Safety of Nirmatrelvir/Ritonavir in Pediatrics and Adolescents: Pharmacovigilance Study of VigiBase

Objective: Nirmatrelvir/Ritonavir (Paxlovid) has become a standard oral antiviral for treatment of COVID-19.In December 2021, the United States Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for adults and adolescents aged 12 years and 40 kg.However, New Drug Application (NDA) approval in May 2023 restricted use to adults aged 18 years due to limited data in younger populations.This study aimed to evaluate the safety of Nirmatrelvir/Ritonavir in pediatrics and adolescents using VigiBase.Methods: A disproportionality analysis was performed based on individual case safety reports (ICSRs), stratified by age (<18 and 18 years).The following Adverse events of interest, listed in the FDA label, were analyzed: hypersensitivity, hepatotoxicity, neurological/sensory, gastrointestinal, and vascular disorders.Logistic regression model was used to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs), adjusted for sex.Results: As of December 2024, 45,307 Nirmatrelvir/Ritonavir-related ICSRs were reported, including 231 (0.5%) in patients <18 years.Significant signals were observed in this group for hepatotoxicity (ROR 2.43; 95% CI 1.91-3.07)and neurological/sensory disorders (ROR 4.64; 95% CI 3.25-6.63).In the within-age group comparison, hepatotoxicity showed approximately threefold higher disproportionality (ROR 3.38; 95% CI 2.66-4.29),whereas the adult-only analysis showed no signal (ROR 0.79; 95% CI 0.77-0.81).Gastrointestinal signals appeared only in adults, while hypersensitivity and vascular disorders showed no signals in either group.Conclusion: This global pharmacovigilance study using VigiBase provides real-world data regarding safety signals on Nirmatrelvir/Ritonavir in younger populations.The observed hepatotoxicity signal in pediatrics and adolescents suggests the need to further evaluate dose appropriateness.Further research, including EPIC-Peds and continued pharmacovigilance, is warranted, as these findings should be interpreted as hypothesis-generating.(PeRM 2026;18:61-76)