Postmarketing safety evaluation of pemetrexed using FAERS and JADER databases

Our plain-English summary of Postmarketing safety evaluation of pemetrexed using FAERS and JADER databases, by L. Lv, X. Wu, Y. Ren, et al (Scientific Reports, 2025).

The study

• Authors: L. Lv, X. Wu, Y. Ren, Y. Guo, H. Wang, X. Li
• Journal: Scientific Reports
• Published: 2025;15(1):18738
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2025. The Author(s).

In plain English

This study looked at the safety of pemetrexed, a chemotherapy drug used for non-small cell lung cancer and malignant pleural mesothelioma. It did not study asbestos exposure. The authors searched two drug side-effect reporting databases, the US FAERS (2004 to 2024) and Japan's JADER (2007 to 2024), and found 12,026 and 4,522 reports involving pemetrexed. They used statistical methods that flag side effects reported unusually often with a drug. In FAERS the most-reported problems were anemia (701 reports), pancytopenia (649) and nausea (644). In JADER the most-reported was interstitial lung disease (677). FAERS produced 400 signals and JADER 58, with 35 found in both. Signals not listed on the drug label included sepsis, myocarditis, hypothyroidism and cholestasis. Among 4,928 FAERS reports with usable dates, the median time to the side effect was 27 days. The authors concluded that the data confirmed known blood, gut and kidney toxicities and suggested new signals. They noted that these reports can be incomplete, cannot establish cause, and often involve other cancer drugs given at the same time. The article gives no results specifically for mesothelioma patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective pharmacovigilance (disproportionality) study of spontaneous adverse-event reports in two databases, plus a time-to-onset analysis
• Who was studied: 12,026 adverse drug event reports from the US FDA FAERS database (Q1 2004 to Q3 2024) and 4,522 from Japan's JADER database (Q1 2007 to Q3 2024), with pemetrexed as the primary suspect drug. The most common reported indication was non-small cell lung cancer.
• Exposure: The chemotherapy drug pemetrexed (brand name Alimta). This is not a study of asbestos exposure.
• Main results:
  • In FAERS, the most frequently reported side effects were anemia (701 reports, 1.83%), pancytopenia (649, 1.70%) and nausea (644, 1.69%)
  • In JADER, the most frequently reported side effect was interstitial lung disease (677 reports, 7.3%)
  • 400 side-effect signals met all positive thresholds in FAERS and 58 in JADER; 35 appeared in both databases
  • At the organ-system level in FAERS, the strongest signal was blood and lymphatic system disorders (ROR 6.72, 95% CI 6.5 to 6.94); in JADER only endocrine disorders (ROR 2.52, 95% CI 2.27 to 2.79) met all four thresholds
  • In FAERS, pseudocellulitis had few reports but a very high signal strength (45 reports, ROR 746.23, 95% CI 519.47 to 1071.97)
  • In FAERS, the authors identified signals not listed on the drug label, including sepsis, respiratory failure, electrolyte imbalance, myocarditis, gastrointestinal perforation, hypothyroidism and cholestasis
  • After excluding reports in which other drugs were given at the same time, 1,124 reports remained; signals that persisted included pancytopenia, pneumonia, febrile neutropenia, neutropenia, thrombocytopenia, anemia, renal failure, pleural effusion and erysipelas
  • Among 4,928 FAERS reports (41.0%) with valid timing data, the median time from starting pemetrexed to the side effect was 27 days (interquartile range 7 to 84 days)
  • The Weibull analysis of FAERS timing data showed an early-failure pattern (upper limit of the 95% CI of the shape parameter 0.70, below 1), meaning the reported likelihood of a side effect decreased over time
  • In FAERS reports, recorded outcomes included hospitalization (3,902 reports, 32.4%) and death (2,597 reports, 21.6%)
• The authors' conclusion: The authors concluded that the findings confirm known hematologic, gastrointestinal and renal toxicities of pemetrexed and identify novel safety signals such as cardiac disorders, endocrine dysfunction and thromboembolic events, which need further clinical study to validate.
• Limitations the authors state:
  • Spontaneous reports may be incomplete or inaccurate, which may introduce bias
  • The databases cannot establish that pemetrexed caused the reported events
  • Pemetrexed is usually given with other drugs, so attributing effects to pemetrexed alone is difficult even with the sensitivity analysis
  • Data came mainly from the US and Japan, which may limit generalizability to other populations
  • Too few JADER reports had timing data, so the time-to-onset analysis used FAERS only

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Antifolate, Non-Small Cell Lung Cancer, Pleural Mesothelioma, Clinical Trial, Odds Ratio, Neutropenia.

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• Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model — F. Sonvico, S. Barbieri, et al. (2018)
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• Safety of indwelling pleural catheter use in patients undergoing chemotherapy: a five-year retrospective evaluation — C.C. Hak, P. Sivakumar, et al. (2016)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)

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