Drug class: Antipsychotics, Miscellaneous

Introduction

Fixed combination containing xanomeline (a muscarinic agonist) and trospium (a muscarinic antagonist); antipsychotic agent.¹

Uses for Xanomeline and Trospium

Schizophrenia

Treatment of schizophrenia in adults.^{1 2 3 4 5}

Antipsychotic therapy is integral to the management of schizophrenia, both for treatment of acute psychotic symptoms and for maintenance treatment to prevent symptom recurrence.^{6 28 29 30 32}

American Psychiatric Association (APA) and Department of Veterans Affairs/Department of Defense recommend antipsychotic agents for acute and long-term maintenance treatment of schizophrenia.^{6 28} Choice of antipsychotic agent should be based on 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).^{6 28}

Xanomeline and Trospium Dosage and Administration

General

Pretreatment Screening

• Assess liver enzymes and bilirubin.¹

• Assess heart rate.¹

Patient Monitoring

• Assess liver enzymes and bilirubin as clinically indicated during treatment.¹

• Assess heart rate as clinically indicated during treatment.¹

• Monitor for symptoms of urinary retention during treatment.¹

Administration

Oral Administration

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 ≥1 hour before meals or ≥2 hours after meals¹

Do not open capsules.¹

Dosage

Dosage of xanomeline tartrate expressed in terms of xanomeline; dosage of trospium chloride expressed in terms of the salt.¹

Adults

Schizophrenia

Oral

Recommended starting dosage is 50 mg xanomeline/20 mg trospium chloride twice daily for at least 2 days.¹ Increase dosage to 100 mg xanomeline/20 mg trospium chloride twice daily for at least 5 days.¹

May increase dosage based on patient tolerability and response up to maximum recommended dosage of 125 mg xanomeline/30 mg trospium chloride twice daily.¹

Special Populations

Hepatic Impairment

Not recommended for patients with mild hepatic impairment; contraindicated in patients with moderate to severe hepatic impairment.¹

Renal Impairment

No dosage adjustment is recommended in patients with mild renal impairment.¹ Not recommended for use in patients with moderate or severe renal impairment.¹

Geriatric Patients

Recommended starting dosage in geriatric patients is 50 mg xanomeline/20 mg trospium chloride orally twice daily.¹ Slow titration should be considered up to recommended maximum dosage of 100 mg xanomeline/20 mg trospium chloride orally twice daily.¹

Cautions for Xanomeline and Trospium

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

Urinary Retention

Urinary retention may occur; increased risk in geriatric patients, and patients with significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia [BPH], diabetic cystopathy).¹

Contraindicated in patients with pre-existing urinary retention and 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 dose or discontinuing, or referring patients for urologic evaluation as clinically indicated.¹

Risk of Use in Patients with Hepatic Impairment

Higher systemic exposures of xanomeline with hepatic impairment, compared to normal hepatic function, increasing incidence of adverse reactions.¹

Contraindicated in patients with moderate or severe hepatic impairment and not recommended with mild hepatic impairment.¹

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

Patients with Biliary Disease

Transient increases in liver enzymes with rapid decline observed.¹

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 patient experiences signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels >5 times the ULN or 5 times baseline values.¹

Decreased GI Motility

Decreased GI motility may occur.¹

Administer with caution in patients with GI obstructive disorders and conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis, due to risk of gastric retention.¹

Angioedema

Angioedema reported with use of xanomeline/trospium and trospium chloride.¹

If angioedema involving tongue, hypopharynx, or larynx occurs, discontinue xanomeline/trospium and initiate appropriate therapy and/or measures to maintain patent airway.¹

Contraindicated in patients with hypersensitivity to trospium chloride.¹

Patients with Narrow-angle Glaucoma

Pupillary dilation may occur due to anticholinergic effects; this may trigger acute angle closure attack in patients with anatomically narrow angles.¹

Should only be used in patients with anatomically narrow angles if potential benefits outweigh risks and with careful monitoring.¹

Increases in Heart Rate

Increase in heart rate may occur.¹

Assess heart rate at baseline and as clinically indicated during treatment.¹

Anticholinergic Adverse Reactions in Patients with Renal Impairment

Systemic exposure of trospium is higher in patients with moderate and severe renal impairment.¹ Greater anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) expected in patients with moderate and severe renal impairment.¹

CNS Effects

Anticholinergic CNS effects including dizziness, confusion, hallucinations, and somnolence reported with trospium chloride.¹

Monitor patients for signs of anticholinergic effects, particularly after beginning treatment or increasing 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 patient experiences anticholinergic CNS effects.¹

Specific Populations

Pregnancy

Insufficient data in pregnant women to determine whether there is drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹ Embryofetal and developmental toxicities observed in animal reproductive studies with use of xanomeline alone or in combination with trospium chloride at maternal toxic doses.¹

