European Journal of Clinical Pharmacology

, Volume 60, Issue 11, pp 821–829 | Cite as

Agranulocytosis associated with dipyrone (metamizol)

  • Luisa Ibáñez
  • Xavier Vidal
  • Elena Ballarín
  • Joan-Ramon LaporteEmail author
Pharmacoepidemiology and Prescription



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.


Aplastic Anaemia Agranulocytosis Dipyrone Metamizol Thiamazole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



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. 1.
    Kaufman DW, Kelly JP, Levy M, Shapiro S (1991) The drug etiology of agranulocytosis and aplastic anemia. Oxford University Press, New YorkGoogle Scholar
  2. 2.
    Kaufman DW, Kelly JP, Levy M, Shapiro S (1986) The drug etiology of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. JAMA 256:1749–1757CrossRefPubMedGoogle Scholar
  3. 3.
    van der Klauw MM, Goudsmit R, Halie MR, van’t Veer MB, Herings RMC, Wilson JHP, Stricker BHCh (1999) A population-based case-cohort study of drug-associated agranulocytosis. Arch Intern Med 159:369–374CrossRefPubMedGoogle Scholar
  4. 4.
    Maj S, Lis Y (2002) The incidence of metamizol sodium-induced agranulocytosis in Poland. J Int Med Res 30:488–495PubMedGoogle Scholar
  5. 5.
    Hedenmalm K, Spigset O (2002) Agranulocytosis and other blood dyscrasias associated with metamizol (metamizol). Eur J Clin Pharmacol 58:265–274CrossRefPubMedGoogle Scholar
  6. 6.
    Ibáñez L, Juan J, Pérez E, Carné X, Laporte J-R (1991) Agranulocytosis associated with aprindine and other antiarrhythmic drugs: an epidemiological approach. Eur Heart J 12:639–641PubMedGoogle Scholar
  7. 7.
    Laporte JR, Capellà D, Juan J (1990) Agranulocytosis induced by cinepazide. Eur J Clin Pharmacol 38:387–388CrossRefPubMedGoogle Scholar
  8. 8.
    Ibáñez L, Ballarín E, Pérez E, Vidal X, Capellà D, Laporte JR (2000) Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug. Eur J Clin Pharmacol 55:761–764CrossRefPubMedGoogle Scholar
  9. 9.
    Ibáñez L, Ballarín E, Vidal X, Laporte JR (2000) Agranulocytosis associated with calcium dobesilate. Clinical course and risk estimation with the case-control and the case-population approaches. Eur J Clin Pharmacol 56:763–767CrossRefPubMedGoogle Scholar
  10. 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. 11.
    Discombe G (1952) Agranulocytosis caused by amidopyrine: an avoidable cause of death. BMJ i:1270–1273Google Scholar
  12. 12.
    Huguley CM (1964) Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic. JAMA 189:938–941PubMedGoogle Scholar
  13. 13.
    Palva IP, Mustala DO (1970) Drug induced agranulocytosis with special reference to aminophenazone. Acta Med Scand 187:109–115PubMedGoogle Scholar
  14. 14.
    Böttiger LE, Westerholm B (1973) Drug-induced blood dyscrasias in Sweden. BMJ iii:339–343Google Scholar
  15. 15.
    Varonos DD, Santamouris S, Karambali S (1979) The incidence of dipyrone induced agranulocytosis in Greece during 1975. J Int Med Res 7:564–568PubMedGoogle Scholar
  16. 16.
    Laporte JR, Carné X (1987) Blood dyscrasias and the relative safety of non-narcotic analgesics. Lancet i:809CrossRefGoogle Scholar
  17. 17.
    Bäckstrom M, Hägg S, Mjörndal T, Dahlqvist R (2002) Utilization pattern of metamizol in northern Sweden and risk estimates of agranulocytosis. Pharmacoepidemiol Drug Saf 11:239–245CrossRefPubMedGoogle Scholar
  18. 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. 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
  20. 20.
    Herxheimer A, Yudkin JS (1984) Agranulocytosis and pyrazolone analgesics. Lancet i:730CrossRefGoogle Scholar
  21. 21.
    Shapiro S (1984) Agranulocytosis and pyrazolone. Lancet i:1471.CrossRefGoogle Scholar
  22. 22.
    Laporte J-R, Ibáñez L, Vidal X, Vendrell L, Leone R (2004) Upper gastrointestinal bleeding associated with the use of NSAIDs. Newer versus older agents. Drug Saf 27:411–420PubMedGoogle Scholar
  23. 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
  24. 24.
    Böttiger LE, Westerholm B (1973) Acquired hemolytic anaemia. I. Incidence and aetiology. Acta Med Scand 193:223–226PubMedGoogle Scholar
  25. 25.
    Van der Klauw MM, Stricker B-HCh, Herings RMC, Cost WS, Valkenburg HA, Wilson JH (1993) A population based case-cohort study of drug-induced anaphylaxis. Br J Clin Pharmacol 35:400–408PubMedGoogle Scholar
  26. 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
  27. 27.
    Laporte JR, Carné X, Vidal X, Moreno V, Juan J , The Catalan Countries Study on Upper Gastrointestinal Bleeding (1991) Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Lancet 337:85–89CrossRefPubMedGoogle Scholar
  28. 28.
    Andrade SE, Martínez C, Walker AM (1998) Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol 51:1357–1365CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Luisa Ibáñez
    • 1
  • Xavier Vidal
    • 1
  • Elena Ballarín
    • 1
  • Joan-Ramon Laporte
    • 1
    Email author
  1. 1.Fundació Institut Català de Farmacologia, WHO Collaborating Centre for Research and Training in Pharmacoepidemiology, Department of Pharmacology, Therapeutics and Toxicology, Institut Català de la SalutUniversitat Autònoma de Barcelona, and Hospital Universitari Vall d’HebronBarcelonaSpain

Personalised recommendations