DOI: https://doi.org/https://doi.org/10.57187/5062
4-methylaminoantipyrine (also: N-methyl-4-aminoantipyrine); primary active metabolite of metamizole
Adverse drug reaction
Anatomical Therapeutic Chemical classification system
Strongest warning in product information to highlight a serious risk
Confidence interval
Defined daily dose; the DDD is the assumed average maintenance dose per day for a drug’s main adult indication
Direct Healthcare Professional Communication; safety notice to healthcare professionals on important safety information
European Medicines Agency
Full blood count
Human leucocyte antigen
Individual case safety report
Left ventricular ejection fraction
Marketing authorisation holder
Medical Dictionary for Regulatory Activities
Non-steroidal anti-inflammatory drug
Pharmacovigilance Risk Assessment Committee (EMA)
Standardised MedDRA Query
Uppsala Monitoring Centre (WHO Programme for International Drug Monitoring)
WHO global database of individual case safety reports (ICSR), maintained by the UMC
Web-based analytics and signal-detection interface to VigiBase (UMC)
World Health Organization
Metamizole (dipyrone), first marketed in 1922 [1], is converted to its active metabolite 4-methylaminoantipyrine (4-MAA) [2]. It provides analgesic, antipyretic and spasmolytic effects and is an inducer of hepatic enzymes, which is relevant for drug–drug interactions in older patients with polypharmacy [3].
Metamizole is widely used in several countries, including Germany, Spain and Switzerland, but is banned in others – including the United States, Canada, the United Kingdom, Australia, France, Norway, Sweden and Japan – primarily due to concerns about agranulocytosis [4]. In Switzerland, utilisation has increased over the last decade, with marked regional heterogeneity and higher use among older patients when non-steroidal anti-inflammatory drugs (NSAID) are contraindicated [5].
Metamizole-induced agranulocytosis is a very rare, idiosyncratic, potentially fatal adverse reaction. It can occur at any time during treatment or shortly after discontinuation, is dose-independent and may arise even after uneventful prior use. Metamizole-induced agranulocytosis is characterised by abrupt, severe neutropenia with a high risk of infection, sepsis and death if not promptly recognised and treated.
Case example: Fatal metamizole-induced agranulocytosis. – This case was reported to Swissmedic as an individual case safety report (ICSR): An adult patient had been taking metamizole for several weeks to manage musculoskeletal pain. A few days after discontinuation, the patient presented to a primary care physician with symptoms including headache, sore throat and cold sweats. During the consultation, he suffered a cardiac arrest and was immediately resuscitated. Following initial stabilisation in hospital, investigations revealed severely reduced left ventricular ejection fraction (LVEF), right heart strain and no significant coronary artery disease. Laboratory findings indicated elevated inflammatory markers, impaired liver and kidney function and haematological aplasia. Further diagnostics revealed bilateral pulmonary infiltrates, left-sided otitis externa and a coated right tonsil. Despite intensive medical intervention, the patient progressed to septic shock and died the following day.
The affected blood cell lineages can decline within 24 hours. Early symptoms are non-specific (sore throat, fatigue, mucosal ulcers, with or without fever) and may be masked when metamizole is taken for febrile illness or together with antibiotics. At the first signs of infection or mucosal symptoms, metamizole must be stopped immediately and an urgent full blood count with differential obtained. Re-exposure is strictly contraindicated.
The reported incidence of metamizole-induced agranulocytosis varies by study design and population [6]. In a German statutory health insurance analysis, the reported risk of drug-induced agranulocytosis/neutropenia after metamizole prescription was 1:1602 [7]. This estimate likely overstates metamizole-induced agranulocytosis risk, because the outcome definition included neutropenia in addition to agranulocytosis and the proportion of patients with malignancies and chemotherapy was higher than in the control group [7]. In the Berlin Case-Control Surveillance Study, approximately 2 million defined daily doses (DDD) of metamizole were dispensed per metamizole-induced agranulocytosis case, corresponding to ~143,000 two-week courses at standard dosing or 0.96 cases per million population per year [8].
