Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain
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Published on: November 8, 2015
Miguel-Ángel Maciá-Martínez1, Belén Castillo-Cano2, Patricia García-Poza2
1Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain. mmacia@aemps.es.
Purpose:
We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).
Methods:
A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).
Results:
The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID.
Conclusions:
Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.
Insights
Metamizole use was associated with a higher risk of agranulocytosis compared to non-steroidal anti-inflammatory drugs (NSAIDs). While rare, this serious adverse drug event necessitates careful consideration of metamizole
Area of Science:
- Pharmacovigilance and Pharmacoepidemiology
- Drug Safety and Risk Assessment
- Hematology and Immunology
Background:
- Metamizole is an analgesic and antipyretic medication with known risks of serious adverse events.
- Agranulocytosis, a severe reduction in white blood cells, is a rare but critical side effect associated with certain medications, including metamizole.
- Understanding the comparative risk of agranulocytosis between metamizole and other analgesics like NSAIDs is crucial for clinical decision-making and patient safety.
Purpose of the Study:
- To estimate the absolute incidence and relative hazard ratio (HR) of agranulocytosis associated with metamizole compared to non-steroidal anti-inflammatory drugs (NSAIDs).
- To assess the risk of agranulocytosis using different analytical approaches, including varying the assumed onset date of the event.
- To investigate the association between metamizole and hospitalized neutropenia as a secondary outcome.
Main Methods:
- A large cohort study was conducted using the BIFAP database in Spain, including new users of metamizole and NSAIDs aged 2 years or older from 2005 to 2022.
- Patients were followed from their first dispensation until treatment cessation to identify hospitalizations for idiosyncratic agranulocytosis.
- Incidence rates and adjusted hazard ratios were calculated, with sensitivity analyses performed by varying the agranulocytosis onset date and using opioids-paracetamol as a negative control.
Main Results:
- The study included over 440,000 metamizole users and over 3.8 million NSAID users.
- Agranulocytosis was rare, with 21 cases identified after the first week of treatment.
- The hazard ratio for agranulocytosis associated with metamizole versus NSAIDs was 7.20 (95% CI: 1.92-26.99) when using hospitalization date and 4.40 (95% CI: 0.90-21.57) when assuming onset 7 days prior. Metamizole showed a higher risk of neutropenia (HR: 2.98 [1.57-5.65] vs NSAID).
Conclusions:
- Agranulocytosis is a rare but significantly more common adverse event with metamizole than with other analgesics like NSAIDs.
- The precise risk estimation for metamizole-induced agranulocytosis was limited by its lower usage compared to comparators.
- An increased risk of hospitalized neutropenia supports a link between metamizole and severe hematological events, though specific triggers remain unidentified.
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