Cobenfy Dosing for Schizophrenia
Cobenfy (xanomeline-trospium) is dosed at 50 mg/20 mg twice daily initially, with titration up to the target dose of 125 mg/30 mg twice daily for the treatment of schizophrenia in adults. 1
Initial Dosing and Titration
- Start with 50 mg xanomeline/20 mg trospium twice daily for the first week to allow for tolerability assessment 1
- Titrate to the target maintenance dose of 125 mg xanomeline/30 mg trospium twice daily after the initial titration period 1, 2
- The medication should be administered twice daily (morning and evening) to maintain therapeutic levels 1
Mechanism and Rationale
- Xanomeline acts as a dual muscarinic-1 and muscarinic-4 preferring receptor agonist, providing a novel mechanism distinct from traditional dopamine-blocking antipsychotics 1
- Trospium chloride is included specifically to reduce peripheral cholinergic adverse events associated with xanomeline, allowing for higher therapeutic doses of the active muscarinic agonist 2, 3
- This combination represents a planned therapeutic drug interaction where the second agent (trospium) reduces adverse effects of the first agent (xanomeline) 3
Efficacy Data at Target Dose
- At the 125 mg/30 mg twice daily dose, Cohen's d effect size was approximately 0.60 for the primary endpoint in phase 3 trials 1
- Patients achieved significant reductions in PANSS positive and negative subscales, PANSS Marder negative factors, and CGI-S scores compared to placebo 1
- In long-term studies, more than 75% of participants achieved >30% improvement on PANSS total score after 52 weeks, with a mean decrease of 33.3 points 1
Tolerability Profile
- The medication was well-tolerated with most adverse events rated as mild-to-moderate across all clinical trials 1
- The inclusion of trospium specifically addresses the peripheral cholinergic side effects that would otherwise limit xanomeline dosing 2
- Patients previously on placebo who switched to active treatment showed statistically significant improvement on all efficacy measures starting at week 2, indicating relatively rapid onset of benefit 1
Clinical Considerations
- Do not use lower maintenance doses as the 125 mg/30 mg twice daily regimen demonstrated optimal efficacy in pivotal trials 1
- The twice-daily dosing schedule must be maintained to ensure consistent muscarinic receptor engagement throughout the day 1
- This represents the first FDA-approved non-dopaminergic treatment for schizophrenia, offering an alternative for patients who experience intolerable dopamine-related adverse effects from traditional antipsychotics 2