The pathophysiology of metamizole-induced agranulocytosis remains controversial; immune-mediated mechanisms and direct toxic/metabolic effects have been discussed [6, 9]. To date, no robust HLA association or genome-wide risk locus has been identified for metamizole-induced agranulocytosis [10, 11]. Reported case-fatality rates range from 5% to 23.6% [6], but early treatment with granulocyte colony-stimulating factor (e.g. filgrastim) can shorten the duration of neutropenia and is associated with improved clinical outcomes [12].
In a German retrospective analysis (1990−2012), ≥25% of metamizole-induced agranulocytosis cases were associated with off-label use: ~70% for mild-to-moderate pain and ~30% for first-line fever. Only 3.1% occurred within the licensed indication (high-grade fever unresponsive to other therapy), where recognition is particularly difficult because of symptom overlap [13]. A recent report confirmed a continued increase in off-label metamizole use [14].
This article describes metamizole utilisation in Switzerland, summarises post-marketing safety reporting on metamizole-induced agranulocytosis and outlines the rationale and scope of recently implemented regulatory measures. We additionally examined fatal metamizole-induced agranulocytosis individual case safety reports (ICSR) in VigiLyze to characterise frequently co-reported concomitant medicines and to screen for potential drug-drug interaction signals (e.g. methotrexate).
Exposure was defined as total DDD per calendar year across outpatient and inpatient distribution channels and all formulations. Aggregated national sales data were obtained from all marketing authorisation holders (MAH) of metamizole-containing medicinal products marketed in Switzerland, covering all dosage forms (tablets, drops, ampoules, suppositories) and the period 2014–2023. These data were provided as part of a regulatory procedure to characterise exposure and time trends. Sales data were converted to DDD using the WHO ATC/DDD assignment for metamizole (N02BB02; 3 g/day across oral, parenteral and rectal routes) [15]. Sales-based DDDs are a supply-based proxy and may be influenced by inventory dynamics (stocking, returns, wastage). Results are presented as market-level aggregates across MAHs.
Swissmedic collects and assesses ICSRs and transmits them to the Uppsala Monitoring Centre (UMC) for inclusion in VigiBase, the World Health Organization’s (WHO) global database of spontaneous safety reports. Data were retrieved from VigiBase via VigiLyze, the UMC web-based analysis interface. The primary analysis used Swiss ICSRs; global data were extracted for contextual comparisons. All extractions used the 27 August 2025 VigiLyze data snapshot.
Searches captured metamizole/dipyrone at ATC N02BB (class level) and required the drug to be recorded as suspect or interacting. Reactions were identified using the MedDRA SMQ “Agranulocytosis” (narrow) (MedDRA v28.0).
Fatal outcome status was taken as coded in VigiLyze. Potential duplicates were handled using UMC’s automated deduplication, supplemented by targeted manual review of remaining potential duplicates.
As with all spontaneous reporting systems, the data are subject to underreporting, variable report quality and missing information, and do not provide incidence estimates. Cross-country comparisons may be influenced by differences in exposure, reporting practices and case ascertainment.
Co-reporting was assessed in VigiLyze by reviewing the medication list of fatal Swiss metamizole-induced agranulocytosis ICSRs and flagging cases in which methotrexate was recorded as a concomitant drug (based on the ICSR drug-role field). For this analysis, we used the full Swiss fatal metamizole-induced agranulocytosis set irrespective of onset year (initial report dates 2011–2025; VigiLyze snapshot 27 August 2025) and compared it with the corresponding global fatal set.
Annual counts of Swiss spontaneous reports of metamizole-induced agranulocytosis and annual metamizole utilisation were summarised by calendar year. Utilisation was expressed in DDD. The utilisation-normalised reporting rate was calculated for each year as the number of metamizole-induced agranulocytosis reports divided by annual utilisation and expressed as reports per million DDD.
