Xanomeline tartrate and trospium chloride (xanomeline/trospium) is a fixed combination of xanomeline (a muscarinic agonist) and trospium (a muscarinic antagonist).1 The combination preparation is an antipsychotic agent.1
The fixed combination of xanomeline tartrate and trospium chloride (xanomeline/trospium) is used for the treatment of schizophrenia in adults.1
Safety and efficacy of xanomeline/trospium have been established in two phase 3, double-blind, randomized, placebo-controlled trials (EMERGENT-2 and EMERGENT-3) in patients 18-65 years of age with a diagnosis of schizophrenia who were experiencing acute symptoms; additional supportive evidence is derived from a phase 2 trial (EMERGENT-1).2, 3, 4 The primary efficacy endpoint of all of these studies was the change from baseline to week 5 in the Positive and Negative Syndrome Scale (PANSS).1, 2, 3 The PANSS measures severity of positive and negative symptoms and general psychiatric symptoms of schizophrenia, and has been used to demonstrate the efficacy of numerous antipsychotic agents approved by FDA for the treatment of schizophrenia.4
A total of 252 patients in EMERGENT-2 and 256 patients in EMERGENT-3 were randomized to xanomeline/trospium or placebo.2, 3 Patients in all studies, including EMERGENT-1, were dosed under the same protocol.2 During the first 2 days of treatment, patients received 50 mg xanomeline and 20 mg trospium chloride as the fixed-dose combination twice daily; dosage was increased to 100 mg xanomeline and 20 mg trospium chloride twice daily for the next 3-7 days.2, 3 Beginning on day 8, optional dose increases were allowed to a maximum of 125 mg xanomeline and 30 mg trospium chloride twice daily based on tolerability.2, 3 Among the patients enrolled in both phase 3 trials, the median age was 46 years; 25% were female, 31% were white, and 68% were Black or African American.1 Both EMERGENT-2 and EMERGENT-3 showed a greater reduction in PANSS total score at week 5 in the xanomeline/trospium group compared to placebo (placebo-subtracted difference of -9.6 and -8.4, respectively).2, 3, 4 The results of the phase 2 EMERGENT-1 trial were consistent with the phase 3 trials, with xanomeline/trospium demonstrating a significant improvement compared to placebo in the change from baseline to week 5 in PANSS score.4
A meta-analysis of short-term, randomized controlled trials (3-8 weeks) in adults with a diagnosis of schizophrenia experiencing acute symptoms was conducted to compare treatment with xanomeline/trospium to aripiprazole, risperidone, and olanzapine.5 A total of 33 trials were evaluated; the mean age of patients was 34-46 years of age.5 All 4 antipsychotic agents were significantly better than placebo in reducing positive and negative symptoms; however, there were no significant differences between the drugs.5
Antipsychotic therapy is integral to the management of patients with schizophrenia, both for management of acute psychotic symptoms and for maintenance treatment to prevent symptom recurrence.28, 29, 30, 32 The American Psychiatric Association (APA) guidelines recommend that patients with schizophrenia be treated with an antipsychotic agent.28 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic drug will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.28 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).28 Patients whose symptoms improve on an antipsychotic drug should continue such treatment long-term; in most patients, it is appropriate to continue the same antipsychotic drug rather than switch to another antipsychotic medication for maintenance therapy.28
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic drugs for acute and maintenance treatment of schizophrenia.6 Choice of a specific agent should be based on patient-specific factors and the side effect profiles of the different antipsychotic drugs.6 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.6
The fixed combination of xanomeline tartrate and trospium chloride (xanomeline/trospium) is administered orally.1 The drug is commercially available as capsules in 3 different dosage combinations: 50 mg of xanomeline and 20 mg of trospium chloride (50 mg/20 mg), 100 mg of xanomeline and 20 mg of trospium chloride (100 mg/20 mg), and 125 mg of xanomeline and 30 mg of trospium chloride (125 mg/30 mg).1
Administer the capsules at least 1 hour before a meal or at least 2 hours after a meal.1
Do not open the capsules.1
Store the capsules at 20-25ºC.1
Dosage of xanomeline tartrate is expressed in terms of xanomeline, and dosage of trospium chloride is expressed in terms of the salt.1
