AHFS Class:

• Antipsychotics, Miscellaneous 28:16.08.92

Brands:

• Cobenfy^®

Generic Name(s):

• Xanomeline Tartrate

• Trospium Chloride

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

Xanomeline/trospium has the following uses:

Xanomeline/trospium is indicated for the treatment of schizophrenia in adults.1

General

Xanomeline/trospium is available in the following dosage form(s) and strength(s):

Capsules containing xanomeline and trospium chloride in the following fixed-combination dosage strengths: 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Assess liver enzymes and bilirubin prior to initiating treatment with xanomeline/trospium and as clinically indicated during treatment.1
• Assess heart rate at baseline and as clinically indicated during treatment with xanomeline/trospium.1
• Recommended starting dosage of xanomeline/trospium is 50 mg/20 mg (containing 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days, then increase the dosage to 100 mg/20 mg (containing 100 mg of xanomeline and 20 mg of trospium chloride) twice daily for at least five days.1
• Dosage may be increased to maximum of 125 mg/30 mg (containing 125 mg of xanomeline and 30 mg of trospium chloride) orally twice daily based on patient tolerability and response.1
• Take at least 1 hour before a meal or at least 2 hours after a meal.1 Do not open capsules.1
• Geriatric patients: Recommended starting dosage of xanomeline/trospium is 50 mg/20 mg (containing 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily.1 Consider a slower titration.1 The maximum recommended dosage is 100 mg/20 mg (containing 100 mg of xanomeline and 20 mg of trospium chloride) twice daily.1

Contraindications

• Patients with urinary retention.1
• Patients with moderate or severe hepatic impairment.1
• Patients with gastric retention.1
• Patients with history of hypersensitivity to xanomeline/trospium or trospium chloride.1
• Patients with untreated narrow-angle glaucoma.1

Warnings/Precautions

Risk of Urinary Retention

Xanomeline/trospium can cause urinary retention.1 Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia [BPH], diabetic cystopathy) may be at increased risk of urinary retention.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

In patients taking xanomeline/trospium, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria.1 Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider.1 Urinary retention is a known risk factor for urinary tract infections.1 In patients with symptoms of urinary retention, consider reducing the dose of xanomeline/trospium, discontinuing the combination drug, 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, a component of xanomeline/trospium, compared to patients with normal hepatic function, which may result in increased incidence of xanomeline/trospium-related adverse reactions.1

Xanomeline/trospium is contraindicated in patients with moderate or severe hepatic impairment.1 Xanomeline/trospium is not recommended in patients with mild hepatic impairment. 1

Assess liver enzymes prior to initiating xanomeline/trospium and as clinically indicated during treatment.1

Risk of Use in Patients with Biliary Disease

In clinical studies with xanomeline/trospium, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.1

Xanomeline/trospium is not recommended for patients with active biliary disease such as symptomatic gallstones.1 Assess liver enzymes and bilirubin prior to initiating xanomeline/trospium and as clinically indicated during treatment.1 The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated.1

Discontinue xanomeline/trospium in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than 5 times the upper limit of normal (ULN) or 5 times baseline values.1

Decreased GI Motility

Xanomeline/trospium contains trospium chloride.1 Trospium chloride, like other antimuscarinic agents, may decrease GI motility.1 Administer xanomeline/trospium with caution in patients with GI obstructive disorders because of the risk of gastric retention.1 Use xanomeline/trospium with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.1

Risk of Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with xanomeline/trospium and trospium chloride.1 In one case, angioedema occurred after the first dose of trospium chloride.1 Angioedema associated with upper airway swelling may be life-threatening.1 If involvement of the tongue, hypopharynx, or larynx occurs, discontinue xanomeline/trospium and initiate appropriate therapy and/or measures necessary to ensure a patent airway.1 Xanomeline/trospium is contraindicated in patients with a history of hypersensitivity to trospium chloride.1

Risk of Use in Patients with Narrow-angle Glaucoma

Pupillary dilation may occur due to the anticholinergic effects of xanomeline/trospium.1 This may trigger an acute angle closure attack in patients with anatomically narrow angles.1 In patients known to have anatomically narrow angles, xanomeline/trospium should only be used if the potential benefits outweigh the risks and with careful monitoring.1

Increases in Heart Rate

Xanomeline/trospium can increase heart rate.1 Assess heart rate at baseline and as clinically indicated during treatment with xanomeline/trospium.1

Anticholinergic Adverse Reactions in Patients with Renal Impairment

Trospium chloride, a component of xanomeline/trospium, is substantially excreted by the kidney.1 Xanomeline/trospium is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min).1 Systemic exposure of trospium is higher in patients with moderate and severe renal impairment.1 Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.1

CNS Effects

Trospium chloride, a component of xanomeline/trospium, is associated with anticholinergic CNS effects.1 A variety of CNS anticholinergic effects have been reported with trospium, including dizziness, confusion, hallucinations, and somnolence.1 Monitor patients for signs of anticholinergic CNS 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 If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications, including xanomeline/trospium, during pregnancy.1 Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting online at http://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/. 1

There are no available data on xanomeline/trospium use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.1 There are risks to the mother associated with untreated schizophrenia.1 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.1 At these maternally toxic doses, embryofetal and developmental toxicities included decreased fetal and neonatal weight, stillborn pups, and/or neonatal deaths.1 The no observed adverse effect level (NOAEL) of xanomeline or xanomeline/trospium combination for maternal, embryofetal, and/or developmental toxicity is equal to or higher than the xanomeline/trospium dose at the maximum recommended human dose (MRHD) of 250/60 mg xanomeline/trospium chloride, based on mg/m² body surface area (BSA).1