Time trends in utilisation-normalised reporting rates were assessed using ordinary least-squares linear regression with calendar year as the predictor and the annual utilisation-normalised reporting rate as the outcome (absolute change per year). For the regression slope, we report the point estimate and 95% confidence intervals (CI) derived from the slope estimate and its standard error using the t-distribution. Analyses were performed in Microsoft Excel 2024 (Microsoft Corporation, Redmond, WA, USA). Given the small number of annual observations, model fit and assumptions were assessed by visual inspection of the fitted trend and residual diagnostic plots; results should be interpreted descriptively.
Ethics approval was not required.
This work was conducted as part of a pharmacovigilance safety signal assessment to support regulatory risk-minimisation activities. No a priori study protocol was prepared, and the work was not registered in a public registry; protocol deviations are therefore not applicable.
All analyses were performed in Microsoft Excel 2024. No additional software libraries, frameworks or packages were used, and no standalone analytical scripts were developed; therefore, there is no analytical code to share.
Metamizole utilisation in Switzerland rose markedly over the past decade. Based on aggregated sales data, total DDD (see Methods) increased from 9,154,329 in 2014 to 16,410,403 in 2023 – an overall rise of ~79% (figure 1). Across 2014−2023, the cumulative formulation mix was 95.7% tablets/drops, 4.2% ampoules and 0.1% suppositories.
Figure 1Annual metamizole utilisation in Switzerland (2014–2023). Annual metamizole DDD estimated from aggregated national sales data (outpatient and inpatient), stratified by formulation (see Methods). The contribution from suppositories is too small to be visible at this y-axis scale.
Spontaneous ICSRs were retrieved from VigiBase (see Methods).
We identified 407 Swiss ICSRs of metamizole-induced agranulocytosis for 2014–2024, of which 31 (7.6%) were classified as fatal. For the methotrexate co-reporting analysis, we used a broader fatal set (2011–2025; n = 38); proportions are therefore calculated on 38.
Annual report counts increased from 13 (2014) to 57 (2024) with marked variability (median 36; range 13–57). The fatal fraction declined across periods: 13.5% (17/126) in 2014–2018, 5.8% (13/224) in 2019–2023 and 1.8% (1/57) in 2024 (figure 2). Case summaries showed no consistent age predominance. Co-reported methotrexate was noted in 39.5% (15/38) of Swiss fatal metamizole-induced agranulocytosis ICSRs in the full Swiss fatal set (initial dates 2011–2025) versus 19.8% (48/243) globally, suggesting a potential interaction signal but subject to confounding and reporting biases.
Figure 2Annual spontaneous reports of metamizole-induced agranulocytosis in Switzerland, 2014–2024. Source: VigiLyze (see Methods).
Internationally, Switzerland contributes a disproportionately high absolute number of cumulative metamizole-induced agranulocytosis reports compared with many larger countries (figure 3). Cross-country comparisons should be interpreted cautiously because exposure denominators and reporting practices differ.
Figure 3Cumulative global metamizole-induced agranulocytosis reports by country. Switzerland is highlighted in red. Source: VigiLyze (see Methods).
The utilisation-normalised reporting rate increased from 1.42 to 3.29 reports of metamizole-induced agranulocytosis per million DDD. Aggregated by period, rates were 2.25 per million DDD in 2014–2018 vs 2.93 in 2019–2023 (rate ratio 1.30). Fatal reporting rates remained low and trended downward (0.304 vs 0.170 per million DDD; rate ratio 0.56). Across 2014–2023, mean rates were 2.566 (total) and 0.249 (fatal) reports per million DDD.
When fitted by linear regression, the utilisation-normalised reporting rate of metamizole-induced agranulocytosis increased by 0.142 reports per million DDD per year (95% CI 0.031 to 0.253), whereas the fatal utilisation-normalised reporting rate showed a weak downward trend (-0.043 reports per million DDD per year; 95% CI -0.100 to 0.013), with no fatal reports in 2023 (figure 4).
