Xanomeline

The mechanism of action of xanomeline in the treatment of schizophrenia is unclear; however, its efficacy is thought to be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system. Trospium chloride is a muscarinic antagonist.

• COBENFY is indicated for the treatment of schizophrenia in adults. COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, indicated for the treatment of schizophrenia in adults.ICD-10: F20.9

• COBENFY is contraindicated in patients with: • urinary retention [see Warnings and Precautions (5.1) ] . • moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.2) ] .contraindicated

• Assess liver enzymes and bilirubin prior to initiating treatment with COBENFY and as clinically indicated during treatment. ( 2.1 ) • Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 2.1 ) • Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily for at least two days, then increase the dosage to 100 mg/20 mg twice daily for at least five days. ( 2.2 ) • Dosage may be increased to 125 mg/30 mg orally twice daily based on patient tolerability and response. ( 2.2 ) • See the full prescribing information for the recommended titration and maximum recommended dosage. ( 2.2 ) • Take at least 1 hour before a meal or at least 2 hours after a meal. Do not open capsules. ( 2.2 ) • Geriatric patients: Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily. Consider a slower titration. The maximum recommended dosage is 100 mg/20 mg twice daily. ( 2.3 ) 2.1 Recommended Testing and Monitoring Prior to Initiation and During Treatment with COBENFY • Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment [see Contraindications (4) and Warnings and Precautions (5.2 , 5.3) ] . • Assess heart rate at baseline and as clinically indicated during treatment [see Warnings and Precautions (5.7) ] . 2.2 Recommended Dosage and Administration The recommended dosage of COBENFY is as follows: • The recommended starting dosage is one 50 mg/20 mg capsule (contains 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days.

• Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with bladder outlet obstruction and incomplete bladder emptying are at increased risk. Monitor patients for symptoms of acute urinary retention. ( 5.1 ) • Risk of Use in Patients with Hepatic Impairment: COBENFY is contraindicated in patients with moderate to severe hepatic impairment and is not recommended in patients with mild hepatic impairment. ( 5.2 ) • Risk of Use in Patients with Biliary Disease: Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury. ( 5.3 ) • Decreased Gastrointestinal Motility: COBENFY may decrease gastrointestinal motility. Use with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. ( 5.4 ) • Risk of Angioedema: Angioedema of the face, lips, tongue and/or larynx has been reported with COBENFY. ( 5.5 ) • Risk of Use in Patients with Narrow-angle Glaucoma: Use COBENFY only if the potential benefits outweigh the risks and with careful monitoring. ( 5.6 ) • Increases in Heart Rate: COBENFY may increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 5.7 ) • Anticholinergic Adverse Reactions in Patients with Renal Impairment: COBENFY is not recommended for use in patients with moderate and severe renal impairment. Anticholinergic adverse reactions are expected to be greater in these patients.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Urinary Retention [see Warnings and Precautions (5.1) ] • Risk of Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.2) ] • Risk of Use in Patients with Biliary Disease [see Warnings and Precautions (5.3) ] • Decreased Gastrointestinal Motility [see Warnings and Precautions (5.4) ] • Risk of Angioedema [see Warnings and Precautions (5.5) ] • Risk of Use in Patients with Narrow-angle Glaucoma [see Warnings and Precautions (5.6) ] • Increases in Heart Rate [see Warnings and Precautions (5.7) ] • Anticholinergic Adverse Reactions in Patients with Renal Impairment [see Warnings and Precautions (5.8) ] • Central Nervous System Effects [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence ≥ 5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastrointestinal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• Moderate or Severe Renal Impairment: Not recommended. ( 8.6 ) • Mild Hepatic Impairment: Not recommended. ( 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications, including COBENFY, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/ . Risk Summary There are no available data on COBENFY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia ( see Clinical Considerations ). In animal reproduction studies, oral administration of xanomeline alone or in combination with trospium chloride during the period of organogenesis or during pregnancy and lactation caused maternal toxicities of adverse clinical signs, decreased body weight, weight gain and food consumption, and/or maternal death. At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.

Metabolism

Following COBENFY administration, xanomeline area under the plasma concentration-time curve during a 12-hour dosing interval (AUC 0-12 ) at steady state and maximum concentration (C max ) increased 50% when the COBENFY dose increased from 100 mg/20 mg twice daily to 125 mg/30 mg twice daily. Trospium exposures increase dose-proportionally over the COBENFY dosage range of 100 mg/20 mg twice daily to 125 mg/30 mg twice daily.

