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Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990–2012

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgments

The authors would like to thank Siobhan O’Leary and Henry Pachl for the editing assistance.

Author contribution

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.

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Authors and Affiliations

  1. Drug Commission of the German Medical Association (DCGMA), Herbert-Lewin-Platz 1, 10623, Berlin, Germany

    Thomas Stammschulte, Wolf-Dieter Ludwig, Bernd Mühlbauer, Elisabeth Bronder & Ursula Gundert-Remy

  2. Department of Hematology, Oncology, and Tumor Immunology, HELIOS Klinikum Berlin-Buch, Berlin, Germany

    Wolf-Dieter Ludwig

  3. Department of Pharmacology, Klinikum Bremen-Mitte gGmbH, Bremen, Germany

    Bernd Mühlbauer

Authors
  1. Thomas Stammschulte
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  2. Wolf-Dieter Ludwig
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  3. Bernd Mühlbauer
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  4. Elisabeth Bronder
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  5. Ursula Gundert-Remy
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Corresponding author

Correspondence to Thomas Stammschulte.

Electronic supplementary material

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ESM 1

Indications for metamizole in 161 spontaneous reports of suspected metamizole-induced agranulocytosis (TIFF 1.14 mb)

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Stammschulte, T., Ludwig, WD., Mühlbauer, B. et al. Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990–2012. Eur J Clin Pharmacol 71, 1129–1138 (2015). https://doi.org/10.1007/s00228-015-1895-y

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  • DOI: https://doi.org/10.1007/s00228-015-1895-y

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