Figure 4Annual Swiss utilisation-normalised reporting of metamizole-induced agranulocytosis (reports per million DDD), 2014–2023, with fitted linear trend lines. Denominator: total DDD from aggregated national sales (outpatient and inpatient). Reports: VigiLyze. Utilisation data were available to 2023 only (see Methods).
In response to rising metamizole exposure and persistent reports of metamizole-induced agranulocytosis in Switzerland, Swissmedic conducted a reassessment and introduced additional measures to mitigate metamizole-induced agranulocytosis risk, including:
In parallel, the EMA initiated a referral procedure for metamizole (Article 107i) [16]. Several recommendations of the Pharmacovigilance Risk Assessment Committee (PRAC) have already been incorporated into the Swiss prescribing information, notably:
The Swiss product information was further updated to include a boxed warning emphasising the risk of agranulocytosis and the importance of early symptom recognition, with specific guidance on the interaction between metamizole and methotrexate; co-administration should be avoided. This includes the instruction to discontinue metamizole and perform an immediate blood count if agranulocytosis is suspected, and to stop treatment pending results [17]. Indications were revised to reinforce appropriate use:
To enhance patient awareness, a red-framed statement was added to the outer packaging instructing patients to consult the leaflet before use.
A Direct Healthcare Professional Communication (DHPC) informed Swiss healthcare providers of these changes. A side-by-side summary of measures adopted by Swissmedic versus PRAC recommendations is provided in table 1.
Table 1Comparative summary of risk-minimisation measures and safety communications (EMA vs Swissmedic).
| Domain | Measure | Content | EMA | Swissmedic |
| Product information | Boxed warning | On metamizole-induced agranulocytosis | ✓ | ✓ |
| Avoid concomitant use with methotrexate | ✗ | ✓ | ||
| Therapeutic indications | More precise definition / restriction | ✗ | ✓ | |
| Contraindications | Clarified (history of metamizole-induced agranulocytosis, bone-marrow dysfunction, haematological disease) | ✓ | ✓ | |
| Warnings / Precautions | Strengthened information on agranulocytosis (early recognition, immediate FBC, stop treatment pending results) | ✓ | ✓ | |
| Interaction with methotrexate | ✗ | ✓ | ||
| Outer carton (secondary packaging) | Red-framed warning on outer carton | Directing patients to read the package leaflet | ✗ | ✓ |
| Safety communication | DHPC | ✓ * | ✓ [17] |
DHPC: Direct Healthcare Professional Communication.
* National implementation example (Germany): Federal Institute for Drugs and Medical Devices (BfArM) [18]
Between 2014 and 2023, metamizole utilisation in Switzerland increased markedly. Over the same period, both the absolute number of Swiss spontaneous metamizole-induced agranulocytosis reports and the utilisation-normalised reporting rate increased. Reporting activity thus expanded faster than utilisation, which may be compatible with intensified pharmacovigilance awareness and case-finding, and possibly with shifts in use patterns (e.g. more methotrexate co-medication).
In contrast, utilisation-normalised fatal reporting decreased over time and was very low towards the end of the observation period. The fatal proportion likewise declined. These patterns may be compatible with earlier recognition and improved management, and/or shifts in case mix; however, random variability, residual confounding and reporting biases cannot be excluded. Notably, methotrexate was more frequently co-reported in Swiss fatal cases than in the global fatal set, which may indicate a potential interaction signal, though confounding by indication (e.g. underlying malignancy, tumour pain) remains a plausible alternative explanation.
