Metamizole-induced agranulocytosis: utilisation trends, pharmacovigilance signals and regulatory risk-minimisation in Switzerland.

Abstract

 INTRODUCTION: The therapeutic role of metamizole (dipyrone) remains controversial because of the risk of metamizole-induced agranulocytosis, a very rare, idiosyncratic, life-threatening adverse reaction. We described utilisation, spontaneous reporting and recent regulatory actions in Switzerland.

Methods:  We estimated national metamizole utilisation as defined daily doses (DDD; WHO DDD 3 g/day) for 2014-2023, derived from aggregated national sales data; individual case safety reports (ICSR) of metamizole-induced agranulocytosis were retrieved from VigiBase (the WHO global safety database) for 2014-2024. Outputs included annual counts, fatal proportion and utilisation-normalised reporting (metamizole-induced agranulocytosis per million DDD); analyses were primarily descriptive.

Results: Utilisation increased by ~79% during the analysed period with a formulation mix of 95.7% oral, 4.2% ampoules, 0.1% suppositories. Metamizole-induced agranulocytosis reports rose from 13 (2014) to 57 (2024), with year-to-year variability; the fatal proportion declined from 13.5% (2014-2018; 17/126) to 5.8% (2019-2023; 13/224) and 1.8% in 2024 (1/57). Utilisation-normalised reporting increased from 1.42 to 3.29 per million DDD (total), while fatal reports remained low and trended downward (mean 0.249 per million DDD, 2014-2023). Among Swiss fatal cases, methotrexate was co-reported as a concomitant drug in 39.5% (15/38) (extended fatal set 2011-2025; fatal ICSRs irrespective of onset year). Switzerland contributes a disproportionately high absolute number of cumulative metamizole-induced agranulocytosis reports.

Regulatory actions:  EMA and Swissmedic implemented strengthened warnings; Swissmedic additionally required a red-framed outer carton statement, clarified indications (second-line severe pain; refractory high fever) and advised avoiding concomitant methotrexate; a Direct Healthcare Professional Communication was issued.

Conclusion: Regulatory assessments by EMA and Swissmedic concluded that the benefits of metamizole continue to outweigh the risks, provided the drug is used appropriately, action is taken promptly at first symptoms and concomitant methotrexate is avoided. However, the number of reported cases of agranulocytosis underscores the known risk in the context of widespread use. Spontaneous reports reflect reporting intensity, not incidence; ongoing monitoring of risk-minimisation effectiveness is warranted.