The recommended initial dosage of xanomeline/trospium for the treatment of schizophrenia in adults is 50 mg xanomeline/20 mg trospium chloride orally twice daily for at least 2 days.1 Increase the dosage to 100 mg xanomeline/20 mg trospium chloride orally twice daily for at least 5 days.1 The dosage may be increased based on patient tolerability and response up to a maximum recommended dosage of 125 mg xanomeline/30 mg trospium chloride orally twice daily.1
Xanomeline/trospium is not recommended for patients with mild hepatic impairment and is contraindicated in patients with moderate to severe hepatic impairment.1
No dosage adjustment is recommended in patients with mild renal impairment.1 Xanomeline/trospium is not recommended for use in patients with moderate or severe renal impairment.1
The recommended starting dosage of xanomeline/trospium in geriatric patients is 50 mg xanomeline/20 mg trospium chloride orally twice daily.1 A slow titration should be considered up to a recommended maximum dosage of 100 mg xanomeline/20 mg trospium chloride orally twice daily.1
Xanomeline/trospium can cause urinary retention; patients with an increased risk include geriatric patients, and patients with significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia [BPH], diabetic cystopathy).1
Xanomeline/trospium is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment.1
Monitor for symptoms of urinary retention, including hesitancy, weak stream, incomplete bladder emptying, and dysuria.1 In patients with symptoms of urinary retention, consider reducing the dose or discontinuing xanomeline/trospium, or referring patients for urologic evaluation as clinically indicated.1
Risk of Use in Patients with Hepatic Impairment
Patients with hepatic impairment have higher systemic exposures of xanomeline compared to patients with normal hepatic function, increasing the incidence of adverse reactions.1
Xanomeline/trospium is contraindicated in patients with moderate or severe hepatic impairment and is not recommended in patients with mild hepatic impairment.1
Assess liver enzymes prior to initiating treatment and as clinically indicated during treatment.1
Transient increases in liver enzymes with rapid decline have been observed in patients treated with xanomeline/trospium.1
Xanomeline/trospium is not recommended in patients with active biliary disease such as symptomatic gallstones.1
Assess liver enzymes and bilirubin prior to initiating treatment and as clinically indicated during treatment.1 Symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should be promptly assessed for gallbladder disorders, biliary disorders, and pancreatitis as clinically indicated.1
Discontinue treatment if a patient experiences signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels >5 times the upper limit of normal or 5 times baseline values.1
Xanomeline/trospium can cause decreased GI motility.1
Administer with caution in patients with GI obstructive disorders and conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis, due to the risk of gastric retention.1
Angioedema has been reported in patients receiving xanomeline/trospium and trospium chloride.1 In a single case, angioedema occurred after the first dose of trospium.1
If angioedema involving the tongue, hypopharynx, or larynx occurs, discontinue xanomeline/trospium and initiate appropriate therapy and/or measures to maintain a patent airway.1 Xanomeline/trospium is contraindicated in patients with hypersensitivity to trospium chloride.1
Patients with Narrow-angle Glaucoma
Xanomeline/trospium can cause pupillary dilation due to its anticholinergic effects; this may trigger an acute angle closure attack in patients with anatomically narrow angles.1
Xanomeline/trospium should only be used in patients with anatomically narrow angles if the potential benefits outweigh the risks and with careful monitoring.1
Xanomeline/trospium can cause an increase in heart rate.1
Assess heart rate at baseline and as clinically indicated during treatment.1
Anticholinergic Adverse Reactions in Patients with Renal Impairment
Trospium is renally eliminated, and therefore systemic exposure is higher in patients with moderate or severe renal impairment.1 Anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in such patients.1
Xanomeline/trospium is not recommended in patients with moderate to severe renal impairment.1
Anticholinergic CNS effects have been reported with trospium chloride including dizziness, confusion, hallucinations, and somnolence.1
Monitor patients for signs of anticholinergic effects, particularly after beginning treatment or increasing the dose.1 Advise patients not to drive or operate heavy machinery until they know how xanomeline/trospium affects them.1 Consider dose reduction or discontinuing xanomeline/trospium if a patient experiences anticholinergic CNS effects.1
