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NSAID LABEL WARNINGS FOR AGRANULOCYTOSIS AND APLASTIC ANEMIA ARE ADEQUATE, FDA CMTE. SAYS: NO NEW WARNINGS FOR INDOMETHACIN ARE REQUIRED

Executive Summary

Current NSAID label references to agranulocytosis and aplastic anemia as possible adverse experiences are sufficient, FDA's Arthritis Drugs Advisory Committee concurred at its Dec. 1 meeting. The committee's decision responds to the International Agranulocytosis and Aplastic Anemia Study, published in the Oct. 3 issue of the Journal of the American Medical Association ("The Pink Sheet" Oct. 6, T&G-3). The advisory committee was asked by FDA to evaluate whether or not the study supported "changes in the current labeling of any particular nonsteroidal anti-inflammatory drugs (NSAIDs) or all NSAIDs as a class." Summarizing the committee's consensus, committee Chairman Robert Pinals, MD, Rutgers School of Medicine said: "We think the information available right now is insufficient" to warrant a labeling change for NSAIDs. "At the present moment, we all recommend that you stick with what you have." The international study, a non-randomized, case-control trial, found that while the incidence rate of agranulocytosis and aplastic anemia was "very low," particular products were associated with relatively higher risks for the blood disorders. Because NSAID labeling currently notes that agranulocytosis and aplastic anemia are rare adverse experiences that may be associated with the drugs, the committee agreed that a further labeling statement based on the findings of the international study would be unnecessary. The committee also noted that the study did not implicate all NSAIDs as being associated with increased risks for the blood disorders. The study, which includes information from over 300 hospitals in eight countries, found that indomethacin, butazones (phenylbutazone and oxyphenbutazone) and dipyrone "were significantly associated with agranulocytosis," while indomethacin, diclofenac sodium and butazones "were significantly associated with aplastic anemia." For agranulocytosis, the excess risk per million people was found to be 1.1 for dipyrone, .2 for the butazones, and .6 for indomethacin. The excess risk per million for aplastic anemia was found to be 6.6 for butazones, 10.1 for indomethacin, and 6.8 for diclofenac. Of the products cited in the study as having increased risks, indomethacin and the butazones are the only ones marketed in the U.S. Phenylbutazone (Geigy's Butazolidin) labeling highlights, in a boxed warning statement, aplastic anemia and agranulocytosis as adverse events associated with the drug. The committee agreed that the international study results would not support a similar type of labeling statement for indomethacin. Citing a British study that did not find increased risk of agranulocytosis or aplastic anemia with indomethacin, committee member Norman Gottlieb, MD, University of Miami, said in his summarizing remarks: "Based on the discrepancy" between the trials as well as methodological problems in the international study, "I would speak against incorporating into the package insert anything that might impute one drug relative to another."
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