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Executive Summary

Label changes to highlight phenylbutazone (Butazolidin) and oxyphenbutazone (Tandearil) use as last line therapy remain an alternative to removing the products from the market, HHS Secty. Heckler concluded Aug. 7. Denying a Health Research Group (HRG) petition that the nonsteroidal anti-inflammatories (NSAID) be banned, Heckler concluded that "the labeling of the drugs can be revised to include additional information about risks and appropriate uses." Relabeling, as well as possible educational efforts, should "eliminate any currently indicated uses that cannot be justified in light of the benefit-to-risk ratio." In recommendations to the FDA commissioner, subsequently forwarded to HHS, the agency staff recommended "an immediate change in labeling for the two drugs to emphasize that they should be used only when safer NSAIDs have been unsuccessful, to redirect their use to appropriate patients, and to define the risks more fully, particularly with respect to identifying patients (older women) at particular risk." In its recommendations, the agency staff pointed out that although several sections of the drugs' current labeling "suggest they occupy a 'second-line' status," the inserts do "not specifically identify the drugs as agents to be used only after other NSAIDs have failed." The agency also recommended that mfrs. be called on to enlist support from groups such as the American Medical Assn. and Arthritis Foundation to aid in alerting MDs to the label revisions. Revised labeling would also highlight the changes in the Drug Bulletin, the agency noted. The FDA report also suggested that patient labeling be considered. In addition to the near-term actions, FDA urged that the drugs' risk/benefit be reviewed, "especially in osteoarthritis (even for short-term use) and painful shoulder, where there seems less present consensus that the drugs have special usefulness," by outside experts including the agency's Arthritis Advisory Cmte. The agency left open the possibility that it might in the future seek the drugs' removal if labeling changes did not adequately limit their use. "We would not rule out the possibility that persistent extensive use for inappropriate purposes would cause us to reconsider our present conclusions," the FDA report asserted. Heckler's decision comes seven months after HRG filed a petition for removal of Butazolidin and Tandearil under the "imminent hazard" provisions of the Food, Drug & Cosmetic Act. FDA held a public hearing on the issue Jan. 31. In its petition, HRG contended that the drugs' fatality rate due to two blood disorders, aplastic anemia and agranulocytosis, is 25.3 deaths per one million users. Heckler said FDA analyzed the results of three published and two unpublished epidemiological studies to determine fatality rate. She noted that the best data was from the study by Inman, conducted in England in 1974-75, which HRG relied upon. However, "FDA determined that Inman's data must be adjusted to account for differences in population distribution between England in 1974-75 and the U.S. at the present time," Heckler said. Upon making these adjustments, FDA concluded that "the best estimate of fatal reactions for both drugs from aplastic anemia or agranulocytosis, at the present time in the U.S., is 16 deaths per one million users." Phenylbutazone/Oxyphenbutazone Fatality Rates Are In Acceptable Range Set In Phenformin Case -- Heckler "Further adjustment of the data to reflect differences in duration of therapy would, in FDA's view, probably further lower the estimated fatality rate, as risk is increased with long-term usage and present U.S. usage is believed to be of shorter duration than English usage in 1974-75," Heckler added. However, she said the Inman data are not sufficiently detailed to permit such an adjustment. Heckler also pointed out that when HHS decided to suspend approval of phenformin due to the risk of death from lactic acidosis in 60 to 1,000 per million users, it used as benchmarks several drugs in general usage that were associated with fatal reaction rates from specific causes. For example, she said, penicillin may result in death due to anaphylaxis in 20 cases per million, and oral contraceptives may cause death from thromboembolism at a rate of 10 to 30 per million patient years. The risk of death from phenformin was estimated at 60 to 1,000 per million users. The secty. said the risk of death from phenylbutazone due to the two blood disorders "is in the same range as the benchmark fatality rates found acceptable in the phenformin decision, and below the range found unacceptable. Thus, the risk from the two blood disorders does not warrant a finding that the drugs are imminent hazards." FDA also compared the fatality rates of phenylbutazone and oxyphenbutazone against the fatality rates of 12 other nonsteroidal anti-inflammatories. The agency found that the two drugs "rank relatively high among the 12 NSAIDs in the rate of total fatal reactions per million Rxs and relatively high in five of the six body systems studied." However, the drugs rank first in only one system -- blood and lymphatic reactions -- "and overall fatality rates are not clearly separated from those for the other NSAIDs." Heckler said her conclusion "is not inconsistent with the decision by other countries to remove the drugs from the market or to restrict their use." Norway banned both drugs, and England and Israel have proposed removing oxyphenbutazone from the market and limiting phenylbutazone use to the treatment of ankylosing spondylitis. "The regulatory anthorities in [other] countries are required to apply their own legal and policy standards to the facts before them," Heckler commented. "I am required to apply the statutory standard in the federal Food, Drug & Cosmetic Act for drugs that are imminent hazards, and I find that the facts before me do not meet that standard."

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