What is the safe management of Xanomaline?

Safe Management of Xanomeline-Trospium (Cobenfy™)

Xanomeline-trospium is a newly FDA-approved first-in-class muscarinic agonist for schizophrenia that requires careful dose titration, monitoring of cholinergic side effects, and strategic management of concomitant medications to maximize efficacy while ensuring tolerability. 1, 2

Dosing and Titration

• Start at xanomeline 50 mg/trospium 20 mg twice daily and titrate to maximum dose of 125 mg/30 mg twice daily over approximately one week 3, 2
• The medication was studied with rapid titration in inpatient settings, but outpatient initiation requires slower, more cautious dose escalation based on tolerability 4
• Administer with food to reduce gastrointestinal side effects 4

Monitoring Cholinergic vs. Anticholinergic Effects

The key to safe management is tracking the balance between central cholinergic activation (from xanomeline) and peripheral anticholinergic blockade (from trospium): 4

Cholinergic Side Effects (indicating excess xanomeline activity):

• Nausea (19.2% vs 1.6% placebo) 3
• Vomiting (16.0% vs 0.8% placebo) 3
• Diarrhea 4
• Dyspepsia (16.0% vs 1.6% placebo) 3

Anticholinergic Side Effects (indicating excess trospium activity):

• Gastroesophageal reflux 4
• Constipation (12.8% vs 3.9% placebo) 3
• Urinary retention 4

Adjust dosing, titration speed, and timing of administration based on which side effect profile predominates 4

Safety Advantages Over Traditional Antipsychotics

• No direct D2 dopamine receptor blockade, eliminating risk of extrapyramidal symptoms, weight gain, and somnolence that are common with traditional antipsychotics 3, 2
• Extrapyramidal symptom measures were similar between xanomeline-trospium and placebo groups 3
• Weight gain and somnolence rates comparable to placebo 3
• No increased risk of metabolic syndrome, hyperprolactinemia, or QT prolongation that plague conventional antipsychotics 1, 3

Discontinuation and Tolerability

• Discontinuation rates due to adverse events are low (6.4% vs 5.5% placebo), with most side effects rated as mild-to-moderate 5, 3
• Over 75% of participants in long-term studies (52 weeks) achieved >30% improvement in PANSS total score 5
• Most common reason for discontinuation is gastrointestinal intolerance, which can be mitigated with slower titration and administration with food 4

Real-World Outpatient Considerations

Unlike clinical trials where patients were tapered off previous antipsychotics before starting xanomeline-trospium, real-world practice often requires: 4

• Initiating xanomeline-trospium while maintaining current antipsychotic due to safety concerns in outpatient settings 4
• Managing polypharmacy and comorbidities (autism, dementia, substance use) that were excluded from trials 4
• Slower titration schedules than the rapid 1-week protocol used in inpatient trials 4

Concomitant Medication Management

• Avoid combining with other anticholinergic medications, as this may reduce xanomeline's central efficacy 4
• Consider potential for improved cognitive function in patients with comorbid autism or dementia, though this requires further study 4
• No specific drug-drug interactions reported in trials, but monitor for additive cholinergic effects with other cholinergic agents 3

Position in Treatment Algorithm

The 2025 INTEGRATE guidelines note that xanomeline-trospium represents a promising new mechanism of action for schizophrenia, though its exact position in treatment algorithms requires further evaluation as clinical experience accumulates 1

• Represents first non-dopaminergic antipsychotic approved for schizophrenia 2
• May be particularly valuable for patients who cannot tolerate dopamine antagonists due to extrapyramidal symptoms or metabolic side effects 3
• Long-term data show sustained efficacy with mean PANSS total score reduction of 33.3 points at 52 weeks 5

Common Pitfalls to Avoid

• Do not titrate too rapidly in outpatient settings—this increases gastrointestinal side effects and discontinuation risk 4
• Do not assume all gastrointestinal symptoms are the same—distinguish cholinergic (nausea, vomiting, diarrhea) from anticholinergic (reflux, constipation) to guide dose adjustments 4
• Do not abruptly discontinue previous antipsychotics before initiating xanomeline-trospium in outpatients—maintain safety while establishing therapeutic effect 4
• Do not exceed maximum dose of 125 mg/30 mg twice daily—this was established as the maximum tolerated dose in clinical trials 6, 3