Risk to pregnant patient from untreated schizophrenia.¹ Adverse perinatal outcomes with schizophrenia, including preterm birth, but not known whether this is direct result of illness or other comorbid conditions.¹

Pregnancy exposure registry at 1-866-961-2388 or[Web].¹

Lactation

Unknown whether xanomeline or trospium is distributed into human milk, or if drug has any effects on the breastfed infant or on milk production.¹ Xanomeline and trospium are present in animal milk and likely present in human milk.¹ Consider developmental and health benefits of breastfeeding along with mother’s clinical need for xanomeline/trospium and any potential adverse effects on breastfed infant from drug or underlying maternal condition.¹

Females and Males of Reproductive Potential

Fertility studies in humans not conducted.¹ No effects on fertility observed in male and female rats following administration of xanomeline; no effects on fertility observed in rats following administration of trospium chloride.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Safety and efficacy not established in geriatric patients ≥65 years of age.¹ Slower titration and lower maximum dosage recommended in geriatric patients due to increased risk of urinary retention.¹

Hepatic Impairment

Higher xanomeline exposures in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) compared to patients with normal hepatic function.¹ Safety and efficacy not established in patients with severe hepatic impairment.¹ Contraindicated in patients with moderate or severe hepatic impairment and not recommended in patients with mild hepatic impairment.¹

Renal Impairment

No clinically significant differences in safety and efficacy in patients with mild renal impairment.¹ Not recommended in patients with moderate and severe renal impairment due to increased risk of urinary retention and anticholinergic CNS adverse effects.¹

Common Adverse Effects

Most common adverse reactions (≥5%): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, GI reflux disease.¹

Drug Interactions

Xanomeline and its metabolites are not inhibitors or inducers of major CYP enzymes at the systemic level; xanomeline inhibits intestinal CYP3A4.^{1 4}

Xanomeline and its metabolites are not inhibitors of all major transporters at the systemic level; xanomeline inhibits intestinal P-glycoprotein (P-gp).^{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

Strong CYP2D6 inhibitors: Monitor for increased frequency and/or severity of adverse reactions of xanomeline/trospium in patients taking strong CYP2D6 inhibitors and xanomeline/trospium concomitantly.¹

CYP3A4 substrates: Monitor 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

P-gp substrates: Monitor for increased frequency and/or severity of adverse reactions related to oral drugs that are narrow therapeutic index substrates of P-gp in patients taking xanomeline/trospium concomitantly.¹

Active tubular secretion: Monitor for increased frequency and/or severity of adverse reactions of xanomeline/trospium and drugs that are eliminated by active tubular secretion when used concomitantly, due to competition for elimination pathway.¹

Antimuscarinic Drugs

Concomitant use with other antimuscarinic drugs may increase frequency and/or severity of anticholinergic adverse reactions (e.g., dry mouth, constipation).¹ Monitor patients for such adverse effects when used concomitantly.¹

GI Absorption of Drugs

May potentially alter 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 and Trospium Pharmacokinetics

Absorption

Food

Trospium: Maximum plasma concentration reduced by 70-75% when taken with food.¹

Distribution

Plasma Protein Binding

Xanomeline: 95%.¹

Trospium: 80%.¹

Elimination

Metabolism

Xanomeline: Metabolized primarily by CYP2D6, CYP2B6, CYP1A2, CYP2C9, CYP2C19, flavin monooxygenase (FMO)1, and FMO3.¹

Trospium: Primarily metabolized by ester hydrolysis and glucuronic acid conjugation.¹

Elimination Route

Xanomeline: 78% eliminated in urine.¹

Trospium: 85-90% eliminated unchanged through tubular secretion.¹

Half-life

Xanomeline: 5 hours.¹

Trospium: 6 hours.¹

Stability

Storage

Oral

Capsules

Store at 20–25º C.¹

Actions

• Fixed combination of xanomeline (a muscarinic agonist) and trospium (a muscarinic antagonist).¹

• Unlike other antipsychotic agents, which are D₂ dopamine receptor antagonists, xanomeline/trospium is an agonist at M₁ and M₄ muscarinic acetylcholine receptors in 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}

• Xanomeline reduces psychotic symptoms and improves cognition; however, is associated with adverse GI effects.² Addition of trospium thought to decrease adverse effects of xanomeline by antagonizing muscarinic receptors in peripheral tissues.²

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 an exposure registry that monitors outcomes in females exposed to xanomeline/trospium during pregnancy.¹

• Advise patients to inform their clinician if they are or plan to breast-feed.¹

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Inform patients of other important precautionary information.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.

Preparations

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.

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