There are insufficient data on the use of xanomeline/trospium in pregnant women to determine whether there is a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 In animal reproductive studies, use of xanomeline alone or in combination with trospium chloride was associated with embryofetal and developmental toxicities at maternal toxic doses.1
There is risk to the pregnant patient from untreated schizophrenia.1 Schizophrenia is associated with adverse perinatal outcomes, including preterm birth, but it is not known whether this is a direct result of the illness or other comorbid conditions.1
There is an exposure registry that monitors outcomes in women exposed to psychiatric medications during pregnancy.1 Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting [Web].1
It is not known whether xanomeline or trospium is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production.1 Xanomeline and trospium are present in animal milk; therefore, the drug is likely present in human milk.1 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for xanomeline/trospium and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.1
Females and Males of Reproductive Potential
No effects on fertility were observed in male rats following oral administration of xanomeline at doses of 15, 44, and 150 mg/kg per day; no effects on fertility were observed in male and female rats following subcutaneous administration of xanomeline at doses of 1, 5, and 25 mg/kg per day.1 No effects on fertility were observed following administration of trospium chloride in rats at doses up to 200 mg/kg per day.1
The safety and effectiveness of xanomeline/trospium have not been established in pediatric patients.1
Safety and efficacy of xanomeline/trospium have not been established in geriatric patients 65 years of age and older.1 A slower titration and lower maximum dosage is recommended in geriatric patients due to the increased risk of urinary retention.1
Patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) have higher xanomeline exposures compared to patients with normal hepatic function.1 Safety and efficacy of xanomeline/trospium have not been established in patients with severe hepatic impairment.1
Xanomeline/trospium is contraindicated in patients with moderate or severe hepatic impairment and is not recommended in patients with mild hepatic impairment.1
No clinically significant differences in safety and efficacy were observed in patients with mild renal impairment.1 Use of xanomeline/trospium is not recommended in patients with moderate and severe renal impairment due to the increased risk of urinary retention and anticholinergic CNS adverse effects.1
Most common adverse reactions (≥5%) reported with xanomeline/trospium in clinical studies were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and GI reflux disease.1
Xanomeline and its metabolites are not inhibitors or inducers of major cytochrome P-450 (CYP) enzymes at the systemic level; however, xanomeline inhibits CYP3A4 at the gut level.1, 4
Xanomeline and its metabolites are not inhibitors of major transporters at the systemic level; however, xanomeline inhibits P-glycoprotein (P-gp) at the gut level.1, 4
Trospium is not an inhibitor or inducer of major CYP enzymes nor an inhibitor of major drug transporters.4
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of xanomeline/trospium with strong CYP2D6 inhibitors may increase plasma concentrations of xanomeline.1
Monitor patients for increased frequency and/or severity of adverse reactions of xanomeline/trospium in patients taking xanomeline/trospium with strong inhibitors of CYP2D6.1
Concomitant use of xanomeline/trospium with oral drugs that are sensitive substrates of CYP3A4 may result in increased plasma concentrations of the oral drugs that are sensitive substrates.1
Monitor patients for increased frequency and/or severity of adverse reactions to oral drugs that are sensitive substrates of CYP3A4 in patients concomitantly taking xanomeline/trospium.1
Drugs Affecting or Affected by Transport Systems
Concomitant use of xanomeline/trospium with oral drugs that are substrates of P-gp may result in increased plasma concentrations of the oral drugs that are substrates of P-gp.1
Monitor patients for increased frequency and/or severity of adverse reactions related to oral drugs that are narrow therapeutic index substrates of P-gp in patients concomitantly taking xanomeline/trospium.1
