Cobenfy
(trospium chloride)Dosage & Administration
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Cobenfy Prescribing Information
COBENFY is indicated for the treatment of schizophrenia in adults.
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)].
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.
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)].
COBENFY is available as:
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- 50 mg/20 mg (xanomeline/trospium chloride): Buff capsules imprinted with Karuna 50/20 mg
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- 100 mg/20 mg (xanomeline/trospium chloride): Brown capsules imprinted with Karuna 100/20 mg
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- 125 mg/30 mg (xanomeline/trospium chloride): Swedish Orange capsules imprinted with Karuna 125/30 mg
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/m2 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 orally treated during pregnancy and lactation with 30, 75, and 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 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. Trospium chloride alone did not cause maternal or developmental toxicity.
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.
Pregnant rabbits were treated during the period of organogenesis with trospium chloride at doses up to 200 mg/kg/day. Maternal toxicity (reduced feces, hunched posture, and diarrhea) was observed at 200 mg/kg/day. The NOAEL for maternal toxicity is 20 mg/kg/day, which is approximately 3 times the trospium chloride dose at the MRHD based on BSA.
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. The NOAEL for maternal and developmental toxicity is 20 mg/kg/day, which is approximately 3 times the trospium chloride dose at the MRHD, based BSA.
Lactation
Risk Summary
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. Xanomeline and trospium are present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COBENFY and any potential adverse effects on the breastfed infant from COBENFY or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of COBENFY in pediatric patients have not been established.
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)].
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) [see Warnings and Precautions (5.1 , 5.8) and Clinical Pharmacology (12.3)].
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.
COBENFY is contraindicated in patients with:
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- urinary retention [see Warnings and Precautions (5.1)].
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- moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.2)].
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- gastric retention [see Warnings and Precautions (5.4)].
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- history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride [see Warnings and Precautions (5.5)].
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- untreated narrow-angle glaucoma [see Warnings and Precautions (5.6)].
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.
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.
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.
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.
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.
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)].
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)].
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.
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.