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Xanomeline And Trospium Chloride

FDA Drug Information • Also known as: Cobenfy

Brand Names
Cobenfy
Dosage Form
CAPSULE
Product Type
DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist. The chemical name of xanomeline tartrate is pyridine, 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methyl-, (2R,3R)-2,3-dihydroxybutanedioate (1:1). Its molecular formula is C 14 H 23 N 3 OS.C 4 H 6 O 6 and its molecular weight is 431.51 g/mol. Xanomeline tartrate is a white to slightly tan crystalline solid. Xanomeline tartrate is highly soluble in protic solvents, such as methanol and water, and in polar organic solvents such as DMF and dimethyl sulfoxide (DMSO). It is poorly soluble in lipophilic organic solvents, such as hexane or octanol. The chemical structure of xanomeline tartrate is: Trospium chloride is a quaternary ammonium compound with the chemical name of spiro[8-azoniabicyclo[3.2.1]octane-8,1′-pyrrolidinium], 3-[(2-hydroxy-2,2-diphenylacetyl)oxy]-, chloride (1:1), (1α,3β,5α). The molecular formula of trospium chloride is C 25 H 30 NO 3 .Cl and its molecular weight is 427.96 g/mol. Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. Trospium chloride is highly soluble in water, freely soluble in methanol, and practically insoluble in methylene chloride. The chemical structure of trospium chloride is: COBENFY (xanomeline and trospium chloride) is for oral administration and is available in capsules in the following strengths:

  • 50 mg/20 mg (equivalent to 76.7 mg xanomeline tartrate and 18.3 mg trospium).
  • 100 mg/20 mg (equivalent to 153.3 mg xanomeline tartrate and 18.3 mg trospium).
  • 125 mg/30 mg (equivalent to 191.7 mg xanomeline tartrate and 27.5 mg trospium). COBENFY capsules contain a combination of pellets of xanomeline and pellets of trospium chloride. Inactive ingredients: The xanomeline tartrate pellets contain ascorbic acid, microcrystalline cellulose, and talc. The trospium chloride pellets contain lactose monohydrate, microcrystalline cellulose, and talc. The capsules,...

    • What Is Xanomeline And Trospium Chloride Used For?

    1 INDICATIONS AND USAGE 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. ( 1 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • 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.
  • Increase the dosage to one 100 mg/20 mg capsule (contains 100 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least five days.
  • The dosage may be increased to one 125 mg/30 mg capsule (contains 125 mg of xanomeline and 30 mg of trospium chloride) orally twice daily based on patient tolerability and response [see Clinical Studies (14) ] .
  • Maximum recommended dosage is 125 mg/30 mg orally twice daily. Administer COBENFY orally at least one hour before a meal or at least two hours after a meal [see Clinical Pharmacology (12.3) ] . Do not open the capsules. 2.3 Dosage Recommendations in Geriatric Patients The recommended starting dosage of COBENFY in geriatric patients is one 50 mg/20 mg capsule orally twice daily. Consider a slower titration for geriatric patients. The maximum recommended dosage in geriatric patients is one 100 mg/20 mg capsule twice daily [see Warnings and Precautions (5.1 , 5.8) and Use in Specific Populations (8.5) ] .

