xanomeline/trospium

Last reviewed 2026-03-13

Reviewed by PsychMed Editorial Team.

Compare xanomeline/trospium Review evidence

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Antipsychotic

Brands: COBENFY

Sources updated 2024 • 6 references

Quick summaryPrint sheet

At a glance

Class: Antipsychotic
Category: Antipsychotic
Typical dose: Standard titration: 50/20 mg BID (Days 1-2) → 100/20 mg BID (Days 3-7) → 125/30 mg BID (Day 8 onward). Maximum dose 125/30 mg twice daily.
Half-life: Single-dose mean 5 h; Steady-state mean 5 h
LAI available: No
Last reviewed: 2026-03-13

General information

Xanomeline/trospium (brand Cobenfy) is a first-in-class muscarinic receptor agonist antipsychotic approved by the FDA in September 2024 for schizophrenia in adults. Developed by Karuna Therapeutics (acquired by Bristol-Myers Squibb in 2024 for $14 billion), it is the first antipsychotic to work through a non-dopaminergic mechanism since chlorpromazine launched the antipsychotic era in the 1950s.

Xanomeline targets muscarinic M1 and M4 receptors in the brain. Trospium chloride is a peripheral muscarinic antagonist that does not cross the blood-brain barrier, added to counteract the gastrointestinal and urinary cholinergic side effects that limited xanomeline when studied alone in the 1990s for Alzheimer's disease.

Because Cobenfy does not block dopamine D2 receptors, it avoids the extrapyramidal symptoms, tardive dyskinesia, significant weight gain, metabolic syndrome, and prolactin elevation that have limited traditional antipsychotics for decades.

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U.S. approvals

Schizophrenia (adults) (2024)

Formulations & strengths

Capsules: 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg (xanomeline/trospium chloride). A starter pack containing the titration sequence is available.

Generic availability

No generic available. Brand Cobenfy (Bristol-Myers Squibb). Annual list price approximately $22,500.

Cobenfy is the most significant mechanistic advance in antipsychotic pharmacology in over 70 years. Its non-D2 profile eliminates many side effects that drive non-adherence, potentially expanding the treatable population. Phase 3 trials are underway for Alzheimer's psychosis, Alzheimer's agitation/cognition, bipolar disorder, and autism spectrum disorder.

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Mechanism of action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Xanomeline is a muscarinic receptor agonist with preferential activity at M1 and M4 subtypes. M4 agonism in the striatum modulates dopamine release indirectly, while M1 activity in the cortex and hippocampus may support cognitive function. Neither component blocks dopamine D2, serotonin 5-HT2A, histamine H1, or adrenergic receptors.

Trospium chloride is a nonselective peripheral muscarinic antagonist that does not cross the blood-brain barrier. It blocks the peripheral cholinergic effects of xanomeline (nausea, diarrhea, hypersalivation, urinary urgency) while preserving its central therapeutic activity.

This dual-component design—central muscarinic agonism with peripheral muscarinic antagonism—was the key pharmacologic innovation that made the drug viable after xanomeline alone failed tolerability testing in the 1990s.

Xanomeline: preferential agonist at M1 and M4 muscarinic receptors. No meaningful affinity for D2, 5-HT2A, H1, or adrenergic receptors.
Trospium: nonselective muscarinic antagonist; does not cross the blood-brain barrier; does not inhibit CYP enzymes.

Metabolism & pharmacokinetics

Xanomeline is metabolized by CYP2D6, CYP2B6, CYP1A2, CYP2C9, CYP2C19, and flavin monooxygenases (FMO1, FMO3). Oral bioavailability is less than 1% due to extensive first-pass metabolism. Half-life is approximately 5 hours; steady state in 3-5 days.
Trospium is not CYP-metabolized. It undergoes ester hydrolysis and glucuronic acid conjugation, with elimination primarily by active tubular secretion. Oral bioavailability is ~10%; half-life ~6 hours.
CYP2D6 polymorphisms affect xanomeline exposure: intermediate metabolizers show ~28% higher Cmax; ultrarapid metabolizers show ~43% lower exposure. Poor metabolizer dosing is not well characterized.
High-fat meals reduce trospium Cmax by 70-75% and AUC by 85-90%, requiring empty-stomach dosing (1 hour before or 2 hours after eating).
Xanomeline transiently inhibits CYP3A4 and P-glycoprotein locally in the gut, potentially increasing exposure to sensitive substrates administered concurrently.

