Agranulocytosis associated with dipyrone (metamizol)
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Reported estimates of the risk of agranulocytosis associated with metamizol have varied by several orders of magnitude. We assessed this association in a large database for the surveillance of blood dyscrasias.
Since 1980, all laboratory units of haematology in a defined area (3.3–4.1×106 inhabitants) contribute to the ascertainment of all cases of agranulocytosis meeting strict diagnostic criteria. These cases of patients with agranulocytosis and sex-, age-, hospital- and date-matched controls were interviewed using a structured questionnaire about previous drug exposures, and relative risks were calculated for several categories of exposure to metamizol.
After a total follow-up of 78.73×106 person-years, 273 community cases of agranulocytosis had been found—of which 96 were excluded for various reasons and 177 were included in the case-control analysis—and were compared with 586 matched controls. Thirty cases of agranulocytosis (16.9%) and nine controls (1.5%) had been exposed to metamizol during the week before the index day. The adjusted relative risk was 25.8 [95% confidence interval (CI), 8.4–79.1], and the attributable incidence was 0.56 (0.4–0.8) cases per million inhabitants and per year. The risk disappeared after more than 10 days since the last dose of metamizol, and it increased with duration of use. Those with agranulocytosis exposed to metamizol had taken the drug for longer periods than the exposed controls. Compared with the cases recently reported from Sweden, the duration of use of metamizol by our exposed cases was substantially shorter, and the use of concomitant medications potentially causing agranulocytosis was lower.
In our milieu, agranulocytosis attributable to metamizol is rare. Geographical disparities in its risk estimate can be partly explained by differences in its patterns of use, in terms of dose, duration and concomitant medications.
KeywordsAplastic Anaemia Agranulocytosis Dipyrone Metamizol Thiamazole
To the patients who participated in the study. The following haematologists collaborated in case reporting: E. Abella, E. Alonso, R. Ayats, C. Besses, A. Bosch, S. Brunet, N. Crespo, I. De Diego, A. Domingo, J. Estella, M. García, J.A. Hernández, A. Julià, R. López, P. Marín, F. Millà, J. Moll, T. Navarro, B. Nomdedéu, T. Olivé, L. Ortega, E. Pérez, J. Peris, A. Pineda, I. Roig, A. Solé, R. Soto and T. Toll. Dr. A. Julià (Service of Haematology, Hospital Vall d’Hebron) reviewed and confirmed the cases of agranulocytosis. Financial support was received from Hoechst AG (Frankfurt) from 1980 to 1986, and from Agencia Española del Medicamento (AEM, Spanish Medicines Agency) since 1998. Institut Català de la Salut provided personnel from 1987 to 2001. Since 2001, financial support was received from the AEM and from Aventis and Boehringer Ingelheim.
- 1.Kaufman DW, Kelly JP, Levy M, Shapiro S (1991) The drug etiology of agranulocytosis and aplastic anemia. Oxford University Press, New YorkGoogle Scholar
- 10.International Agranulocytosis and Aplastic Anemia Study (1983) The design of a study of the drug etiology of agranulocytosis and aplastic anemia. Eur J Clin Pharmacol 24:833–836Google Scholar
- 11.Discombe G (1952) Agranulocytosis caused by amidopyrine: an avoidable cause of death. BMJ i:1270–1273Google Scholar
- 14.Böttiger LE, Westerholm B (1973) Drug-induced blood dyscrasias in Sweden. BMJ iii:339–343Google Scholar
- 18.Capellà D, Laporte JR, Vidal X, Wiholm B-E, Bégaud B, Langman MJS, Rawlins M (1999) European network for the case-population surveillance of rare diseases (Euronet). A prospective feasibility study. Eur J Clin Pharmacol 53:299–302Google Scholar
- 19.Coordinating Centre (1999) A feasibility study of a European case-cohort surveillance network (EURONET) of serious ADRs to new pharmaceutical products. Euronet: final report. Contract n° BMH4-CT95-0467 (DG 12 – SSMA). DG XII, European Commission, BrusselsGoogle Scholar
- 23.Ibáñez L, Pérez E, Vidal X, Laporte J-R, The Grup d’Estudi Multicèntric d’Hepatotoxicitat Aguda de Barcelona (GEMHAB) (2002) Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 37:592–600CrossRefPubMedGoogle Scholar
- 26.Roujeau J-C, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F, Mockenhaupt M, Paoletti C, Shapiro S, Shear N, Schöpf E, Kaufman DW (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600–1607CrossRefPubMedGoogle Scholar