Overdose of COBENFY may produce cholinergic, anticholinergic or a combination of cholinergic and anticholinergic signs and symptoms: • Cholinergic Signs and Symptoms: seizures, vomiting, diarrhea, abdominal pain, hyperhidrosis, salivary hypersecretion, and hypotension possibly preceded by hypertension. • Anticholinergic Signs and Symptoms (geriatric patients may be more susceptible): delirium, agitation, garbled speech, dizziness, hypertension, tachycardia, dry mouth and eyes, ileus, blurred vision, and urinary retention. Consider calling the Poison Help Line 1-800-222-1222 or a medical toxicologist for specific treatment recommendations.

• Sep 26, 2024NDANDA216158Bristol-myers

1. 1Nausea35821%
2. 2Vomiting28717%
3. 3Constipation1287.4%
4. 4Off Label Use1196.8%
5. 5Urinary Retention1076.2%
6. 6Dizziness764.4%
7. 7Vision Blurred683.9%
8. 8Dyspepsia633.6%
9. 9Hyperhidrosis613.5%
10. 10Dry Mouth452.6%
11. 11Drug Ineffective432.5%
12. 12Treatment Noncompliance432.5%
13. 13Somnolence402.3%
14. 14Drooling392.2%
15. 15Gastrooesophageal Reflux Disease382.2%

The 10 most recently updated of 40 ClinicalTrials.gov registrations naming Xanomeline as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• A Study to Evaluate the Effects of KarXT on the Drug Levels of Midazolam, Fexofenadine, and Digoxin
  Recruiting · Phase 1 · Interventional · 60 enrolled · Karuna Therapeutics, Inc., a Bristol Myers Squibb company
  NCT07118215updated 2026-06-11
• A Phase 3 Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-1)
  Recruiting · Phase 3 · Interventional · 352 enrolled · Bristol-Myers Squibb
  NCT07011732updated 2026-06-10
• A Study to Evaluate the Efficacy and Safety of Adjunctive KarXT for the Treatment of Mania, With or Without Mixed Features, in Participants With Bipolar-I Disorder Taking Lithium, Valproate, or Lamotrigine
  Recruiting · Phase 3 · Interventional · 424 enrolled · Bristol-Myers Squibb
  NCT07140913updated 2026-06-10
• A Phase 3 Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-2)
  Recruiting · Phase 3 · Interventional · 352 enrolled · Bristol-Myers Squibb
  NCT07011745updated 2026-06-10
• A Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-2)
  Recruiting · Phase 3 · Interventional · 274 enrolled · Bristol-Myers Squibb
  NCT06951711updated 2026-06-04
• A Study to Evaluate the Effect of KarXT on Urological Safety
  Recruiting · Phase 4 · Interventional · 60 enrolled · Bristol-Myers Squibb
  NCT07221877updated 2026-06-03
• The Impact of Cobenfy Maintenance on Cocaine's Effects
  Not yet recruiting · Phase 1 · Phase 2 · Interventional · 32 enrolled · Joshua A. Lile, Ph.D.
  NCT07624227updated 2026-06-03
• Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease (ADEPT-3)
  Recruiting · Phase 3 · Interventional · 800 enrolled · Karuna Therapeutics, Inc., a Bristol Myers Squibb company
  NCT05980949updated 2026-06-02
• A Study to Assess Efficacy and Safety of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease (ADEPT-2)
  Recruiting · Phase 3 · Interventional · 500 enrolled · Karuna Therapeutics, Inc., a Bristol Myers Squibb company
  NCT06126224updated 2026-06-02
• A Study to Evaluate Safety and Efficacy of KarXT + KarX-EC as a Treatment for Psychosis Associated With Alzheimer's Disease (ADEPT-5)
  Recruiting · Phase 3 · Interventional · 325 enrolled · Bristol-Myers Squibb
  NCT06947941updated 2026-06-02

Frequently asked questions

How does Xanomeline work?

The mechanism of action of xanomeline in the treatment of schizophrenia is unclear; however, its efficacy is thought to be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system. Trospium chloride is a muscarinic antagonist.

What is Xanomeline used for?

According to FDA labeling, Xanomeline carries indications including: COBENFY is indicated for the treatment of schizophrenia in adults. COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, indicated for the treatment of schizophrenia in adults.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Xanomeline?

Xanomeline is classified as Cholinergic Muscarinic Agonist, Cholinergic Muscarinic Agonists, Cytochrome P450 3A4 Inhibitors, P-Glycoprotein Inhibitors.

What are the brand names for Xanomeline?

Xanomeline is marketed under brand names including Cobenfy.

What are the contraindications for Xanomeline?

Xanomeline labeling lists contraindications including: COBENFY is contraindicated in patients with: • urinary retention [see Warnings and Precautions (5.1) ] . • moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.2) ] .. Always consult the full prescribing information and a clinician.