Dosing & administration

Standard titration: 50/20 mg BID (Days 1-2) → 100/20 mg BID (Days 3-7) → 125/30 mg BID (Day 8 onward). Maximum dose 125/30 mg twice daily.
Geriatric patients (≥65 years): Start 50/20 mg BID with slower titration; maximum dose 100/20 mg BID.
Administer on empty stomach: at least 1 hour before a meal or 2 hours after a meal. Do not open capsules.
Extended titration (up to 2 weeks at the starting dose) can reduce the incidence of nausea; some clinicians report GI side effects dropping from common to uncommon with this approach.
Missed dose: take as soon as remembered if the empty-stomach requirement can be met. If close to the next dose, skip. Do not double the dose.
Renal impairment: not recommended if eGFR <60 mL/min. Hepatic impairment: not recommended in mild (Child-Pugh A); contraindicated in moderate to severe (Child-Pugh B/C).

Adverse effects

FDA boxed warnings

Common side effects (≥10%)

Nausea: 19% versus 4% placebo; GI-predominant side effect profile is distinct from traditional antipsychotics. Most events are mild to moderate and diminish with continued dosing.
Dyspepsia: 18% versus 5% placebo; can be mitigated with slower titration and timing doses around meals.
Constipation: 17% versus 7% placebo; related to peripheral anticholinergic effects of trospium.
Vomiting: 15% versus 1% placebo; extended titration significantly reduces incidence. Only 1% discontinued due to vomiting.
Hypertension: 11% versus 2% placebo; blood pressure monitoring is recommended at baseline and during treatment.
Tachycardia: Mean heart rate increase +9.8 bpm at Week 8 (24-hour ABPM). Peak elevation of +13.5 bpm on Day 8, attenuating to +11.4 bpm by Week 5.

Other notable effects

Hepatobiliary effects: ALT/AST ≥3× ULN in 2.8% (vs 0.4% placebo), consistent with transient biliary obstruction. Discontinue if jaundice, pruritus, or ALT >5× ULN develops.
Urinary retention: 3.5% in long-term studies; geriatric patients and those with bladder outlet obstruction are at increased risk.
Angioedema has been reported with both Cobenfy and trospium chloride historically; discontinue immediately if face, lip, tongue, or laryngeal swelling occurs.
Narrow-angle glaucoma risk from anticholinergic pupillary dilation; contraindicated in untreated narrow-angle glaucoma.
Key absent effects: no clinically meaningful EPS, tardive dyskinesia, weight gain (+1.4 kg vs +2.0 kg placebo), metabolic syndrome, prolactin elevation, or sedation.

Interactions

CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, cannabidiol): may increase xanomeline exposure; monitor for increased adverse reactions.
CYP3A4 sensitive substrates taken orally: xanomeline transiently inhibits gut CYP3A4; monitor for increased plasma concentrations of those substrates.
P-glycoprotein substrates: transient intestinal inhibition may increase concentrations; monitor accordingly.
Anticholinergic drugs: additive peripheral anticholinergic effects with trospium; increased risk of constipation, urinary retention, dry mouth, and decreased GI motility.
Active tubular secretion drugs (metformin, digoxin): trospium competes for renal tubular secretion; monitor for increased concentrations of either drug.

Other useful information

Cobenfy's non-D2 mechanism means the side effect profile is fundamentally different from all other antipsychotics. Clinicians should educate patients that GI effects (not weight gain, sedation, or movement problems) are the primary tolerability concern.
Empty-stomach dosing is essential and may require meal planning. Twice-daily dosing timed at least 1 hour before breakfast and 1 hour before dinner is a practical schedule.
Contraindications include urinary retention, gastric retention, moderate or severe hepatic impairment, untreated narrow-angle glaucoma, and hypersensitivity to the drug or trospium chloride.
Pregnancy: Limited data. Use only if benefits outweigh risks. Neonates should be monitored if exposed during the third trimester.
Pipeline: Phase 3 trials are underway for Alzheimer's disease psychosis (ADEPT program), Alzheimer's agitation and cognition, bipolar disorder, and autism spectrum disorder. A Phase 3 adjunctive schizophrenia trial (ARISE) did not meet its primary endpoint in April 2025.

xanomeline/trospium

At a glance

General information

U.S. approvals

Formulations & strengths

Generic availability

Mechanism of action

Metabolism & pharmacokinetics

Dosing & administration

Adverse effects

FDA boxed warnings

Common side effects (≥10%)

Other notable effects

Interactions

Other useful information

References

xanomeline/trospium

At a glance

General information

U.S. approvals

Formulations & strengths

Generic availability

Mechanism of action

Metabolism & pharmacokinetics

Dosing & administration

Adverse effects

FDA boxed warnings

Common side effects (≥10%)

Other notable effects

Interactions

Other useful information

References