Cobenfy

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) ] .

5 WARNINGS AND PRECAUTIONS • Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with bladder outlet obstruction and incomplete bladder emptying are at increased risk. Monitor patients for symptoms of acute urinary retention. ( 5.1 ) • Risk of Use in Patients with Hepatic Impairment: COBENFY is contraindicated in patients with moderate to severe hepatic impairment and is not recommended in patients with mild hepatic impairment. ( 5.2 ) • Risk of Use in Patients with Biliary Disease: Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury. ( 5.3 ) • Decreased Gastrointestinal Motility: COBENFY may decrease gastrointestinal motility. Use with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. ( 5.4 ) • Risk of Angioedema: Angioedema of the face, lips, tongue and/or larynx has been reported with COBENFY. ( 5.5 ) • Risk of Use in Patients with Narrow-angle Glaucoma: Use COBENFY only if the potential benefits outweigh the risks and with careful monitoring. ( 5.6 ) • Increases in Heart Rate: COBENFY may increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 5.7 ) • Anticholinergic Adverse Reactions in Patients with Renal Impairment: COBENFY is not recommended for use in patients with moderate and severe renal impairment. Anticholinergic adverse reactions are expected to be greater in these patients. ( 5.8 ) • Central Nervous System Effects: COBENFY may be associated with CNS effects. Advise patients not drive or operate heavy machinery until they know how COBENFY affects them. ( 5.9 ) 5.1 Risk of Urinary Retention COBENFY can cause urinary retention [see Adverse Reactions (6.1 )] . 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 [see Use in Specific Populations (8.5) ] . COBENFY is contraindicated in patients with pre-existing urinary retention [see Contraindications (4) ] and is not recommended in patients with moderate or severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 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. 5.2 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 [see Clinical Pharmacology (12.3) ] . COBENFY is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4) ] . COBENFY is not recommended in patients with mild hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment. 5.3 Risk of Use in Patients with Biliary Disease In 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 [see Adverse Reactions (6.1) ] . COBENFY is not recommended for patients with active biliary disease such as symptomatic ga…

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 )

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 co…

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 pregnant patient from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Data Animal Data Pregnant rats were orally treated during the period of organogenesis with 150 mg/kg/day xanomeline alone, 100 mg/kg/day trospium chloride alone, or xanomeline/trospium chloride combination at 30/25, 75/50, and 150/100 mg/kg/day, respectively. Xanomeline alone and the high dose combination caused maternal toxicities of decreased body weight, weight gain, and food consumption. At these maternally toxic doses, fetal weights were decreased. The NOAEL for maternal and embryofetal toxicity is 75/50 mg/kg/day for the combination, which is approximately 3 and 8 times the xanomeline and trospium chloride dose, respectively, at the MRHD of 250/60 mg xanomeline/trospium chloride, based on BSA. No fetal malformation was observed. Trospium chloride alone did not cause maternal or embryofetal toxicity. Pregnant rabbits were orally treated during the period of organogenesis with120 mg/kg/day xanomeline alone, 80 mg/kg/day trospium chloride alone, or xanomeline/trospium chloride combination at 30/20, 60/40, and 120/80 mg/kg/day, respectively. Xanomeline alone and the high dose combination caused maternal toxicities of decreased body weight, weight gain, and food consumption, and/or early abortion. At these maternally toxic doses, decreased fetal weight and decreased fetal viability (increased resorption and post-implantation loss) were observed. The NOAEL for maternal and embryofetal toxicity is 60/40 mg/kg/day for the xanomeline/trospium chloride combination, which is 5 and 13 times the xanomeline and trospium chloride dose, respectively at the MRHD, based on BSA. No fetal malformation was observed. Trospium chloride alone did not cause maternal or embryofetal toxicity. Rats were oral…

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…