Xanomeline and trospium chloride

Xanomeline and trospium chloride
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]

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Overview

Xanomeline and trospium chloride is a a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist. that is FDA approved for the treatment of of schizophrenia in adults.. Common adverse reactions include 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..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Assess liver enzymes and bilirubin prior to initiating treatment with COBENFY and as clinically indicated during treatment.

• Assess heart rate at baseline and as clinically indicated during treatment with COBENFY.

• 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.

• Dosage may be increased to 125 mg/30 mg orally twice daily based on patient tolerability and response.

• See the full prescribing information for the recommended titration and maximum recommended dosage.

• Take at least 1 hour before a meal or at least 2 hours after a meal. Do not open capsules.

• 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Xanomeline and trospium chloride in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Xanomeline and trospium chloride in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Xanomeline and trospium chloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Xanomeline and trospium chloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Xanomeline and trospium chloride in pediatric patients.

Contraindications

• urinary retention.

• moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

• gastric retention.

• history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride.

• untreated narrow-angle glaucoma.

Warnings

Risk of Urinary Retention

• COBENFY can cause urinary retention.

• 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.
• COBENFY is contraindicated in patients with pre-existing urinary retention, and is not recommended in patients with moderate or severe renal impairment.
• In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria.
• Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider.
• Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated.

Risk of Use in Patients with Hepatic Impairment

• Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions.

• COBENFY is contraindicated in patients with moderate or severe hepatic impairment.

*COBENFY is not recommended in patients with mild hepatic impairment.

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

Risk of Use in Patients with Biliary Disease

• n clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.
• COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones.
• Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. 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.
• Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.

Decreased Gastrointestinal Motility

• COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility.

• Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.

• Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

Risk of Angioedema

• Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY.

• In one case, angioedema occurred after the first dose of trospium chloride.
• Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

• COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride.

Risk of Use in Patients with Narrow-angle Glaucoma

• Pupillary dilation may occur due to the anticholinergic effects of COBENFY.

• This may trigger an acute angle closure attack in patients with anatomically narrow angles.

• In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring.

Increases in Heart Rate

• COBENFY can increase heart rate.

• Assess heart rate at baseline and as clinically indicated during treatment with COBENFY.

Anticholinergic Adverse Reactions in Patients with Renal Impairment

• Trospium chloride, a component of COBENFY, is substantially excreted by the kidney.

*COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment.

• 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

Central Nervous System Effects

• Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects

.

• A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence.

• Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.

• Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them.

• If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.

Adverse Reactions

Clinical Trials Experience

• Risk of Urinary Retention.

• Risk of Use in Patients with Hepatic Impairment.

• Risk of Use in Patients with Biliary Disease.

• Decreased Gastrointestinal Motility.

• Risk of Angioedema.

• Risk of Use in Patients with Narrow-angle Glaucoma.

• Increases in Heart Rate.

• Anticholinergic Adverse Reactions in Patients with Renal Impairment.

• Central Nervous System Effects.

• 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.
• COBENFY was evaluated for safety in a total of 1,594 subjects exposed to one or more doses, including 1,135 adult patients with schizophrenia and 389 healthy subjects. A total of 347 COBENFY-treated patients had at least 6 months of exposure and 150 patients had at least 1 year of exposure (defined as ≥ 50 weeks) from open-label studies.
• The adverse reaction findings are based on two pooled 5-week, placebo-controlled, flexible-dose studies in 504 adult patients with schizophrenia in which COBENFY or placebo was started at an initial dose of 50 mg/20 mg twice daily for the first 2 days followed by 100 mg/20 mg twice daily for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated to 125 mg/30 mg twice daily unless the patient could not tolerate it. All patients had the option to return to 100 mg/20 mg twice daily for the remainder of the treatment period.

• In the 5-week placebo-controlled studies, 6% of patients treated with COBENFY and 4% of placebo-treated patients discontinued participation due to adverse reactions. Adverse reactions that led to study discontinuation in ≥1% of patients treated with COBENFY include nausea (2%) and vomiting (1%).
• The most common adverse reactions (≥5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.
• Adverse reactions reported with COBENFY at an incidence of at least 2% in patients exposed to COBENFY and greater than the rate of placebo are shown in Table 1.

