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BUTAZOLIDIN/TANDEARIL FDA RECOMMENDATIONS TO HHS COULD INCLUDE RELABELING TO RESTRICT USE, FDA SAYS IN TALK PAPER; ISSUE IN "FINAL STAGES" OF FDA REVIEW

Executive Summary

FDA's recommendations to HHS on phenylbutazone (Butazolidin) and oxyphenbutazone (Tandearil) could include relabeling to further restrict the drug's use, the agency indicated in a March 27 Talk Paper. Noting the agency is in "the final stages of review" of data submitted following the Health Research Group's (HRG) petition to remove the drugs under the FD&C Act's "imminent hazard" provisions, the Talk Paper pointed out that "if FDA does not recommend a complete ban of the drugs, it could nevertheless recommend further limiting the use of one or both drugs through more restrictive labeling." FDA issued the Talk Paper following a March 27 letter to Acting Com. Novitch from HRG Director Sidney Wolfe, MD, reiterating the group's call for removal of the drugs from the U.S. market. In support of its position, HRG cited regulatory actions regarding the drugs in Sweden, Israel and the U.K. "Since the time of our petition, we have learned that although the U.S. still allows the marketing of these deadly drugs, other countries -- Sweden, Israel, and the U.K. -- have now initiated the process of banning the general marketing of these drugs," Wolfe declared. In addition to FDA, copies of the letter were forwarded to Reps. Dingell (D-Mich.), Waxman (D-Calif.) and Weiss (D-N.Y.). In its Talk Paper, FDA stressed that different countries have responded to the phenylbutazone/oxyphenbutazone issue in various ways. "While Norway has banned the drugs and Israel and Sweden are also considering an outright ban, other countries considering the issue are moving toward restricting the drug to conditions which other drugs cannot handle," FDA said. "Britain has proposed restricting phenylbutazone to the treatment in hospital care, of ankylosing spondylitis . . . Germany and Finland plan to restrict the labeling for phenylbutazone to use in ankylosing spondylitis." FDA has been closely monitoring the phenylbutazone/oxyphenbutazone situation abroad. For example, in early March Acting Drug Research & Review Office Director Robert Temple, MD, discussed the British govt.'s position on the drugs with U.K. Health & Social Security Dept. official John Griffin. According to an FDA memo of the telephone conversation, Griffin explained that "sales of phenylbutazone would be monitored for the next 12 months and they were expected to fall to 5% of the current sales. If this did not occur, it was the Medicine Div.'s intent to remove the marketing license." Griffin also noted, the memo said, that oxyphenbutazone will be withdrawn from the U.K. market and phenylbutazone limited to hospital-only use for ankylosing spondylitis. Griffin noted that the U.K.'s yellow card data indicates "that the mortality, corrected for sales, of phenylbutazone and oxyphenbutazone was higher than any of the other non-steroidal anti-inflammatory drugs," the memo stated. He said the distinction between the two drugs was based on data from British doctor W. H. Inman and yellow card data that "indicated an increased risk of aplastic anemia with oxyphenbutazone compared to phenylbutazone." According to another memo, Center for Drugs & Biologics Director Harry Meyer, MD, and other FDA staff contacted Ciba-Geigy on March 12 to ask what the company's position is in light of the action in foreign countries to restrict the two drugs. According to the FDA memo, Ciga-Geigy responded that because labeling differs from country to country, resulting in different use patterns, "one might not expect a 'corporate' position." Maintaining that the company's world operations are not "monolithic," Ciba-Geigy U.S. said, according to the memo, that it "believes the U.S. data . . . does not support the 'emotional' actions now being taken against it by some foreign countries." The Talk Paper explained that while FDA will consider world wide adverse reaction data, including a retrospective study submitted by Ciba-Geigy, in making its recommendations to HHS, greater weight will be accorded U.S. data. "FDA's analysis will give important consideration to the agency's data based on three decades of U.S. experience, which can be analyzed in greater detail than the worldwide data," the Talk Paper said. HRG Contends Ciba-Geigy Delayed Reporting Several Hundred Foreign Deaths The March 27 HRG letter is the most recent effort by the consumer group to try to expedite action on its petition. In a March 6 letter to HHS General Counsel Juan del Real, Public Citizen Litigation Group attorney William Schulz said the consumer group would go to court if a decision was not reached promptly. "We believe that it would be unreasonable for the dept. to wait longer than six weeks after the FDA hearing to reach its decision," Schulz said. The consumer group also alleged that Ciba-Geigy violated FDA adverse drug experience reporting requirements by not informing the agency of several hundred foreign deaths. Wolfe based his contention on Dec. 31, 1983, memo written by FDAer John Harter, MD, which he said stated that a report submitted in November by Ciba-Geigy on internatl. adverse reactions contained "fatal reactions in 564 patients, 101 of whom were reported to FDA prior to the Internatl. Report." Wolfe declared: "In other words, of these 564 phenylbutazone and oxyphenbutazone worldwide fatalities, only 101 had been previously reported to FDA. Thus at least 463 fatalities were first brought to FDA's attention in the Internatl. Report which Dr. Harter received on Nov. 30, 1983." According to FDA regs and the FD&C Act, he maintained, "these deaths, which had occurred over the many years these drugs have been marketed worldwide, are supposed to be reported no more than 12 months after the company learns of them." In a preliminary response to the HRG allegation of reporting violations, the Talk Paper said "FDA will consider this matter but at present has no reason to believe that a violation was committed."

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