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Executive Summary

Rx ANALGESIC ASSOCIATED AGRANULOCYTOSIS AND APLASTIC ANEMIA incidence rate is "very low," but found to be relatively higher with particular analgesics, according to results of the International Agranulocytosis and Aplastic Anemia Study published in the Oct. 3 issue of the Journal of the American Medical Association. "Analgesics significantly associated with agranulocytosis were dipyrone (metamizol sodium), indomethacin, and butazones (phenylbutazone and oxyphenbutazone)," the study concludes, while indomethacin, diclofenac sodium and butazones were "significantly associated with aplastic anemia." The study, sponsored by Hoechst AG, involved cases from 300 hospitals in eight countries including Israel, Spain, West Germany, West Berlin, Italy, Hungary, Bulgaria and Sweden. With regard to agranulocytosis, the study compared analgesic use in the week before onset of illness between 221 cases and 1,425 hospital controls. For dipyrone use, "the rate ratio estimate was 23.7 in Ulm, West Germany, West Berlin, and Barcelona, Spain, and the estimated excess risk for any exposure in a one-week period was 1.1 per million," the study reports. "In Israel and Budapest, Hungary, where the rate ratio estimate was 0.8, there was no evidence of excess risk." The study adds that "in all of the regions combined, the rate ratio estimates were 8.9 for indomethacin and 3.8 for butazones, with excess risk estimates of 0.6 and 0.2 per million, respectively." The study concludes that "the use of dipyrone was associated with agranulocytosis in some of the regions under study, but not in others. Overall, indomethacin and butazones were also associated with an increased risk." In addition, the study states, "there was an association of borderline significance for salicylate use, which was somewhat more pronounced for use that lasted 14 or more days." It further notes that "there was no statistically significant evidence of association for pyrazolones other than dipyrone, acetaminophen or the heterogeneous category of newer nonnarcotic analgesics, although for none of there drugs could increases in risk of twofold to fourfold be ruled out." To assess association of analgesic use with aplastic anemia, investigators compared analgesic use 29 to 180 days before hospital admission in 113 cases and 1,724 controls. "Indomethacin (rate ratio estimate, 12.7), diclofenac sodium (8.8), and butazones (8.7) were significantly associated with aplastic anemia, with estimated excess risks for any exposure in a five-month period of 10.1, 6.8, and 6.6 per million, respectively," the study reports. It notes that for indomethacin and butazones "there was a suggestion that the risk was higher if they were taken regularly and for a sustained period." The study observes that there was no evidence of an association between aplastic anemia and use of dipyrone or other pyrazolones. It adds that "for salicylate use of four or more days' duration, the rate ratio estimate was somewhat elevated, but this result could have been due to chance. Similarly, the association with the use of a mixed group of the newer nonnarcotic analgesics other than diclofenac could also have been due to chance." However, the study notes, "since individual drugs in this category have been implicated in case reports as possible causes of aplastic anemia, these agents require further study." In the same issue of JAMA, FDA Office of Epidemiology and Biostatistics Director Gerald Faich, MD/MPH, praised the analgesic study as an impressive pharmaco-epidemiologic investigation. He said it is important to the clinician because it examines multiple drug exposures and looks at risk across a therapeutic drug class. However, he cautioned that results of the study should not be used to compare the safety profiles of various analgesics. "Lest the study be misinterpreted, it must again be emphasized that what counts is total drug risk," Faich stated. "Gastrointestinal and other organs are far more frequently adversely affected by analgesics than the hematologic system. Even the highest rates found in the study do not greatly exceed a mortality rate of five per million exposures for these drugs." Faich continued: "While no firm cutoff can be set for declaring any drug absolutely safe, it should be recognized that when drug-induced mortality is found to be below five or 10 per million, differential distinctions about the safety of one drug compared with another will be difficult to ascertain and support scientifically. Thus, choices of analgesics, once the need for them is clear, should not be made solely on the basis of the hematologic toxicity described in this study."

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