Concomitant use of xanomeline/trospium with drugs that are eliminated by active tubular secretion may increase plasma concentration of trospium and/or the concomitantly used drug due to competition for this elimination pathway.1
Monitor patients for increased frequency and/or severity of adverse reactions of xanomeline/trospium and drugs that are eliminated by active tubular secretion when used concomitantly.1
Concomitant use of xanomeline/trospium with other antimuscarinic drugs that produce anticholinergic adverse reactions (e.g., dry mouth, constipation) may increase the frequency and/or severity of such effects.1 Monitor patients for increased frequency and/or severity of anticholinergic adverse reactions when xanomeline/trospium is used concomitantly with other antimuscarinic drugs.1
Xanomeline/trospium may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on GI motility.1 Dosage adjustment of concomitant medications may be necessary based on clinical response and tolerability.1
Xanomeline tartrate and trospium chloride (xanomeline/trospium) is a fixed combination of xanomeline (a muscarinic agonist) and trospium (a muscarinic antagonist).1 Unlike currently available antipsychotic agents for schizophrenia, which are direct or functional D2 dopamine receptor antagonists, xanomeline/trospium is an agonist at the M1 and M4 muscarinic acetylcholine receptors in the CNS.1, 2 There is evidence suggesting that an imbalance between muscarinic acetylcholine and dopamine neurotransmitter systems is involved in the pathophysiology of schizophrenia.2, 3 Although xanomeline has been shown to reduce psychotic symptoms and improve cognition, it is associated with higher rates of adverse GI effects.2 The addition of trospium to xanomeline is thought to decrease the adverse effects of xanomeline by antagonizing muscarinic effects in peripheral tissues.2, 4
The maximum plasma concentration of trospium is reduced by 70-75% when taken with food.1 Plasma protein binding of xanomeline and trospium are approximately 95% and 80%, respectively.1 The elimination half-life of xanomeline is 5 hours and the elimination half-life of trospium is 6 hours.1 Xanomeline is metabolized primarily by cytochrome P-450 (CYP) 2D6, CYP2B6, CYP1A2, CYP2C9, CYP2C19, flavin monooxygenase (FMO)1, and FMO3.1 Trospium is primarily metabolized by ester hydrolysis and glucuronic acid conjugation.1 Xanomeline is 78% eliminated in the urine and trospium is 85-90% renally eliminated as unchanged drug through tubular secretion.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 50 mg xanomeline and 20 mg trospium chloride | Cobenfy® | E.R. Squibb & Sons |
100 mg xanomeline and 20 mg trospium chloride | Cobenfy® | E.R. Squibb & Sons | ||
125 mg xanomeline and 30 mg trospium chloride | Cobenfy® | E.R. Squibb & Sons |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. E.R. Squibb & Sons, L.L.C.. Cobenfy® (xanomeline and trospium chloride) ORAL prescribing information. 2024 Sept. [Web]
2. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial [published correction appears in Lancet. 2024 Jun 1;403(10442):2380. doi: 10.1016/S0140-6736(24)01041-9.]. Lancet. 2024;403(10422):160-170.
3. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: A randomized clinical trial [published correction appears in JAMA Psychiatry. 2024 Aug 1;81(8):846. doi: 10.1001/jamapsychiatry.2024.2002.]. JAMA Psychiatry. 2024;81(8):749-756. doi:10.1001/jamapsychiatry.2024.0785
4. US Food and Drug Administration. Center for Drug Evaluations and Research Application Number: 216158Orig1s000 Integrated Review. From FDA website. Accessed 2025 March 17.
5. Wright AC, McKenna A, Tice JA, Rind DM, Agboola F. A network meta-analysis of KarXT and commonly used pharmacological interventions for schizophrenia. Schizophr Res. 2024;274:212-219.
6. U.S. Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for management of first-episode psychosis and schizophrenia, version 2.0. U.S. Department of Veterans Affairs. Updated 2023. Accessed 2025 March 17. [Web]
28. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 3rd ed. American Psychiatric Association Publishing. Washington, DC; 2021. [Web]
29. Barnes TR, Drake R, Paton C et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2020; 34:3-78
30. Hasan A, Falkai P, Wobrock T et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia - a short version for primary care. Int J Psychiatry Clin Pract. 2017; 21:82-90
32. Noel JM, Jackson CW. ASHP therapeutic position statement on the use of antipsychotic medications in the treatment of adults with schizophrenia and schizoaffective disorder. Am J Health Syst Pharm. 2020; 77:2114-2132
33. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019; 381:1753-1761