2.1 Recommended Testing and Monitoring Prior to Initiation and During Treatment with COBENFY

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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)].

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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:

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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.

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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.

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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)].

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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)].

5.1 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 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.

5.4 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 [see Contraindications (4)]. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

5.5 Risk of Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY [see Adverse Reactions (6.2)]. 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.

5.6 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 [see Contraindications (4)].

5.7 Increases in Heart Rate

COBENFY can increase heart rate [see Adverse Reactions (6.1)]. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY [see Dosage and Administration (2.1)].

5.8 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 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.

5.9 Central Nervous System Effects

Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.1)]. 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.

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.

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 [see Warnings and Precautions (5.1)]. 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).

6.2 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.

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

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Gastrointestinal – gastritis

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General – rash

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Musculoskeletal – rhabdomyolysis

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

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

7.1 Clinically Significant Drug Interactions with COBENFY

Table 2 displays clinically significant drug interactions with COBENFY.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of COBENFY in pediatric patients have not been established.

8.5 Geriatric Use

Controlled clinical studies of COBENFY did not include patients older than 65 years of age to determine whether they respond differently from younger adult patients.

Because COBENFY can increase the risk of urinary retention in geriatric patients, including older males with bladder outlet obstruction due to benign prostatic hyperplasia (BPH), a slower titration and lower maximum dosage is recommended in geriatric patients [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

8.6 Renal Impairment

Patients with mild renal impairment (eGFR 60 to <90 mL/min) showed higher systemic exposures to trospium chloride and xanomeline, the components of COBENFY, compared to subjects with normal renal function. However, in the adequate and well-controlled clinical studies, the safety profiles in patients with mild renal impairment were similar to those observed in patients with normal renal function (eGFR ≥90 mL/min). Therefore, the recommended dosage in patients with mild renal impairment is the same as the recommended dosage for patients with normal renal function.

Use of COBENFY is not recommended in patients with moderate or severe renal impairment (eGFR<60 mL/min) [seeWarnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) have higher xanomeline exposures compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. The pharmacokinetics of COBENFY were not studied in patients with severe hepatic impairment (Child-Pugh Class C).

Use of COBENFY is contraindicated in patients moderate or severe hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.2)]. It is not recommended in patients with mild hepatic impairment.

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.

12.2 Pharmacodynamics

Xanomeline binds to muscarinic receptors M1 to M5 with comparable affinity (Ki=10, 12, 17, 7, and 22 nM for the M1, M2, M3, M4, and M5 receptors, respectively) and exhibits higher agonist activity at the M1 and M4 receptors.

Trospium chloride antagonizes the muscarinic receptors primarily in peripheral tissues.

Cardiac Electrophysiology
At the maximum recommended dosage of 125 mg/30 mg twice daily, COBENFY does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Following COBENFY administration, xanomeline area under the plasma concentration-time curve during a 12-hour dosing interval (AUC0-12) at steady state and maximum concentration (Cmax) increased 50% when the COBENFY dose increased from 100 mg/20 mg twice daily to 125 mg/30 mg twice daily. Trospium exposures increase dose-proportionally over the COBENFY dosage range of 100 mg/20 mg twice daily to 125 mg/30 mg twice daily.

Pharmacokinetic properties of COBENFY are provided in Table 3.

Specific Populations

Geriatric Patients
Population pharmacokinetic analysis suggests that AUC0-12h and Cmax of trospium at steady state were 60% higher and 36% higher, respectively, in subjects 65 years and older compared to subjects younger than 65 years old. The exposures (AUC0-12h and Cmax) of xanomeline at steady state were not different between subjects 65 years and older and subjects younger than 65 years old [see Dosage and Administration (2.3) and Use in Specific Populations (8.5)].

Male and Female Patients
Plasma concentrations of xanomeline and trospium are similar between females and males.

Racial or Ethnic Groups
Most subjects in clinical studies were Black.
Xanomeline and trospium exposure did not differ between Black and non-Black subjects. Studies have included too few subjects of Asian descent to evaluate comparisons.

Patients with Renal Impairment
The effect of renal impairment on xanomeline and trospium exposure was assessed in a dedicated study that enrolled healthy subjects and subjects with mild, moderate, or severe renal impairment. Estimated glomerular filtration rate (eGFR) was determined by the MDRD equation.