Switzerland’s comparatively large share of global metamizole-induced agranulocytosis reports may reflect robust national pharmacovigilance practices and infrastructure, rather than necessarily higher intrinsic risk. Spontaneous adverse drug reactions (ADR) are known to be substantially under-reported, including in general practice, which may contribute to differences in reporting completeness across settings [19]. Severe cases such as agranulocytosis often require hospital evaluation, which may increase the likelihood of recognition, laboratory confirmation and subsequent reporting. Computerised monitoring approaches using laboratory triggers and electronic health data have been described as tools that can support detection and reporting of ADRs [20]. Consistent with this, approximately 80% of Swiss national ICSRs originate from regional pharmacovigilance centres based at university hospitals (internal Swissmedic estimate), which may contribute to more complete documentation of serious ADRs such as agranulocytosis. Practically, the data are aligned with risk-minimisation priorities: restrict use to licensed/approved indications, counsel patients on early warning symptoms (with immediate discontinuation and urgent blood count at first signs) and avoid concomitant methotrexate; these measures are intended to maintain benefit while minimising preventable harm.
Regulatory assessments by EMA and Swissmedic concluded that, despite the established risk of agranulocytosis, the benefit–risk profile remains favourable when metamizole is used appropriately and action is taken promptly at first symptoms. Within the analgesic landscape, especially in patients at heightened risk from NSAIDs or opioids, in older adults or where alternative non-opioid analgesics are ineffective or unsuitable, metamizole remains an option with appropriate safeguards. The effectiveness of implemented measures should be evaluated using complementary indicators: pharmacovigilance trends (including severity), prescribing/exposure analyses, awareness/process metrics and clinical outcomes (hospitalisation, mortality). Risk-minimisation measures cannot eradicate an idiosyncratic event such as agranulocytosis; rather, they aim to reduce exposure outside approved indications and to avert severe outcomes through patient counselling, early detection and prompt clinical response.
If current measures prove insufficient, targeted regulatory or educational actions could be considered (e.g. tighter control of dispensing channels, prescriber education/certification or stricter initiation criteria). As one model, the Netherlands restricts oral metamizole to short-term use (≤14 days), initiated by a hospital-based pain specialist and dispensed via hospital/outpatient pharmacies [21, 22].
Finally, linking sales-based DDD to spontaneous reports is valuable for tracking signal evolution but does not establish incidence or risk. DDD aggregates reflect volumes dispensed, not person-time or treatment courses; spontaneous reports are subject to under- and differential reporting and incomplete clinical detail. Accordingly, utilisation-normalised reporting should be interpreted primarily as an indicator of pharmacovigilance activity, not a direct population risk estimate.
Metamizole utilisation increased alongside higher numbers of reported metamizole-induced agranulocytosis cases, while fatal outcomes in spontaneous reports declined. These findings describe reporting patterns but do not allow conclusions about true incidence or the effectiveness of risk minimisation measures. The data are consistent with continued access to metamizole alongside targeted risk-minimisation, ongoing patient counselling and continued pharmacovigilance, and event-triggered benefit–risk re-evaluation to sustain benefit while minimising preventable harm.
Deidentified, aggregated data supporting the findings (annual utilisation in DDD, annual Swiss metamizole-induced agranulocytosis report counts, utilisation-normalised reporting rates and a data dictionary) will be made available from the corresponding author upon reasonable request. Individual case-level spontaneous report data and company-level sales data are not publicly shareable due to database access restrictions and confidentiality obligations. Requests will be assessed for scientific purpose, feasibility and compliance with applicable permissions.
Spontaneous reporting data were accessed via VigiLyze. Data providers had no role in the study design, analysis, interpretation, manuscript preparation or the decision to submit. The views expressed are those of the authors and do not necessarily represent the positions of WHO, UMC or Swissmedic.
No external funding was received. This work was conducted as part of routine pharmacovigilance safety signal evaluation activities.
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflict of interest related to the content of this manuscript was disclosed. Aggregated sales/exposure data were provided by MAHs in the context of a pharmacovigilance safety signal evaluation; the MAHs had no role in study design, analysis, interpretation, manuscript preparation or the decision to submit.
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