Data Sheet 1_Adverse events profiles of pemetrexed: a Food and Drug Administration Adverse Event Reporting System.docx

BackgroundPemetrexed is a folate-pathway-targeting antineoplastic agent widely used in non-squamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma. We used the US Food and Drug Administration Adverse Event Reporting System (FAERS) to characterize pemetrexed-associated adverse events to inform clinical safety monitoring.
MethodsPemetrexed-related reports were retrieved from the FAERS database from first quarter of 2004 through the fourth quarter of 2024. All reports were coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. We performed descriptive analyses and disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical Bayes geometric mean (EBGM), and Bayesian confidence propagation neural network (BCPNN; information component [IC]) to identify safety signals. Statistical significance was defined as ROR >1 with the lower 95% confidence interval (CI) >1.
ResultsWe identified 27,098 pemetrexed-associated reports in the FAERS database (2004–2024), in which pemetrexed was designated as the primary suspect drug. Signal detection based on these reports identified 653 significant signals of disproportionate reporting (SDR) spanning 27 System Organ Classes (SOCs). The strongest signals occurred in Blood and Lymphatic Disorders (ROR = 7.31, 95% CI = 7.16–7.47) and Endocrine disorders (ROR = 4.09, 95% CI = 3.83–4.37), the latter representing unlabeled findings. In addition, we detected previously unlisted AEs, including colitis, oral lesions, immune-mediated pancreatitis, pulmonary toxicity, lung consolidation and tubulointerstitial nephritis. Sex stratification revealed male predominance in respiratory toxicity vs. female predisposition to renal injury. A bimodal time-to-onset distribution was observed: 52.57% of AEs occurred within 0–30 days post-treatment, with a secondary peak (6.63%) at 181–360 days.
ConclusionThis large pharmacovigilance study identifies signals of disproportionate reporting (SDRs) consistent with pemetrexed's established toxicities (e.g., myelosuppression, nephrotoxicity) and detects additional unlabeled safety signals, particularly immune-mediated endocrine, renal, and dermatologic manifestations. The bimodal onset pattern of these SDRs highlights clinically relevant monitoring windows, and observed sex- and age-related differences in SDR reporting suggest a need for individualized risk mitigation. These findings underscore the importance of vigilant surveillance for potential immune-mediated toxicities and adherence to vitamin supplementation protocols to manage hematologic risk. Prospective studies are needed to validate these reporting associations and clarify potential causality for these novel signals.