Agranulocytosis associated with metamizole among EudraVigilance reports involving methotrexate for rheumatoid arthritis

Abstract

Methotrexate (MTX) can induce adverse drug reactions (ADRs) including severe haematotoxic events. This study analyses whether agranulocytosis is disproportionately reported in spontaneous reports involving MTX for rheumatoid arthritis (RA) when use of metamizole, a non-opioid analgesic, which itself has been associated with agranulocytosis, is recorded additionally. Using the EudraVigilance database, we analyzed spontaneous reports of suspected ADRs associated with MTX for RA and including any comedication (from Europe, until 2022). We (i) compared characteristics of reports stratified by metamizole use and the occurrence of agranulocytosis and (ii) performed disproportionality analyses estimating reporting odds ratios (RORs) and 95% confidence intervals (CIs) of agranulocytosis associated with metamizole. We included 7,213 reports with recorded use of MTX for RA (72.1% female, median age: 64 years, 11.3% with an agranulocytosis, 1.7% with metamizole use). Compared to reports with other comedication, metamizole users were older and more often received also other analgesics such as opioids (27.3% vs. 8.9%) while treatment with additional disease-modifying anti-rheumatic drugs (DMARDs) was less common (34.7% vs. 62.2%). Agranulocytosis was disproportionately recorded in reports also involving metamizole (ROR: 9.8; 95% CI: 6.8-14.1). The ROR decreased after adjusting for age, sex, other analgesics and DMARDs (ROR: 5.5; 95% CI: 3.6-8.6). The highest ROR was found in individuals aged 80 + . Our study supports regulatory warnings that a concurrent administration of metamizole can increase the haematotoxic effect of MTX and should therefore be avoided. A sufficient RA therapy might decrease the need for analgesics and should be aimed at also in older RA patients.