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Executive Summary

METHOTREXATE POST-MARKETING SURVEILLANCE STUDY FOR RHEUMATOID ARTHRITIS indication could include investigation of the long-term hepatic effects of the drug, according to FDA's Arthritis Advisory Cmte. Asked by FDA for specific recommendations regarding Phase IV post-marketing studies, committee member Norman Gottlieb, MD, University of Miami, stated: "I think there's a desperate need to know what the long-term effects of methotrexate administration are on liver histology . . . We've heard from one expert that trivial fibrotic changes occur which rarely lead to anything more significant. but I don't feel comfortable with that and I wouldn't look upon that as being the final word to permit us to give methotrexate indefinitely for this disease." At the May 19 meeting, FDA requested the committee to consider whether there were any issue relative to the safety and effectiveness of Lederle's methotrexate "which should be resolved prior to approval" of the drug for treatment of rheumatoid arthritis. The agency also asked for recommendations on Phase IV testing and labeling. Methotrexate is currently approved for treatment of cancer and psoriasis. In other comments on methotrexate post-marketing studies, committee member Carol Lindsley, MD, University of Kansas, suggested that future testing of the drug in rheumatoid arthritis should attempt to "answer the question about the effect [of methotrexate] on the radiographic progression" of the disease. FDA consultant Daniel Furst, MD, American Society of Clinical Pharmacology & Therapeutics, also recommended that studies be done to determine the interaction of methotrexate with various nonsteroidal anti-inflammatory drugs. FDA consultant Harold Paulus, MD, American Rheumatism Assn., also suggested "the possibility" of conducting the type of immunologic studies that Burroughs Wellcome has done with Imuran (azathioprine). Burroughs Wellcome representative Michael Joseph described a rheumatoid arthritis azathioprine registry that was set up by Burroughs Wellcome in 1983 to follow-up patients receiving azathioprine long-term. He also said the firm has conducted a second follow-up study utilizing a database in Saskatchewan, Ontario. Methotrexate is being considered by FDA for second line treatment of rheumatoid arthritis. The proposed labeling states: "In the treatment of psoriasis or rheumatoid arthritis, methotrexate should be restricted to partients with recalcitrant disease not responsive to other forms of therapy, but only when the diagnosis has been established and after appropriate consultation." While acknowledging that "methotrexate clearly is an effective drug in treating active rheumatoid arthritis," committee member Gottlieb questioned whether the lowest effective dose of methotrexate has been determined. In the proposed labeling, the recommended initial dose is 7.5 mg a week given either as a single dose or as 2.5 mg three times at 12 hour intervals. Committee chairman Michael Weisman, MD, University of California/San Diego, suggested that labeling note efficacy has been shown for dosages ranging from 7.5 to 15 mg, but that occasional doses higher than 15 mg have been used.

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