Postmarketing safety evaluation of pemetrexed using FAERS and JADER databases

Pemetrexed, a multi-target antifolate chemotherapeutic widely used in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), is associated with various adverse drug events (ADEs), some of which may be underrecognized in clinical trials. This study conducted a comprehensive pharmacovigilance analysis using two major spontaneous reporting systems-FAERS (2004Q1-2024Q3) and JADER (2007Q1-2024Q3)-to evaluate pemetrexed-related ADEs. Disproportionality analysis was performed using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Time-to-onset (TTO) patterns were assessed using Weibull distribution modeling. A total of 12,026 and 4,522 pemetrexed-related ADE reports were retrieved from FAERS and JADER, respectively. The most frequently reported ADEs included hematologic toxicities (anemia, neutropenia, thrombocytopenia), gastrointestinal disorders (nausea, vomiting, diarrhea), and renal impairment. Strong safety signals were consistently identified for these events. Notably, novel ADE signals such as hepatobiliary injury, endocrine dysfunction, and thromboembolic events were observed in both databases. Subgroup analyses revealed sex- and age-specific ADE patterns, with younger patients and males showing distinct toxicity profiles. Sensitivity analysis excluding combination therapies confirmed the robustness of primary signals. TTO analysis revealed that most ADEs occurred within the first two months after pemetrexed initiation, with a median TTO of 27 days and a predominance of early failure patterns (Weibull β < 1), highlighting the importance of close monitoring during early treatment. Rare but severe ADEs, including myocarditis, sepsis, cholestasis, and pseudocellulitis, were identified, several of which are not currently listed in official drug labeling. This study provides a comprehensive safety assessment of pemetrexed, confirming known toxicities and identifying new safety signals. Continuous pharmacovigilance is essential to optimize its clinical use and improve patient safety.