Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990–2012
- 1.5k Downloads
In 1986, the risk of agranulocytosis prompted German authorities to restrict the indications for metamizole use. After an initial decline, prescriptions increased from <20 million defined daily doses in 1990 to >140 million in 2012. Concurrently, spontaneous reports of agranulocytosis increased from about 10 in 1990 to >50 in 2012. In this study, reports were analyzed to identify targets for risk minimization measures.
Reports of suspected metamizole-induced agranulocytosis (neutrophils <0.5 × 109 cells/l) between 1990 and 2012 were identified in the German spontaneous reporting database. Cases for which original reporting documents were available were eligible for analysis. Patient characteristics, indication, clinical course, and outcome were assessed.
One hundred sixty-one reports were analyzed. The mean age of the patients was 56.8 years (11–93) and 64.6 % were female. Off-label use was identified in about 25 % of cases. Neutrophils fell below 100/μl in 63 and intercurrent infections developed in 109 cases. Thirty-eight patients (23.6 %) died. In two thirds of the cases, agranulocytosis occurred within 6 weeks of permanent or intermittent metamizole treatment, in 30.5 % within 7 days, including 18 cases of immediate onset after the first or second administration.
The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals.
KeywordsMetamizole Dipyrone Agranulocytosis Spontaneous reports Germany
The authors would like to thank Siobhan O’Leary and Henry Pachl for the editing assistance.
Performed research: TS, EB, UGR. Analyzed data: TS, EB, UGR. Wrote manuscript: TS, WDL, BM, EB, UGR.
For this type of study, formal consent is not required.
Conflict of interest
The authors declare that they have no competing interests.
- 9.FDA: List of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness (Federal Register: October 8, 1998 (Volume 63, Number 195)): http://www.fda.gov/ohrms/dockets/98fr/100898b.txt. Accessed 6 Jul 2013.
- 11.Arzneimittelkommission der deutschen Ärzteschaft: Bundesgesundheitsamt schränkt Anwendungsgebiet von Metamizol-haltigen Monopräparaten ein. Dtsch Arztebl 1986;83:3267.Google Scholar
- 12.Schwabe U, Paffrath D (Hrsg.): Arzneiverordnungs-Report (German Drug Report) 2013. Berlin, Heidelberg: Springer Medizin Verlag; 2013Google Scholar
- 16.(Muster-)Berufsordnung für die in Deutschland tätigen Ärztinnen und Ärzte [(Model) Professional Code for Physicians in Germany]: http://www.bundesaerztekammer.de/downloads/MBO_08_20112.pdf. Kiel, 114th German Medical Assembly 2011. Accessed 6 June 2014.
- 17.Development and rational use of standardised MedDRA Queries (SMQs). Geneva: Council for International Organizations of Medical Sciences (CIOMS); 2004.Google Scholar
- 18.World Health Organization: The use of the WHO-UMC system for standardised case causality assessment: http://who-umc.org/Graphics/24734.pdf. Accessed 10 June 2015.
- 19.Stammschulte T, Pachl H, Gundert-Remy U (2013) Do older patients take more drugs and are they at higher risk of adverse drug reactions? What do our spontaneous reports say? Drug Saf 36:813Google Scholar
- 27.Sanofi-Aventis Deutschland GmbH: Fachinformation “Novalgin®”. Stand: Januar 2011.Google Scholar
- 28.Arzneimittelkommission der deutschen Ärzteschaft: “Aus der UAW-Datenbank”: Agranulozytose nach Metamizol - sehr selten, aber häufiger als gedacht. Dtsch Arztebl 2011;108:A 1758-1759.Google Scholar
- 29.BfArM: Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM weist auf richtige Indikationsstellung und Beachtung von Vorsichtsmaßnahmen und Warnhinweisen hin (28.05.2009): http://www.bfarm.de/DE/Pharmakovigilanz/risikoinfo/Archiv/2009/RI-metamizol.html. Accessed 6 Jul 2013.