Real-World Safety Profile of Xanomeline-Trospium (Cobenfy), the First Muscarinic Agonist Antipsychotic: A Disproportionality Analysis of the FDA Adverse Event Reporting System
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2026
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| author | Farquhar, Hayden |
| author_facet | Farquhar, Hayden |
| contents | <p><strong>Background:</strong> Xanomeline-trospium (Cobenfy), the first antipsychotic with a non-dopaminergic mechanism approved in over 30 years, received FDA approval for schizophrenia in September 2024. We characterised its post-marketing safety profile using pharmacovigilance signal detection and active-comparator analyses against six D2 antagonist antipsychotics.</p> <p><strong>Methods:</strong> We conducted a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS), Q4 2024 to Q4 2025, using a four-method battery (ROR, PRR, IC, EBGM) with consensus defined as positivity on three or more methods. Active-comparator analyses used Bonferroni-corrected ROR against olanzapine, risperidone, aripiprazole, quetiapine, lurasidone, and brexpiprazole. Time-to-onset, E-value, polypharmacy sensitivity, and disease-manifestation classification analyses were performed. Pre-registered on OSF (doi:10.17605/OSF.IO/2PWUD). Reported per READUS-PV.</p> <p><strong>Findings:</strong> Among 1,808,859 deduplicated FAERS cases, 1,423 listed xanomeline-trospium as suspect. We identified 56 consensus signals (37 pharmacological, 19 disease manifestations). Dominant signals were gastrointestinal (nausea ROR 7.5, vomiting 8.4, constipation 6.5) and muscarinic/anticholinergic (urinary retention 44.0, drooling 61.0, dry mouth 6.2). Weight gain (ROR 0.10-0.14 vs all comparators), EPS, metabolic events, and hyperprolactinaemia were significantly lower. All events were early-onset (Weibull beta < 1, median 0-3 days). E-values for 46/56 signals exceeded 3.0.</p> <p><strong>Interpretation:</strong> The post-marketing safety profile confirms the expected mechanistic trade-off: gastrointestinal and cholinergic burden in exchange for markedly reduced metabolic and extrapyramidal liability. Drooling and urinary retention warrant targeted monitoring.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_19627308 |
| institution | Zenodo |
| language | eng |
| publishDate | 2026 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Real-World Safety Profile of Xanomeline-Trospium (Cobenfy), the First Muscarinic Agonist Antipsychotic: A Disproportionality Analysis of the FDA Adverse Event Reporting System Farquhar, Hayden xanomeline-tropsium Cobenfy KarXT pharmacovigilance FAERS disproportionality analysis schizophrenia antipsychotic muscarinic agonist adverse drug reactions post-marketing surveillance active comparator reporting odds ratio <p><strong>Background:</strong> Xanomeline-trospium (Cobenfy), the first antipsychotic with a non-dopaminergic mechanism approved in over 30 years, received FDA approval for schizophrenia in September 2024. We characterised its post-marketing safety profile using pharmacovigilance signal detection and active-comparator analyses against six D2 antagonist antipsychotics.</p> <p><strong>Methods:</strong> We conducted a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS), Q4 2024 to Q4 2025, using a four-method battery (ROR, PRR, IC, EBGM) with consensus defined as positivity on three or more methods. Active-comparator analyses used Bonferroni-corrected ROR against olanzapine, risperidone, aripiprazole, quetiapine, lurasidone, and brexpiprazole. Time-to-onset, E-value, polypharmacy sensitivity, and disease-manifestation classification analyses were performed. Pre-registered on OSF (doi:10.17605/OSF.IO/2PWUD). Reported per READUS-PV.</p> <p><strong>Findings:</strong> Among 1,808,859 deduplicated FAERS cases, 1,423 listed xanomeline-trospium as suspect. We identified 56 consensus signals (37 pharmacological, 19 disease manifestations). Dominant signals were gastrointestinal (nausea ROR 7.5, vomiting 8.4, constipation 6.5) and muscarinic/anticholinergic (urinary retention 44.0, drooling 61.0, dry mouth 6.2). Weight gain (ROR 0.10-0.14 vs all comparators), EPS, metabolic events, and hyperprolactinaemia were significantly lower. All events were early-onset (Weibull beta < 1, median 0-3 days). E-values for 46/56 signals exceeded 3.0.</p> <p><strong>Interpretation:</strong> The post-marketing safety profile confirms the expected mechanistic trade-off: gastrointestinal and cholinergic burden in exchange for markedly reduced metabolic and extrapyramidal liability. Drooling and urinary retention warrant targeted monitoring.</p> |
| title | Real-World Safety Profile of Xanomeline-Trospium (Cobenfy), the First Muscarinic Agonist Antipsychotic: A Disproportionality Analysis of the FDA Adverse Event Reporting System |
| topic | xanomeline-tropsium Cobenfy KarXT pharmacovigilance FAERS disproportionality analysis schizophrenia antipsychotic muscarinic agonist adverse drug reactions post-marketing surveillance active comparator reporting odds ratio |
| url | https://doi.org/10.5281/zenodo.19627308 |