Adverse Reactions Reported in ≥2% of COBENFY-Treated Patients and Greater than Rate of Placebo in Two 5-week Schizophrenia Trials

a Dyspepsia includesdyspepsia, esophageal discomfort b Hypertension includes hypertension, blood pressure increased, labile hypertension, orthostatic hypertension c Abdominal Pain includesabdominal discomfort, abdominal pain upper, abdominal pain, abdominal pain lower, abdominal tenderness d Tachycardia includestachycardia, heart rate increased, sinus tachycardia e Cough: includes cough, productive cough f EPS (non-akathisia) includes dyskinesia, drooling, dystonia, extrapyramidal disorder, muscle contraction involuntary, muscle spasms

Increases in Heart Rate

• In a dedicated 8-week clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 133 patients with schizophrenia. A total of 95 patients had acceptable ABPM recordings at both baseline and Week 8. In that group, there was a mean change in 24-hour heart rate of 9.8 beats per minute (bpm) (95% CI 7.5, 12.2) from baseline to Week 8.
• In the two placebo-controlled schizophrenia studies, COBENFY was associated with increases in heart rate compared to placebo, with peak elevation occurring on Day 8 of study treatment (13.5 bpm in the COBENFY group and 4.0 bpm in the placebo group), partially attenuating with continued dosing (11.4 bpm in the COBENFY group and 5.5 bpm in the placebo group at Week 5).

Liver Enzyme Elevations

• In the 5-week, placebo-controlled schizophrenia studies, the proportions of patients with ALT or AST elevations of ≥3 times the upper limits of the normal reference range were 2.8% (6/214) for COBENFY-treated patients compared to 0.4% (1/224) of placebo-treated patients.
• Twenty-five (1.6%) of the total 1,594 subjects exposed to COBENFY had elevated liver enzymes. The majority of liver enzyme elevations occurred within the first month of treatment and resolved with continued COBENFY use, suggestive of liver adaptation; some cases required treatment interruption, and one was associated with an increase in bilirubin.

Urinary Retention

• In the 5-week, placebo-controlled studies, urinary retention (urinary hesitation, dysuria, and urinary retention) was reported in 0.8% of COBENFY-treated patients and 0.4% on placebo.
• In the long-term, open-label studies, urinary retention was reported in 3.5% of COBENFY-treated patients. Urinary retention was more common in males, geriatric patients, and those with certain risk factors.

*Urinary retention occurred at all doses but was predominately observed at the maximum COBENFY dose. 

• In the long-term, open-label studies, urinary tract infections were reported in 2.3% of COBENFY-treated patients and were more commonly reported in females than males. Of the total 1,594 subjects exposed to COBENFY (including healthy volunteers and patients with schizophrenia or other conditions), four subjects required a Foley catheter, including one with elevated serum creatinine and one with urinary tract infections. Four subjects with urinary retention required reduction of COBENFY dose, four discontinued COBENFY, and four received medications for the treatment of benign prostatic hyperplasia (BPH).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of trospium chloride, one of the components of COBENFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiovascular – chest pain, hypertensive crisis, palpitations, supraventricular tachycardia, syncope.

• Gastrointestinal – gastritis.

• General – rash.

• Musculoskeletal – rhabdomyolysis.

• Nervous System – confusion, delirium, dizziness, hallucinations, somnolence, vision abnormal.

• Skin and subcutaneous tissue disorders – angioedema, anaphylactic reaction, Stevens-Johnson syndrome.

Drug Interactions

Clinically Significant Drug Interactions with COBENFY

Table 2 displays clinically significant drug interactions with COBENFY.

Other Antimuscarinic Drugs

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

Effects on Absorption of Drugs

• COBENFY may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.
• Dosage adjustment of concomitant medications may be necessary based on clinical response and tolerability.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Xanomeline and trospium chloride in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Xanomeline and trospium chloride in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Xanomeline and trospium chloride during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Xanomeline and trospium chloride in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Xanomeline and trospium chloride in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Xanomeline and trospium chloride in geriatric settings.

Gender

There is no FDA guidance on the use of Xanomeline and trospium chloride with respect to specific gender populations.

Race

There is no FDA guidance on the use of Xanomeline and trospium chloride with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Xanomeline and trospium chloride in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Xanomeline and trospium chloride in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Xanomeline and trospium chloride in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Xanomeline and trospium chloride in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Xanomeline and trospium chloride Administration in the drug label.

Monitoring

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

IV Compatibility

There is limited information regarding the compatibility of Xanomeline and trospium chloride and IV administrations.

Overdosage

There is limited information regarding Xanomeline and trospium chloride overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Xanomeline and trospium chloride Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Xanomeline and trospium chloride Mechanism of Action in the drug label.

Structure

There is limited information regarding Xanomeline and trospium chloride Structure in the drug label.

Pharmacodynamics

There is limited information regarding Xanomeline and trospium chloride Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Xanomeline and trospium chloride Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Xanomeline and trospium chloride Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Xanomeline and trospium chloride Clinical Studies in the drug label.

How Supplied

There is limited information regarding Xanomeline and trospium chloride How Supplied in the drug label.

Storage

There is limited information regarding Xanomeline and trospium chloride Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Xanomeline and trospium chloride Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Xanomeline and trospium chloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Xanomeline and trospium chloride Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Xanomeline and trospium chloride Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.