COBENFY

/ Bristol Myers Squibb (Israel) Ltd.

Recommended Testing and Monitoring Prior to Initiation and During Treatment
* Assess liver enzymes and bilirubin prior to initiation and as clinically indicated during treatment.
* Assess heart rate at baseline and as clinically indicated during treatment.
Recommended Dosage and Administration
* The recommended starting dosage is one 50/20 mg capsule orally twice daily for at least two days.
* Increase the dosage to one 100/20 mg capsule orally twice daily for at least five days.
* The dosage may be increased to one 125/30 mg orally twice daily based on patient tolerability and response.
* Maximum recommended dosage is 125/30 mg orally twice daily.
Administer at least one hour before a meal or at least two hours after a meal.
Swallow the capsules whole. Do not open the capsules. There is no data on using the capsules this way.
Dosage Recommendations in Geriatric Patients
The recommended starting dosage 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.

Treatment of schizophrenia in adults

* Urinary retention
* Moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment
* Gastric retention
* Hypersensitivity to trospium chloride or xanomeline or to any of the excipients. Angioedema has been reported.
* Untreated narrow-angle glaucoma

Risk of Urinary Retention
This medical product can cause urinary retention. 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.
In patients taking this medical product, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose, discontinuing, or referring patients for urologic evaluation as clinically indicated.
Risk of Use in Patients with Hepatic Impairment
Patients with hepatic impairment have higher systemic exposure to xanomeline compared with those with normal hepatic function, which may increase the incidence of related adverse reactions. Assess liver enzymes prior to initiation and monitor as clinically indicated during treatment.
Risk of Use in Patients with Biliary Disease
In clinical studies, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.
This medical product is not recommended for patients with active biliary disease such as symptomatic gallstones. 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 treatment 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.
Decreased Gastrointestinal Motility
Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.
Risk of Angioedema
Angioedema of the face, lips, tongue, and/or larynx has been reported.
Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue treatment and initiate appropriate therapy and/or measures necessary to
ensure a patent airway.
Risk of Use in Patients with Narrow-angle Glaucoma
Pupillary dilation may occur due to the anticholinergic effects. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, this medical product should only be used if the potential benefits outweigh the risks and with careful monitoring.
Anticholinergic Adverse Reactions in Patients with Renal Impairment
Trospium chloride, is substantially excreted by the kidney. This medical product 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. 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.
Central Nervous System Effects
Trospium chloride, is associated with anticholinergic central nervous system (CNS) effects. 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. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.

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.
See prescribing information for full details.

Strong Inhibitors of CYP2D6: CYP2D6 contributes significantly to the metabolism of xanomeline. Concomitant use may increase plasma concentrations of xanomeline, which may increase the frequency and/or severity of adverse reactions. Examples of strong CYP2D6 inhibitors include buproprion, fluoxetine, paroxetine, quinidine and terbinafine.
Drugs Eliminated by Active Tubular Secretion: May increase plasma concentrations of trospium, 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 this medical product or the drug eliminated by active tubular secretion. Examples of drugs eliminated by active tubular secretion include: – OAT1/OAT3 transporter: adefovir, oseltamivir, tenofovir, cefaclor, ceftizoxime, ciprofloxacin, penicillin G, bumetanide, furosemide, baricitinib, famotidine, methotrexate. – MATE1/MATE2-K/OCT transporter: metformin.
Oral Drugs That Are Sensitive Substrates of CYP3A4: Xanomeline, transiently inhibits CYP3A4 locally in the gut but not systemically. Concomitant use 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.
Oral Drugs That Are Substrates of P-glycoprotein: Xanomeline, transiently inhibits Pglycoprotein locally in the gut but not systemically. Concomitant use 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. Examples of clinical substrates for P-gp include dabigatran etexilate, digoxin, edoxaban, and fexofenadine.
Other Antimuscarinic Drugs: Concomitant use with other antimuscarinic drugs that produce anticholinergic adverse reactions (e.g., dry mouth, constipation) may increase the frequency and/or severity of such effects.
Effects on Absorption of Drugs: This medical prodcut 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: There are no available data in pregnant women use, 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
Lactation: There are no data on the presence of xanomeline or trospium in human milk, the effects on the breastfed infant, or the effects on milk production.          
See prescribing information for full details.

Overdose 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.