Background: Rabeprazole is a widely used proton pump inhibitor whose long-term safety profile warrants further investigation. Based on the FAERS database, we systematically evaluated rabeprazole-associated adverse events (AEs). Methods: Data were extracted from FAERS (2004Q1 – 2025Q2), and four disproportionality methods including ROR, PRR, BCPNN and EBGM were applied for signal detection. Furthermore, we also conducted subgroup analyses by gender and patient outcomes, and evaluated the time to onset of AEs. Results: Among 3,696 rabeprazole-related cases, serious outcomes account for 59.9% of cases, including 6.4% fatalities. Females reported more AEs (45.7% vs 28.7%) with earlier onset (median 10 vs. 15 days, p=0.00054). Renal and urinary disorders were the only System Organ Class (SOC) meeting all signal criteria, showing significant associations with tubulointerstitial nephritis, acute kidney injury, and renal failure, which frequently associated with serious or fatal outcomes. Other notable signals involved gastrointestinal disorders (e.g., gastric/duodenal polyps, hemorrhagic enterocolitis), skin and subcutaneous tissue disorders (e.g., erythema multiforme, drug eruption), metabolism and nutrition disorders (e.g., hypomagnesemia, hypocalcemia, vitamin B 12 deficiency), respiratory and neurological AEs. Several rare but strong signal such as leukocyte adhesion deficiency (n = 3; ROR = 1103.35, 95% CI: 321.44–3787.3) were also detected. Conclusion: This study identifies multi-system safety signals for rabeprazole, notably delayed renal toxicity and early gastrointestinal or cutaneous reactions. Long-term users require regular monitoring of renal function, electrolytes and vitamin B 12, with prompt drug withdrawal upon serious adverse events. While FAERS provides critical real-world evidence, its inherent limitations necessitate further validation through prospective studies.
