Gastrointestinal adverse reactions and metabolism-nutrition disorders associated with hypomethylating agents: a pharmacovigilance study with exploratory mechanistic analysis.

Background: Hypomethylating agents, particularly azacitidine and decitabine, are widely used for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Gastrointestinal adverse events and metabolism- and nutrition-related disorders may compromise nutritional intake, metabolic homeostasis, treatment tolerance, and clinical outcomes. However, real-world evidence regarding these safety profiles remains limited. Objective: This study aimed to characterize gastrointestinal and metabolism- and nutrition-related adverse event reporting signals associated with azacitidine and decitabine, examine cross-database signal consistency, assess exploratory time-to-onset patterns, and explore potential mechanistic clues. Methods: FAERS reports from database inception through 2025 Q4 were analyzed for azacitidine and decitabine recorded as suspected drugs. Disproportionality was assessed at the preferred-term level using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. Selected signals were examined in the Canada Vigilance database for cross-database signal consistency. Exploratory time-to-onset patterns were evaluated using Weibull modeling among reports with valid date information, and network toxicology was conducted as a hypothesis-generating analysis. Results: Fourteen thousand two hundred sixteen azacitidine-related reports and 3,591 decitabine-related reports were included. Neutropenic colitis showed the strongest gastrointestinal disproportionality signal for azacitidine and decitabine, with reporting odds ratios of 23.65 and 26.05, respectively. Tumor lysis syndrome was the most prominent metabolism- and nutrition-related signal, with 165 azacitidine-related reports and 47 decitabine-related reports. Both signals showed consistent disproportional reporting patterns in the Canada Vigilance database. Additional signals included iron overload, hypoalbuminemia, electrolyte disturbances, cachexia, failure to thrive, and decreased appetite. Time-to-onset analysis suggested an early reporting tendency among reports with valid date information. Exploratory network toxicology identified 45 common targets, including Conclusion: Azacitidine and decitabine showed clinically relevant gastrointestinal, metabolic, and nutrition-related disproportionality reporting signals in spontaneous reporting databases. Early monitoring of gastrointestinal symptoms, electrolyte balance, tumor lysis indicators, albumin levels, appetite, and iron metabolism may support nutritional risk management and individualized supportive care in patients receiving hypomethylating agents.