The committee decided that the development of nasal tumors in lab rats exposed to high doses of lidocaine metabolite 2,6 xylidine cannot be extrapolated as a risk to humans. While agreeing that there was sufficient evidence on the metabolism of lidocaine to associate the carcinogenicity of 2,6-xylidine with lidocaine, the committee concluded that the risk was low enough that lidocaine should continue to be marketed for its present indications: OTC topical analgesia, Rx topical anesthesia, ventricular arrhythmia and local injection anesthesia. The committee made its decision after hearing 2,6 xylidine carcinogenicity data from a variety of government and industry sources such as the Nonprescription Drug Manufacturers Association, the National Toxicology Program (NTP), the National Center for Toxicological Research (NCTR) and lidocaine innovator Astra. Center for Drug Evaluation & Research Pharmacologist Lucy Jean, PhD, presented data from the 1990 NTP report (#278), "Carcinogenicity of 2,6 xylidine in Charles River CD Rats." The NTP data included the results from a series of two-year rat studies with 2,6 xylidine. The studies, which recorded the incidence of tumors at low (300 parts per million), medium (1,000 ppm), and high doses (3,000 ppm), showed a rise in the incidence of nasal and subcutaneous tumors at high doses of 2,6 xylidine. The NTP data showed little tumor activity at the lower doses, with only one tumor in 112 laboratory rats recorded. However, at the high dose, nasal tumors were identified in 52 of 112 rats. NTP concluded from the studies that, "2,6 xylidine was clearly carcinogenic in rats in the nasal septum," and results in "rare tumors at high doses," the report states. Jean stated that while "there is inadequate evidence in humans for the carcinogenicity of 2,6 xylidine . . . there is sufficient evidence in animals that 2,6 xylidine is possibly carcinogenic to humans." FDA-invited guest Raymond Woosley, MD, Georgetown University Medical Center, remarked that "animal data are interesting but the human variability for metabolism is so tremendous that it's going to be almost impossible to look at a few human subjects and generalize to the broad population." NCTR official David Gaylor, PhD, who also presented data on the cancer risk assessments for 2,6 xylidine in humans, seemed to confirm Woosley's contention when he stated that "risk is proportional [to the] total lifetime dose." The NCTR report presented by Gaylor was a combined study of animal testing data, risk estimates and known human exposure to 2,6 xylidine. Gaylor stated that the human cancer risk estimate "equals 10 per mg/kg of 2,6 xylidine." Gaylor summarized human cancer risk of normal clinical use of lidocaine, assuming exposure to 2,6 xylidine at the 10 mg/kg level, to be "one additional cancer per 100,000" persons. FDA consultant Walter Watkins, MD, Montifiore Hospital, Pittsburgh, commented that he and committee member Lawrence Saidman, MD, San Diego Medical Center, "were figuring [10 mg/kg] was a gigantic dose [of lidocaine]," and therefore not likely to be attained during actual OTC or Rx pharmaceutical use. Although the committee decided that the 2,6 xylidine rat data were not relevant to humans, the group agreed to reconvene in November to review the results of a 2,6 xylidine liver slice study in humans. Because the committee is awaiting that data, it also held off on deciding whether a package insert should be required to discuss the animal carcinogenicity data. Initially, the committee voted against requiring package inserts per the urging of NDMA. At the meeting, NDMA consultant Gary Williams, MD, who is also director of medical sciences at the American Health Foundation, agreed that the data showed 2,6 xylidine to be a carcinogen in rats but argued that "relevance to humans, if based on the biology, is highly questionable." Williams added that "the NTP carcinogenicity data in rats are inadequate to implicate 2,6 xylidine as a cancer hazard under the conditions of OTC exposure to lidocaine." NDMA commented after the meeting that "the committee made a reasonable decision" by not requiring package inserts until the results of additional data are presented in November. NDMA added that it feels "comfortable" with the proposed liver slice studies. CDER Office of Research Resources Director Jerry Collins, PhD, will conduct the human liver slice studies with frozen liver samples. The objective of the liver sample study will be to establish the baseline metabolism of lidocaine from four to six samples. If the study reveals that 2,6 xylidine is not metabolized by humans, it would reaffirm the committee's conclusion that the rodent studies are not relevant to humans. Collins will report the results of the human liver slice study to the advisory committee in November.

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