Exploring ifosfamide-related central nervous system adverse events based on the FAERS database and clinical feature analysis of cases
Abstract
Ifosfamide, an alkylating agent used to treat various malignancies, has limited real-world safety data on neurotoxicity. Therefore, this study analyzed ifosfamide-related Central Nervous System Adverse Events (CNS AEs) to provide a reference for drug risk management. The disproportionality study was performed leveraging the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2024. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Information Component (IC) were applied to identify and evaluate potential CNS AEs associated with ifosfamide. The Weibull distribution was applied to characterize the risk of AEs over time. Case reports from PubMed and SpringerLink were reviewed to summarize the clinical characteristics of these AEs. This study identified 786 reports of ifosfamide-related CNS AEs. Disproportionality analysis revealed encephalopathy as the strongest signal (n=252, ROR = 101.19). Six label-unlisted adverse events were also identified, including brain oedema, hydrocephalus, spinal cord compression, cerebral ischemia, gaze palsy, and Guillain-Barré syndrome. The time-to-onset analysis revealed an early failure pattern with a median onset of 2 days after drug exposure. Brain oedema exhibited the highest mortality rate (83.33%). Subgroup analysis suggested greater susceptibility to encephalopathy in female patients and to confusion and coma in elderly patients. The systematic case review included 61 cases from 42 articles, involving patients aged 3–77 years. Therein, 46 (75.41%) cases experienced central neurotoxic reactions after receiving one to three cycles of ifosfamide-containing chemotherapy and the common clinical symptoms included impaired consciousness, hallucinations, seizures, delirium, disorientation, and various psychiatric or behavioral abnormalities. This study corroborates clinical observations by systematically characterizing the features of ifosfamide-related CNS toxicity and identifying potentially label-unlisted AEs, supporting further validation in prospective epidemiological studies.