Tolterodine Tartrate

Tolterodine tartrate extended-release capsules are an antimuscarinic indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (

• 4 mg capsules taken orally once daily with water and swallowed whole. (
  
  
  
  2.1 Dosing Information

  The recommended dose of tolterodine tartrate extended-release capsules is 4 mg once daily with water and swallowed whole. The dose may be lowered to 2 mg daily based on individual response and tolerability; however, limited efficacy data are available for tolterodine tartrate extended-release capsules 2 mg [

  see

  CLINICAL STUDIES

  ].
  )
  
  
• 2 mg capsules taken orally once daily with water and swallowed whole in the presence of:
  
  
  
  
    °  mild to moderate hepatic impairment (Child-Pugh class A or B)  (
  
  
  
  2.2 Dosage Adjustment in Specific Populations

  For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).  Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  WARNINGS AND PRECAUTIONS

  and

  USE IN SPECIFIC POPULATIONS

  ]

  .
  )
  
  
  
  
    °  severe renal impairment [Creatinine Clearance (CCr) 10 to 30 mL/min] (
  
  
  
  2.2 Dosage Adjustment in Specific Populations

  For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).  Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  WARNINGS AND PRECAUTIONS

  and

  USE IN SPECIFIC POPULATIONS

  ]

  .
  )
  
  
  
  
    °  drugs that are potent CYP3A4 inhibitors. (
  
  
  
  2.2 Dosage Adjustment in Specific Populations

  For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).  Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  WARNINGS AND PRECAUTIONS

  and

  USE IN SPECIFIC POPULATIONS

  ]

  .
  )
  
  
• Tolterodine tartrate extended-release capsules are not recommended for use in patients with CCr <10 mL/min. (
  
  
  
  2.2 Dosage Adjustment in Specific Populations

  For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).  Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  WARNINGS AND PRECAUTIONS

  and

  USE IN SPECIFIC POPULATIONS

  ]

  .
  )
  
  
• Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). (
  
  
  
  2.2 Dosage Adjustment in Specific Populations

  For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10 to 30 mL/min), the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).  Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  WARNINGS AND PRECAUTIONS

  and

  USE IN SPECIFIC POPULATIONS

  ]

  .
  )
  
  

Capsules: 2 mg and 4 mg (

• Renal Impairment:
  Tolterodine tartrate extended-release capsules are not recommended for use in patients with CCr <10 mL/min. Dose adjustment in severe renal impairment (CCr: 10 to 30 mL/min). (
  
  
  
  8.6 Renal Impairment

  Renal impairment can significantly alter the disposition of tolterodine immediate release and its metabolites. In a study conducted in patients with creatinine clearance between 10 and 30 mL/min, tolterodine and 5-HMT levels were approximately 2 to 3 fold higher in patients with renal impairment than in healthy volunteers. Exposure levels of other metabolites of tolterodine (e.g., tolterodine acid,

  N

  -dealkylated tolterodine acid,

  N-

  dealkylated tolterodine, and

  N

  -dealkylated hydroxy tolterodine) were significantly higher (10 to 30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with severe renal impairment (CCr: 10 to 30 mL/min) is tolterodine tartrate extended-release capsules 2 mg daily. Patients with CCr<10 mL/min have not been studied and use of tolterodine tartrate extended-release capsules in this population is not recommended [

  see

  DOSAGE AND ADMINISTRATION

  and

  WARNINGS AND PRECAUTIONS

  ]

  .

  Tolterodine tartrate extended-release capsules have not been studied in patients with mild to moderate renal impairment [CCr 30 to 80 mL/min].
  )
  
  
• Hepatic Impairment:
  Not recommended for use in severe hepatic impairment (Child Pugh Class C). Dose adjustment in mild to moderate hepatic impairment (Child Pugh Class A, B). (
  
  
  
  8.7 Hepatic Impairment

  Liver impairment can significantly alter the disposition of tolterodine immediate release. In a study of tolterodine immediate release conducted in cirrhotic patients (Child-Pugh Class A and B), the elimination half-life of tolterodine immediate release was longer in cirrhotic patients (mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4 hours). The clearance of orally administered tolterodine immediate release was substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) is tolterodine tartrate extended-release capsules 2 mg once daily. Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see

  DOSAGE AND ADMINISTRATION

  and

  WARNINGS AND PRECAUTIONS

  ] .
  )
  
  

• Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of   tolterodine tartrate extended-release capsules. (
  
  
  
  5.1 Angioedema

  Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended-release capsules. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, tolterodine tartrate extended-release capsules should be discontinued and appropriate therapy promptly provided.
  )
  
  
• Urinary Retention: use caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. (
  
  
  
  5.2 Urinary Retention

  Administer tolterodine tartrate extended-release capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [

  see

  CONTRAINDICATIONS

  ].
  )
  
  
• Gastrointestinal Disorders: use caution in patients with gastrointestinal obstructive disorders or decreased gastrointestinal motility because of the risk of gastric retention. (
  
  
  
  5.3 Gastrointestinal Disorders

  Administer tolterodine tartrate extended-release capsules with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.

  Tolterodine tartrate extended-release capsules, like other antimuscarinic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions associated with decreased gastrointestinal motility (e.g., intestinal atony) [

  see

  CONTRAINDICATIONS

  ].
  )
  
  
• Controlled Narrow-Angle Glaucoma: use caution in patients being treated for narrow-angle glaucoma. (
  
  
  
  5.4 Controlled Narrow-Angle Glaucoma

  Administer tolterodine tartrate extended-release capsules with caution in patients being treated for narrow-angle glaucoma [

  see

  CONTRAINDICATIONS

  ].
  )
  
  
• Central Nervous System Effects: Somnolence has been reported with tolterodine tartrate extended-release capsules. Advise patients not to drive or operate heavy machinery until they know how tolterodine tartrate extended-release capsules affect them. (
  
  
  
  5.5 Central Nervous System Effects

  Tolterodine tartrate extended-release capsules are associated with anticholinergic central nervous system (CNS) effects

  [see Adverse Reactions ]

  including dizziness and somnolence

  [see Adverse Reactions ]

  . Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until the drug's effects have been determined. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
  )
  
  
• Myasthenia Gravis: use caution in patients with myasthenia gravis. (
  
  
  
  5.8 Myasthenia Gravis

  Administer tolterodine tartrate extended-release capsules with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
  )
  
  
• QT Prolongation : consider observations from the thorough QT study in clinical decisions to prescribe tolterodine tartrate extended-release capsules to patients with a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. (
  
  
  
  5.9 Use in Patients with Congenital or Acquired QT Prolongation

  In a study of the effect of tolterodine immediate release tablets on the QT interval [

  see

  CLINICAL PHARMACOLOGY

  ], the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped.

  These observations should be considered in clinical decisions to prescribe tolterodine tartrate extended-release capsules to patients with a known history of QT prolongation or to patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. There has been no association of Torsade de Pointes in the international post-marketing experience with tolterodine tartrate immediate release tablets or tolterodine tartrate extended-release capsules.
  )