Comparative Pharmacovigilance Analysis of Methotrexate-Associated Adverse Drug Reactions Using EudraVigilance, DAEN, and Canada Vigilance Databases

Abstract Background: Methotrexate is a cornerstone antineoplastic agent associated with serious adverse events including myelosuppression, hepatotoxicity, and nephrotoxicity. Comparative safety data across EudraVigilance, DAEN, and Canada Vigilance remain limited. Objective: To characterize and compare the adverse drug reaction (ADR) profile of methotrexate using spontaneous reports from three international pharmacovigilance databases. Methods: ADR reports for Methotrexate in all indications were extracted from EudraVigilance 01-May-2025 to 20-Jun-2025, DAEN 01-Jul-2025 to 31-Mar-2026, and Canada Vigilance 01-Jan-2026 to 31-Mar-2026. Reports in which methotrexate was identified as the suspect drug across all therapeutic indications were included. The most frequently reported adverse events included pancytopenia, febrile neutropenia, hepatotoxicity, Drug intoleranceand acute kidney injury. Results : A total of 1057 methotrexate cases were identified: DAEN n=217, Canada n=798, EV n=42. Demographics from DAEN: 37% aged 18-64, 36% >65, 48% female. Top ADRs in DAEN: Acute Liver Injury (n=15), Toxicity (n=10), Sepsis (n=8), 9 fatal reports. Top ADRs in Canada: Febrile Neutropenia, Pancytopenia, Mucositis, Hepatotoxicity, 17 fatal reports. Top ADRs in EV: Nausea (n=24), Pancytopenia (n=11), Oral Herpes (n=10), 1 fatal report. The most frequently reported adverse events across the three databases were pancytopenia, febrile neutropenia, hepatotoxicity, mucositis, and acute kidney injury, and recorded 27 fatal reports. Conclusions: This three-database analysis reveals consistent reporting patterns for myelosuppression and infections across regions, with database-specific variations in renal and hepatic toxicity. These findings support enhanced monitoring and region-specific risk minimization for methotrexate in every indication. Future studies with access to individual case-level data should evaluate disproportionality signals to further characterize methotrexate safety across regions.