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Executive Summary

Abbott's clarithromycin is safe for use in women of childbearing potential despite several animal studies suggesting that the broad-spectrum macrolide anitbiotic may be teratogenic, FDA's Anti-Infective Drugs Advisory Committee unanimously agreed at its July 18 meeting. The committee, however, split 5-5 on whether the product should be contraindicated in pregnant women. Committee member Robert Redfield, MD, Walter Reed Army Institute of Research, commented: "Data was presented that showed that this particular antibiotic was safe and efficaious in adult populations for relatively superficial infections for which there is alternative therapy . . . [But] I don't have adequate data to recommend its use in pregnancy." With its split vote, the committee stopped short of recommending what Chairman Thomas Beam, MD, Buffalo Veterans Administration Medical Center, termed a "blanket exclusion" of pregnant women in the label. The committee also voted 10-0 that, if the drug is indicated for any condition "where no alternative therapy is appropriate," its use in pregnant women should be allowed. Abbott presented preclinical data from 14 teratology studies in four animal species. One rat study showed increased fetal abnormalities at the highest dose. One mouse study showed a 31% increase in cleft palates in fetuses. Of most concern to the committee, however, was a study of six pregnant cynomolgus monkeys (macaques) in which four aborted. Additional studies showed that doses in the range of the maximum human dose caused one abortion in 10 monkeys, the same as control. Redfield and others said that the data made them "uncomfortable," but the committee voted 6-4 that further primate studies should not be not necessary. Abbott maintained that teratogenicity was seen only in doses that were also toxic to the pregnant female. "The developing conceptus is not at any risk . . . so long as the mother is shown to be tolerant" of the dose involved, the company said. By contrast, FDA's Reviewing Pharmacology Officer Norma Browder, PhD, found the fetal abnormalities appearing "at doses toxic to the dam and in some instances at doses not toxic to the dam." The FDA reviewer added that "recommendations have been made to label this drug either pregnancy category X [contraindication for pregnancy] or pregnancy category C [indicating that benefits may outweigh an unknown risk in pregnant women(BRACKET)." The committee voted unanimously to reject indicating the drug for treatment of Legionella pneumonia based on a single open-label study performed in Pakistan. The committee felt that it would not be "appropriate to extrapolate the outcome of these data to the U.S. population." The study involved 46 patients at a single center in Pakistan, where Legionnaire's Disease is more common than in the U.S. Abbott presented data showing a 100% cure rate for all 34 patients who completed the study. The committee, however, felt that the data were not conclusive. Members questioned the diagnostic procedures and suggested that patients may have been responding to previous antibiotic therapy or to antituberculosis medication many of them were receiving. The committee's vote went against the recommendation of FDA Medical Reviewer Nasim Moledina, MD. The committee noted that she had recommended "clarithromycin for the treatment of pneumonias including Legionella pneumonia." Center for Drug Evaluation and Research Deputy Director for Medical Affairs Bruce Burlington, MD, told the committee that "one of the implications of the issue for us now . . . is, is this pneumonia, Legionella, a separate indication, or is it simply a different organism that causes pneumonia? . . . We think that's kind of a technical interpretation question and we didn't want to try at this meeting to resolve that today." FDA's limited questions at the meeting, covering just the Legionella and teratology issues, appear to represent FDA's concerns following the first level of review for the product. Moledina indicated that she has completed her review, although the product "has not been reviewed by the secondary reviewer." A setback on the Legionnaire's Disease indication seems unlikely by itself to have a major impact on clarithromycin's indication profile. Abbott Anti-Infective Division representative Andre Pernet, PhD, told the committee that Abbott is seeking five indications for the antibiotic: pharyngitis, sinusitis, bronchitis, pneumonia, and skin and skin structure infections. The molecule, synthesized by the Japenese firm Taisho and licensed to Abbott, was designed to improve upon erythromycin, Pernet said, by avoiding the creation of an anhydrous metabolite that adversely affects bioavailability and has been implicated in gastrointestinal side effects. An NDA for clarithromycin (NDA #50-662) was filed in December 1989. Clarithromycin has a longer half-life (seven hours v. two) and greater bioavailability than erythromycin, Pernet said. It will be given twice-daily in doses of 250 mg and 500 mg, he said. Erythromycin is usually given four times a day. Clinical trials supporting the NDA included 2,618 patients in controlled trials, of which about half were evaluable for efficacy, the company said. An additional 600 patients were involved in uncontrolled trials. Clarithromycin showed efficacy similar to existing therapies in all five therapeutic categories studied in head-to-head trials against penicillins, cephalosporins, and erythromycin, according to data Pernet presented. Clarithromycin appeared to be better tolerated than erythromycin. Safety data presented by Pernet showed that the incidence of gastrointestinal side effects was 13% on clarithromycin v. 32% on erythromycin. The committee, however, was not asked to review the total NDA package at the July 18 session. In May, Abbott said that it plans to file an NDA for pediatric use of clarythromycin "late this year" ("The Pink Sheet" May 27, p. 8). The drug is also in Phase II for treating Mycobacterium avium complex in AIDS patients.

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