Global Characterization of Fluorouracil-Induced Oral Mucositis: A Disproportionality Analysis and Signal Detection Study Using FAERS and EudraVigilance Databases

Abstract

Background: Oral mucositis (OM) is a debilitating dose-limiting toxicity of fluorouracil (5-FU) chemotherapy. Despite its clinical prevalence, large-scale real-world evidence characterizing its onset, demographic risk factors, and signal strength across global populations remains limited. This study aims to evaluate the safety profile of 5-FU-related OM using two major spontaneous reporting databases.

Methods: We conducted a retrospective pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) and EudraVigilance (EV) databases (2004–2025). Disproportionality was assessed using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM). Time-to-onset (TTO) and subgroup analyses by age and sex were performed to identify clinical risk modifiers.

Results: In the FAERS database, 512 reports of 5-FU-related OM were identified, with peaks in 2013 and 2019. The majority of cases involved geriatric patients (≥65 years, 40.23%) and were classified as serious adverse events (95.51%). The median TTO was 13.50 days (IQR: 6.00–36.00), with 68.06% of events occurring within the first 30 days. Strong signals were detected for "Stomatitis" (ROR: 7.02) and "Hemorrhagic stomatitis" (ROR: 15.34). Parallel analysis in EudraVigilance (N = 1,107) corroborated these findings, highlighting significant associations for "Mucosal erosion" and "Aphthous ulcer" specifically in the elderly population.

Conclusion: Our findings confirm that 5-FU-induced oral mucosal toxicity is a high-severity event with a distinct early-onset pattern. Elderly patients represent the highest risk group. Proactive oral care and monitoring are critical during the first month of therapy, particularly around the second week post-administration.