Cobenfy

COBENFY is indicated for the treatment of schizophrenia in adults.

• •Assess liver enzymes and bilirubin prior to initiating treatment with COBENFY and as clinically indicated during treatment. (
  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)]
    .
  )
• •Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. (
  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)]
    .
  )
• •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 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.
  )
• •Dosage may be increased to 125 mg/30 mg orally twice daily based on patient tolerability and response. (
  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.
  )
• •See the full prescribing information for the recommended titration and maximum recommended dosage. (
  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.
  )
• •Take at least 1 hour before a meal or at least 2 hours after a meal. Do not open capsules. (
  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.
  )
• •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 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:

• •50 mg/20 mg (xanomeline/trospium chloride): Buff capsules imprinted with Karuna 50/20 mg
• •100 mg/20 mg (xanomeline/trospium chloride): Brown capsules imprinted with Karuna 100/20 mg
• •125 mg/30 mg (xanomeline/trospium chloride): Swedish Orange capsules imprinted with Karuna 125/30 mg

• •Moderate or Severe Renal Impairment: Not recommended. (
  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)

  [see

  Warnings and Precautions (5.1

  , 5.8)

  and Clinical Pharmacology (12.3)]

  .
  )
• •Mild Hepatic Impairment: Not recommended. (
  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.
  )

• •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 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: 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 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: 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 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 may decrease gastrointestinal motility. Use with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. (
  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.
  )
• •Risk of Angioedema: Angioedema of the face, lips, tongue and/or larynx has been reported with COBENFY. (
  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.
  )
• •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 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 may increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. (
  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)]

  .
  )
• •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 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: COBENFY may be associated with CNS effects. Advise patients not drive or operate heavy machinery until they know how COBENFY affects them. (
  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.
  )