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Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users

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Abstract

Introduction

The analgesic metamizole, which has been withdrawn from the market in several countries due to the risk of agranulocytosis but is still available on the market in Germany and some other countries, has been associated with liver injury in published case reports; however, epidemiological studies on the risk of liver injury are limited.

Objective

The aim of this study was to compare the risk of liver injury up to 270 days after the first start of treatment with metamizole with the corresponding risk in patients starting treatment with paracetamol, using a retrospective cohort incident user design.

Methods

The first prescription for either metamizole or paracetamol in the Intercontinental Medical Statistics (IMS)® Disease Analyzer Germany database during the study period (2009–2018) was identified in patients with at least 365 days of observation and no prior diagnosis of liver events, cancer or HIV, or treatment within the last 6 months with hepatotoxic drugs typically administered for chronic conditions. Each patient was followed for specific liver events for 90 days after the prescription. In case of a new prescription within 90 days, a new 90-day observation period started, up to a maximum of 270 days. Cox regression was used to compare the risk of liver injury in the two groups.

Results

Metamizole was associated with a higher risk of liver injury compared with paracetamol (adjusted hazard ratio 1.69, 95% confidence interval 1.46–1.97). Sensitivity analyses were performed to evaluate the robustness of these findings. In all the sensitivity analyses, metamizole was still associated with a higher risk of liver injury, including an analysis where naproxen was used as a comparator instead of paracetamol.

Conclusions

Results from this study support previous studies suggesting that metamizole is associated with a significant risk of liver injury. Nevertheless, a possible impact of residual confounding cannot be excluded.

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Acknowledgements

The authors gratefully acknowledge Melinda Pálfi, Júlia Pallós, Gergő Merész, and Mátyás Szigeti for their critical review.

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Authors and Affiliations

  1. Data Analytics and Methods Task force, European Medicines Agency, Domenico Scarlattilaan 6, 1083 HS, Amsterdam, The Netherlands

    Karin Hedenmalm, Jim Slattery, Xavier Kurz, Gianmario Candore & Rob Flynn

  2. Department of Laboratory Medicine, Karolinska Institutet, Solna, Stockholm, Sweden

    Karin Hedenmalm

  3. Pharmacovigilance and Epidemiology Department, European Medicines Agency, Amsterdam, The Netherlands

    Alexandra Pacurariu

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  1. Karin Hedenmalm
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  2. Alexandra Pacurariu
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Correspondence to Karin Hedenmalm.

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Funding

No sources of funding were used to assist in the preparation of this article.

Conflicts of interest

Karin Hedenmalm, Alexandra Pacurariu, Jim Slattery, Xavier Kurz, Gianmario Candore and Rob Flynn are employees of the European Medicines Agency and have no conflicts of interest to declare in relation to this article.

Ethics approval

This study was carried out using a deanonymized database (IMS® Disease Analyzer Germany), for which ethics approval was not required.

Consent to participate

Not applicable.

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Not applicable.

Code Availability

Not applicable.

Availability of data and material

The analyses conducted in this study were performed by the authors based on the IMS® Disease Analyzer Germany database, version June 2019. The study has been registered in the EUPAS register (EUPAS 31864). Analytic data sets and custom codes can be made available upon request from the authors.

Author contributions

All authors contributed to the study design and analysis of results. Karin Hedenmalm drafted the manuscript with contributions from all other authors. All authors read and approved the final version.

Disclaimer

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of, or reflecting the position of, the European Medicines Agency or one of its committees or working parties.

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Hedenmalm, K., Pacurariu, A., Slattery, J. et al. Is There an Increased Risk of Hepatotoxicity with Metamizole? A Comparative Cohort Study in Incident Users. Drug Saf 44, 973–985 (2021). https://doi.org/10.1007/s40264-021-01087-7

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