The background risk of major birth defects and miscarriage for the indicated population is unknown.1 All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes.1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

There is a risk to the pregnant patient from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide.1 Schizophrenia is associated with adverse perinatal outcomes, including preterm birth.1 It is not known if this is a direct result of the illness or other comorbid factors. 1

Lactation

There are no data on the presence of xanomeline or trospium in human milk, the effects on the breastfed infant, or the effects on milk production.1 Xanomeline and trospium are present in animal milk.1 When a drug is present in animal milk, it is likely that the drug will be 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 combination drug or from the underlying maternal condition.1

Pediatric Use

The safety and effectiveness of xanomeline/trospium in pediatric patients have not been established.1

Geriatric Use

Controlled clinical studies of xanomeline/trospium did not include patients older than 65 years of age to determine whether they respond differently from younger adult patients. 1

Because xanomeline/trospium can increase the risk of urinary retention in geriatric patients, including older males with bladder outlet obstruction due to benign prostatic hyperplasia (BPH), a slower titration and lower maximum dosage is recommended in geriatric patients.1

Renal Impairment

Patients with mild renal impairment (eGFR 60 to <90 mL/min) showed higher systemic exposures to xanomeline and trospium chloride, compared to subjects with normal renal function.1 However, in the adequate and well-controlled clinical studies, the safety profiles in patients with mild renal impairment were similar to those observed in patients with normal renal function (eGFR ≥90 mL/min).1 Therefore, the recommended dosage in patients with mild renal impairment is the same as the recommended dosage for patients with normal renal function.1

Use of xanomeline/trospium is not recommended in patients with moderate or severe renal impairment (eGFR<60 mL/min).1

Hepatic Impairment

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 The pharmacokinetics of xanomeline/trospium were not studied in patients with severe hepatic impairment (Child-Pugh Class C).1

Use of xanomeline/trospium is contraindicated in patients moderate or severe hepatic impairment.1 It is not recommended in patients with mild hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (incidence ≥ 5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and GI reflux disease.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Drugs Eliminated by Active Tubular Secretion: Monitor for increased frequency and/or severity of adverse reactions related to xanomeline/trospium and to drugs eliminated by active tubular secretion.1
• Strong CYP2D6 Inhibitors: Monitor for increased frequency and/or severity of xanomeline/trospium-related adverse reactions.1
• Sensitive Substrates of CYP3A4 or P-glycoprotein: Monitor for increased frequency and/or severity of adverse reactions from these substrates.1
• Antimuscarinic Drugs: Monitor for increased frequency or severity of anticholinergic adverse reactions.1

Actions

Mechanism of Action

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 CNS. 1

Trospium chloride is a muscarinic antagonist; the drug antagonizes the muscarinic receptors primarily in the peripheral tissues.1

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).1
• Inform patients that xanomeline/trospium may cause urinary retention and that the risk of urinary retention is greater in some patients, including geriatric patients and those with bladder outlet obstruction (e.g., due to BPH) and patients with other causes of reduced bladder emptying (e.g., diabetic cystopathy).1 Urinary retention may occur at any time during treatment with xanomeline/trospium and is more likely when taking higher doses. 1
• Advise patients to monitor for symptoms of urinary retention, such as urinary hesitancy, weak urinary stream, incomplete bladder emptying and pain with urination, and to promptly report these symptoms to their healthcare provider.1 Inform patients that urinary retention may increase the risk of urinary tract infection.1 Advise patients to seek immediate medical attention if they are unable to urinate.1
• Instruct patients to report signs of hepatic impairment (e.g., skin and eyes that appear yellowish, abdominal pain and swelling, itchy skin, dark urine color) and symptoms of hepatic injury (e.g., biliary spasm, pancreatitis, and cholangitis) to their healthcare provider.1
• Inform patients that xanomeline/trospium can increase liver enzymes and about the need for specific monitoring, including liver enzymes and bilirubin levels.1 Inform patients to report symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain to their healthcare provider.1
• Inform patients that xanomeline/trospium can delay or slow emptying of food in their stomach.1 Advise patients to inform their healthcare provider about the presence of or symptoms of GI obstructive disorders and conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.1
• Advise patients that hypersensitivity reactions to xanomeline/trospium could occur and result in life-threatening airway obstruction.1 Instruct patients to seek medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing occurs, and discontinue xanomeline/trospium and seek immediate medical attention.1
• Inform patients that pupillary dilation may occur with xanomeline/trospium use and, in susceptible individuals, can lead to an episode of angle closure glaucoma.1
• Inform patients that xanomeline/trospium can increase heart rate.1
• Inform patients that xanomeline/trospium is associated with anticholinergic adverse reactions such as dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention, and the effects are expected to be greater in patients with renal impairment. 1
• Advise patients that xanomeline/trospium is associated with CNS effects such as dizziness, confusion, hallucinations, and somnolence.1 Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that xanomeline/trospium therapy does not adversely affect their ability to engage in such activities.1
• Instruct patients to take xanomeline/trospium twice daily at least 1 hour before a meal or at least 2 hours after a meal and not to open the capsules.1
• Advise patients to notify their healthcare provider with a known or suspected pregnancy.1 Advise pregnant women that there is a pregnancy exposure registry that monitors outcomes in females exposed to xanomeline/trospium during pregnancy.1
• Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter (OTC) medications because there may be a potential for interactions.1

Additional Information

AHFS first Release^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. E.R. Squibb & Sons, L.L.C.. Cobenfy^® (xanomeline and trospium chloride) ORAL prescribing information. 2024 Sept. [Web]