Plasma concentrations of xanomeline and trospium increased with increasing renal dysfunction [see Use in Specific Populations (8.6)]. For xanomeline, compared to subjects with normal renal function (eGFR: ≥90 mL/min), the steady-state Cmax and AUC0-12h were 2.1 and 1.9 times higher in subjects with mild renal impairment (eGFR: 60 to <90 mL/min), 2.4 and 2.1 times higher in subjects with moderate renal impairment (eGFR: 30 to <60 mL/min), and 2.6 and 2.4 times higher in subjects with severe renal impairment (eGFR: <30 mL/min). For trospium, compared to subjects with normal renal function, the steady-state Cmax and AUC0-12h were 1.6 and 1.6 times higher in subjects with mild renal impairment, 2.7 and 2.2 times higher in subjects with moderate renal impairment, and 2.9 and 2.9 times higher in subjects with severe renal impairment.

Patients with Hepatic Impairment
The effect of hepatic impairment on xanomeline and trospium in combination was assessed in a dedicated study that enrolled healthy subjects and subjects with mild or moderate hepatic impairment as determined by their Child-Pugh score.

Plasma concentrations of xanomeline increased with increasing hepatic dysfunction [see Use in Specific Populations (8.7)]. In subjects with mild hepatic impairment (Child-Pugh Class A), the steady-state Cmax and AUC0-12h of xanomeline was 2.8 and 2.6 times that in subjects with normal hepatic function. Mild and moderate hepatic impairment did not substantially affect trospium exposure, but significantly impacted xanomeline exposures. In subjects with moderate hepatic impairment (Child-Pugh Class B), the steady-state Cmax and AUC0-12h of xanomeline was at least 7 times that in subjects with normal hepatic function [see Contraindications (4) and Warnings and Precautions (5.2)].

The effect of severe hepatic impairment on xanomeline and trospium exposure was not evaluated.

Body Weight
Compared to subjects weighing 70 kg, xanomeline exposures were 30 to 35% lower and trospium exposures were 20 to 35% lower in subjects weighing 120 kg. The lower exposures observed in subjects weighing 120 kg are expected to be clinically not meaningful.

Drug Interaction Studies
Drugs Eliminated by Active Tubular Secretion

Active tubular excretion is a major elimination pathway for trospium. Trospium has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion. Coadministration of COBENFY with these drugs may increase plasma concentrations of trospium and/or the coadministered drug due to competition for this elimination pathway [see Drug Interactions (7.1)].

Metformin
A drug interaction study was conducted in which extended-release trospium chloride 60 mg once daily was coadministered with metformin hydrochloride 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate-release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC0-24 and by 34% for mean Cmax. The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg extended-release trospium chloride once daily under fasted conditions. The effect of metformin at higher doses on trospium pharmacokinetics is unknown.

Drugs That Inhibit CYP2D6
CYP2D6 is a significant contributor to the metabolism of xanomeline. Drugs that are inhibitors of CYP2D6 may increase xanomeline concentrations in plasma [see Drug Interactions (7.1)].

Drugs That Are Substrates of P-glycoprotein
In vitro data suggest that xanomeline does not inhibit P-glycoprotein systemically, but it may transiently inhibit P-glycoprotein locally in the intestine after dosing. COBENFY may increase plasma concentrations of coadministered P-gp substrates [see Drug Interactions (7.1)].

Drugs That Are Substrates of CYP3A4
In vitro data suggest that xanomeline does not inhibit CYP3A4 systemically, but it may transiently inhibit CYP3A4 locally in the intestine after dosing. COBENFY may increase plasma concentrations of coadministered CYP3A4 substrates [see Drug Interactions (7.1)].

12.5 Pharmacogenomics

CYP2D6 is a significant contributor to the metabolism of xanomeline. The gene encoding CYP2D6 has polymorphisms that impact protein function. Based on a population pharmacokinetic analysis, compared to subjects with normal CYP2D6 function, the median Cmax and median AUC0-12h of xanomeline were estimated to increase by 28% and 15% in CYP2D6 intermediate metabolizers (N=84) and decrease by 43% in both parameters for ultrarapid metabolizers (N=12). The pharmacokinetics of xanomeline have not been adequately characterized in subjects who are poor metabolizers.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

In the 2-year dietary study in rats, biliary cysts and/or biliary/biliary ductule dilatation were observed at xanomeline doses equal to or greater than the MRHD of 250/60 mg xanomeline/trospium chloride, based on BSA.