Cobenfy Drug Information

COBENFY is indicated for the treatment of schizophrenia in adults.

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

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. • 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. Do not open the capsules.

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.

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. 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. Table 1: Adverse Reactions Reported in ≥2% of COBENFY-Treated Patients and Greater than Rate of Placebo in Two 5-week Schizophrenia Trials 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 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

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.

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. 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. This may increase the frequency and/or severity of adverse reactions from such substrates. 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.

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.

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 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. 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.

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. Xanomeline alone at ≥ 75 mg/kg/day or in combination with trospium chloride at ≥ 75/50 mg/kg/day caused maternal toxicity of adverse clinical signs, decreased body weight, weight gain, food consumption, and maternal death.

At these maternally toxic doses, developmental toxicity was observed in the offspring, including growth suppression (decreased body weight and weight gain), delayed developmental landmarks, stillborn pups, and neonatal deaths. No drug effect was observed on the neurobehavioral function, including learning and memory, or the reproductive capacity of the offspring. The NOAEL for maternal and developmental toxicity is 30/25 mg/kg/day for the xanomeline/trospium chloride combination, which is approximately 1 and 4 times the xanomeline and trospium chloride dose, respectively at the MRHD, based on BSA.

Pregnant rats were treated during the period of organogenesis with trospium chloride at doses up to 200 mg/kg/day. No malformation or fetal toxicity was observed up to 200 mg/kg/day, which is approximately 32 times the trospium chloride dose at the MRHD of 250/60 mg xanomeline/trospium chloride based on BSA. Maternal toxicity (reduced feces, hunched posture, and diarrhea) was observed at 200 mg/kg/day.

Rats were orally treated during pregnancy and lactation with trospium chloride at doses up to 200 mg/kg/day. Maternal toxicity (death, irregular breathing, increased excitability) and neonatal deaths were observed at 200 mg/kg/day, which is approximately 32 times the MRHD, based on BSA.

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

• COBENFY is contraindicated in patients with:
• 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. COBENFY is contraindicated in:
• Urinary retention
• Moderate or severe hepatic impairment
• Gastric retention
• History of hypersensitivity to COBENFY or trospium chloride
• Untreated narrow-angle glaucoma

• 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.