Xanomeline

12.1 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 central nervous system. Trospium chloride is a muscarinic antagonist. Trospium chloride antagonizes the muscarinic receptors primarily in the peripheral tissues.

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 )

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) ] .

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 mouth 4% 2% Somnolence 3% 2% Vision blurred 3% 0% Salivary hypersecretion 2% 0% Orthostatic hypotension 2% 1% Cough e 2% 1% Extrapyramidal symptoms (EPS), non-akathisia f 2% <1% 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 stu

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 with oral drugs that are substrates of P-glycoprotein may result in increased plasma concentrations of the oral drugs that are substrates of P-glycoprotein, which 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 narrow therapeutic index substrates of P-glycoprotein in patients taking COBENFY with such substrates. 7.2 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. 7.3 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.