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Executive Summary

The development of nasal tumors in laboratory rats exposed to high doses of the lidocaine metabolite 2,6-xylidine cannot be extrapolated as a risk to humans, FDA's Anesthetic & Life Support Advisory Committee concluded during a review of lidocaine carcinogenicity and labeling issues Aug. 23. The advisory committee unanimously agreed that there was sufficient evidence on the metabolism of lidocaine to associate the carcinogenicity of 2,6-xylidine with lidocaine; however, the committee concluded that the risk was low enough that lidocaine should continue to be marketed for its present indications: ventricular arrhythmia, local injection anesthesia, Rx topical anesthesia ant OTC topical analgesia. The committee made its decision after hearing 2,6-xylidine carcinogenicity data from a variety of government and industry sources. The committee heard data from the National Toxicology Program (NTP), National Center for Toxicological Research (NCTR), the Nonprescription Drug Manufacturers Association (NDMA) 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. The FDAer concluded, based on the NTP data, that "[while] there is inadequate evidence in humans for the carcinogenicity of 2,6-xylidine... there is sufficient evidence in animals [to conclude] that 2,6- xylidine is possibly carcinogenic to humans." FDA invited guest James Swenberg, PhD, the director of toxicology at the University of North Carolina, reacted to the NTP conclusions, stating: "When you contrast the 1,000 versus the 3,000 ppm dose group, we have...a 52-fold increase in incidence for a three-fold increase in dose. To try to extrapolate down to those low levels from something that's going on at 3,000 ppm is a real case of faith," Swenberg commented. Swenberg's sentiments were echoed by FDA invited guest Raymond Woosley, MD, Georgetown University Medical Center, who 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." David Gaylor, PhD, NCTR, presented data on the cancer risk assessments for 2,6-xylidine in humans. He seemed to confirm Woosley's assessment when he stated that "risk is proportional [to the] total lifetime dose." The NCTR report 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 estimated 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, Montefiore University Hospital, Pittsburgh, commented that he and committee member Lawrence Saidman, MD, San Diego Medical Center, "were figuring it [10 mg/kg] was a gigantic dose [of lidocaine]," and therefore not likely to be attained during actual pharmaceutical or OTC use. Astra Senior Scientific advisor Stig Agurell, PhD, presented a company report on total lifetime exposure for Astra's prescription lidocaine products, including Xylocaine injectables for ventricular arrhythmias; Xylocaine-MPF for spinal anesthetic in obstetrics; and Xylocaine ointments and sprays for local anesthetics. Agurell stated that "20-50 exposures [to xylocaine products] is 40 mg/kg or less [of lidocaine], which equals 1-5 grams absorbed, of which one-third of that is 2,6-xylidine." He added that, based on the NTP study of 2,6-xylidine in rats, lidocaine has "no genotoxic effect in recent studies and none in over 40 years of clinical use." The committee's decision to minimize the relevance of rodent toxicity studies to humans marks the second time in less than two months that the issue of animal to human risk extrapolation has been taken up by an advisory committee. FDA's Psychopharmacologic Drugs Advisory Committee was convened in July to consider class labeling for antipsychotic drugs to inform physicians of elevations in the hormone prolactin ("The Pink Sheet," July 26, T&G-8). The discussion grew out of preclinical toxicity data from Janssen's Risperdal (riperidone), which is pending approval at the agency. At the meeting, after lengthy discussion, FDA Office of Drug Evaluation I Director Robert Temple summed up the complexities of the issue by noting that "the best people in the business" have "grappled with the question of whether rodent studies are relevant to humans." 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 discussing the animal carcinogenicity data. Initially, the committee voted against requiring package inserts. NDMA consultant Gary Williams, MD, the director of medical sciences at the American Health Foundation, urged the committee not to recommend package inserts for lidocaine. Williams agreed with data that finds 2,6-xylidine is a carcinogen in rats but argued that the "the question of 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 Aug. 27 that the association feels 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 has not had a follow-up with FDA since the meeting but is "comfortable" with the proposed liver slice studies. CDER Director of Office of Research Resources 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 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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