Frontiers in pharmacology · 2026
Adverse reactions of immune checkpoint inhibitors combined with acetaminophen/non-steroidal anti-inflammatory drugs (NSAIDs): a pharmacovigilance analysis of drug-drug interactions.
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Ren Xiayang, Xue Lihui, Wang Yanfeng, Xiao Jian
Аннотация
BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with acetaminophen (APAP) and non-steroidal anti-inflammatory drugs (NSAIDs) is commonly employed in cancer treatment. However, potential drug-drug interactions (DDIs) between these agents remain poorly understood. Our study aimed to identify interaction signals associated with the concomitant use of ICIs and APAP/NSAIDs.
METHODS: Data were obtained from the US FDA Adverse Event Reporting System (FAERS) covering the period from 1 January 2014, to 30 June 2025. Disproportionality analysis was conducted for data mining by calculating the reporting odds ratio and 95% confidence interval (95% CI). Adjusted RORs were analyzed using logistic regression, accounting for age, sex, and reporting year. Further confirmation was performed using both additive and multiplicative models.
RESULTS: We identified 4,613 reports related to the combination of immune checkpoint inhibitors (ICIs) with acetaminophen (APAP) and non-steroidal anti-inflammatory drugs (NSAIDs). Significant interaction signals were observed for gastrointestinal disorders (adjusted ROR: 1.57, 95% CI: 1.41-1.70, additive model: 0.0549), investigations (adjusted ROR: 1.27, 95% CI: 1.13-1.43, additive model: 0.3847, multiplicative model: 1.3135), renal and urinary disorders (adjusted ROR: 4.68, 95% CI: 4.19-5.24, additive model: 3.5771, multiplicative model: 3.6312), and skin and subcutaneous tissue disorders (adjusted ROR: 1.64, 95% CI: 1.47-1.83, additive model: 0.6818, multiplicative model: 1.5996). Subset analysis revealed positive interaction signals for the combination of ICIs with APAP in gastrointestinal disorders and investigations, for all APAP/NSAIDs combinations with ICIs in renal and urinary disorders, and for the combination of NSAIDs with ICIs in skin and subcutaneous tissue disorders.
CONCLUSION: Based on data from the FAERS, four systemic disorders were identified to be associated with drug-drug interactions (DDIs) resulting from the combined use of ICIs and APAP/NSAIDs. Further preclinical trials and well-designed, large-scale clinical studies are needed to explore the potential pharmacodynamic crosstalk, alterations in inflammatory pathway and changes in the tumor immune microenvironment induced by the co-administration of ICIs with APAP/NSAIDs. This will help deepen the understanding of DDIs associated with this combination therapy.
METHODS: Data were obtained from the US FDA Adverse Event Reporting System (FAERS) covering the period from 1 January 2014, to 30 June 2025. Disproportionality analysis was conducted for data mining by calculating the reporting odds ratio and 95% confidence interval (95% CI). Adjusted RORs were analyzed using logistic regression, accounting for age, sex, and reporting year. Further confirmation was performed using both additive and multiplicative models.
RESULTS: We identified 4,613 reports related to the combination of immune checkpoint inhibitors (ICIs) with acetaminophen (APAP) and non-steroidal anti-inflammatory drugs (NSAIDs). Significant interaction signals were observed for gastrointestinal disorders (adjusted ROR: 1.57, 95% CI: 1.41-1.70, additive model: 0.0549), investigations (adjusted ROR: 1.27, 95% CI: 1.13-1.43, additive model: 0.3847, multiplicative model: 1.3135), renal and urinary disorders (adjusted ROR: 4.68, 95% CI: 4.19-5.24, additive model: 3.5771, multiplicative model: 3.6312), and skin and subcutaneous tissue disorders (adjusted ROR: 1.64, 95% CI: 1.47-1.83, additive model: 0.6818, multiplicative model: 1.5996). Subset analysis revealed positive interaction signals for the combination of ICIs with APAP in gastrointestinal disorders and investigations, for all APAP/NSAIDs combinations with ICIs in renal and urinary disorders, and for the combination of NSAIDs with ICIs in skin and subcutaneous tissue disorders.
CONCLUSION: Based on data from the FAERS, four systemic disorders were identified to be associated with drug-drug interactions (DDIs) resulting from the combined use of ICIs and APAP/NSAIDs. Further preclinical trials and well-designed, large-scale clinical studies are needed to explore the potential pharmacodynamic crosstalk, alterations in inflammatory pathway and changes in the tumor immune microenvironment induced by the co-administration of ICIs with APAP/NSAIDs. This will help deepen the understanding of DDIs associated with this combination therapy.