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS 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. 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 [see Clinical Studies (14) ] . 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. 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 includes dyspepsia, esophageal discomfort b Hypertension includes hypertension, blood pressure increased, labile hypertension, orthostatic hypertension c Abdominal Pain includes abdominal discomfort, abdominal pain upper, abdominal pain, abdominal pain lower, abdominal tenderness d Tachycardia includes tachycardia, 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 COBENFY (N=251) Placebo (N=253) Nausea 19% 4% Dyspepsia a 18% 5% Constipation 17% 7% Vomiting 15% 1% Hypertension b 11% 2% Abdominal Pain c 8% 4% Diarrhea 6% 2% Tachycardia d 5% 2% Dizziness 5% 2% Gastroesophageal reflux disease 5% <1% Dry...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Drugs Eliminated by Active Tubular Secretion: Monitor for increased frequency and/or severity of adverse reactions related to COBENFY and to drugs eliminated by active tubular secretion. ( 7.1 )
  • Strong CYP2D6 Inhibitors: Monitor for increased frequency and/or severity of COBENFY-related adverse reactions. ( 7.1 )
  • Sensitive Substrates of CYP3A4 or P-glycoprotein: Monitor for increased frequency and/or severity of adverse reactions from these substrates. ( 7.1 )
  • Antimuscarinic Drugs: Monitor for increased frequency or severity of anticholinergic adverse reactions. ( 7.2 ) 7.1 Clinically Significant Drug Interactions with COBENFY Table 2 displays clinically significant drug interactions with COBENFY. Table 2: Clinically Significant Drug Interactions with COBENFY Strong Inhibitors of CYP2D6 Clinical Implication: CYP2D6 contributes significantly to the metabolism of xanomeline, a component of COBENFY. Concomitant use of COBENFY with strong CYP2D6 inhibitors may increase plasma concentrations of xanomeline, which may increase the frequency and/or severity of adverse reactions from COBENFY [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to COBENFY in patients taking COBENFY with strong inhibitors of CYP2D6. Drugs Eliminated by Active Tubular Secretion Clinical Implication: Concomitant use of COBENFY with drugs that are eliminated by active tubular secretion may increase plasma concentrations of trospium a component of COBENFY, and/or the concomitantly used drug due to competition for this elimination pathway, which may increase the frequency and/or severity of adverse reactions from COBENFY or the drug eliminated by active tubular secretion [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to COBENFY and adverse reactions related to drugs eliminated by active tubular secretion in patients concomitantly receiving such drugs. Oral Drugs That Are Sensitive Substrates of CYP3A4 Clinical Implication: Xanomeline, a component of COBENFY, transiently inhibits CYP3A4 locally in the gut but not systemically. Concomitant use of COBENFY with oral drugs that are sensitive substrates of CYP3A4 may result in increased plasma concentrations of the oral drugs that are sensitive substrates of CYP3A4. This may increase the frequency and/or severity of adverse reactions from such substrates [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to oral drugs that are sensitive substrates of CYP3A4 in patients taking COBENFY with such substrates. Oral Drugs That Are Substrates of P-glycoprotein Clinical Implication: Xanomeline, a component of COBENFY, transiently inhibits P-glycoprotein locally in the gut but not systemically. Concomitant use of COBENFY...

    • Contraindications

    4 CONTRAINDICATIONS 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) ] .
  • gastric retention [see Warnings and Precautions (5.4) ] .
  • history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride [see Warnings and Precautions (5.5) ] .
  • untreated narrow-angle glaucoma [see Warnings and Precautions (5.6) ] . COBENFY is contraindicated in:
  • urinary retention ( 4 )
  • moderate or severe hepatic impairment ( 4 )
  • gastric retention ( 4 )
  • history of hypersensitivity to COBENFY or trospium chloride ( 4 )
  • untreated narrow-angle glaucoma ( 4 )

    • Pregnancy and Breastfeeding

    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. The no observed adverse effect level (NOAEL) of xanomeline or xanomeline/trospium chloride combination for maternal, embryofetal, and/or developmental toxicity is equal to or higher than the xanomeline and trospium chloride dose at the maximum recommended human dose (MRHD) of 250/60 mg xanomeline/trospium chloride, based on mg/m 2 body surface area (BSA) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk There is a risk to the...

    Overdosage

    10 OVERDOSAGE 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.

    • How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied COBENFY is available as:

  • 50 mg/20 mg (xanomeline/trospium chloride): Buff capsules imprinted with Karuna 50/20 mg
  • 100 mg/20 mg (xanomeline/trospium chloride): Brown capsules imprinted with Karuna 100/20 mg
  • 125 mg/30 mg (xanomeline/trospium chloride): Swedish Orange capsules imprinted with Karuna 125/30 mg COBENFY capsules are packaged as described in Table 5. Table 5: COBENFY Packaging Configurations Capsule Strength Total Package Count Package Configuration Package Components NDC Code 50 mg/20 mg 60 Bottle N/A 0003-0050-60 100 Hospital Unit-Dose Blister 10 Blister Cards with 10 Capsules Each 0003-0050-98 100 mg/20 mg 60 Bottle N/A 0003-1100-60 100 Hospital Unit-Dose Blister 10 Blister Cards with 10 Capsules Each 0003-1100-98 125 mg/30 mg 60 Bottle N/A 0003-0125-60 100 Hospital Unit-Dose Blister 10 Blister Cards with 10 Capsules Each 0003-0125-98 50 mg/20 mg (4) 100 mg/20 mg (52) 56 Starter Pack for 100 mg/20 mg dose 1 Mixed Blister Wallet: four (4) 50 mg/20 mg capsules and ten (10) 100 mg/20 mg capsules and 3 Wallets: fourteen (14) 100 mg/20 mg capsules in each wallet 0003-5200-56 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.