Safety profile and potential clinical risks of xanomeline and trospium chloride: A real-world pharmacovigilance study using FAERS

Xanomeline and trospium chloride, the first FDA-approved oral cholinergic therapy for adults with schizophrenia in decades, represents a mechanistic shift in antipsychotic treatment, yet its real-world safety profile remains incompletely defined. Using the FDA Adverse Event Reporting System (FAERS), we conducted a retrospective pharmacovigilance study to characterize early postmarketing adverse events (AEs), prioritize clinically relevant signals, and assess subgroup heterogeneity and time-to-onset (TTO) patterns. We identified 1416 reports in which this combination was the primary suspected drug, comprising 2785 AE records. Disproportionality analyses were performed to assess drug-AE associations. The most prominent signal domain involved gastrointestinal disorders (n = 999, ROR 6.03, PRR 4.22, IC 2.08, EBGM 4.22). Beyond expected labeled events, unexpected signals such as tremor, suicidal ideation, and sedation were also observed. Clinical prioritization indicated that all signals were of low to moderate priority. Subgroup analyses largely preserved the overall safety profile, although some heterogeneity was observed across strata. Most AEs occurred within the first month of treatment (83.15%), with a median onset of 8 days, and onset was earlier in women than in men (6 vs 9 days, log-rank p = 0.0057). Weibull analyses consistently indicated an early-failure pattern, suggesting that risk decreased over time. Overall, the early postmarketing safety profile of xanomeline and trospium chloride was dominated by gastrointestinal intolerance and peripheral anticholinergic events, with additional neuropsychiatric, autonomic, and motor signals warranting continued monitoring, particularly early in treatment and in women and patients at increased risk of gastrointestinal or urinary complications.