This study utilized the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate safety signals for pemetrexed between the first quarter of 2004 and the fourth quarter of 2024. The analysis included 27,098 reports involving patients with non-squamous non-small cell lung cancer and malignant pleural mesothelioma. The primary outcome was the identification of signals of disproportionate reporting (SDRs), with statistical significance defined as a Reporting Odds Ratio (ROR) greater than 1 and a lower 95% confidence interval (CI) greater than 1.
Strongest signals were observed for 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). Additional adverse events included colitis, oral lesions, immune-mediated pancreatitis, pulmonary toxicity, lung consolidation, and tubulointerstitial nephritis. The time-to-onset of adverse events showed a bimodal distribution, with 52.57% occurring within 0–30 days and 6.63% occurring between 181–360 days. Sex stratification revealed a male predominance in respiratory toxicity and a female predisposition in renal injury.
Serious adverse events, discontinuations, and specific tolerability metrics were not reported in this observational dataset. The study notes that prospective studies are needed to validate these reporting associations and clarify potential causality for these novel signals. Associations are based on reporting patterns rather than confirmed clinical incidence.
Practice relevance emphasizes vigilant surveillance for potential immune-mediated toxicities and adherence to vitamin supplementation protocols to manage hematologic risk. Clinicians should interpret these findings as reporting associations and avoid overstating causality until prospective validation is available.
View Original Abstract ↓
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.
