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Tolterodine Extended Release (Tolterodine Tartrate) - Warnings and Precautions

 
 



WARNINGS AND PRECAUTIONS

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

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 (4) ].

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 (4) ].

Controlled Narrow-Angle Glaucoma

Administer tolterodine tartrate extended-release capsules with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS (4) ].

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.

Hepatic Impairment

The clearance of orally administered tolterodine immediate-release was substantially lower in cirrhotic patients than in the healthy volunteers. For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the recommended dose for 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) [see DOSAGE AND ADMINISTRATION and USE IN SPECIFIC POPULATIONS ].

Renal Impairment

Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of tolterodine tartrate extended-release capsules should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10–30 mL/min). 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 USE IN SPECIFIC POPULATIONS ].

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.

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 extended-release capsules.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

At approximately 9–12 times the clinical exposure to the pharmacologically active components of tolterodine tartrate extended-release capsules, no anomalies or malformations were observed in mice (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day). At 14–18 times the exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine has been shown to be embryolethal and reduce fetal weight, and increase the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification). Pregnant rabbits treated subcutaneously at about 0.3 – 2.5 times the clinical exposure (dose of 0.8 mg/kg/day) did not show any embryotoxicity or teratogenicity. There are no studies of tolterodine in pregnant women. Therefore, tolterodine tartrate extended-release capsules should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus.

Nursing Mothers

Tolterodine is excreted into the milk in mice. Offspring of female mice treated with tolterodine 20 mg/kg/day during the lactation period had slightly reduced body weight gain. The offspring regained the weight during the maturation phase.

It is not known whether tolterodine is excreted in human milk; therefore, tolterodine tartrate extended-release capsules should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue tolterodine tartrate extended-release capsules in nursing mothers.

Pediatric Use

Efficacy in the pediatric population has not been demonstrated.

The pharmacokinetics of tolterodine extended-release capsules have been evaluated in pediatric patients ranging in age from 11–15 years. The dose-plasma concentration relationship was linear over the range of doses assessed. Parent/metabolite ratios differed according to CYP2D6 metabolizer status [see CLINICAL PHARMACOLOGY ]. CYP2D6 extensive metabolizers had low serum concentrations of tolterodine and high concentrations of the active metabolite 5-HMT, while poor metabolizers had high concentrations of tolterodine and negligible active metabolite concentrations.

A total of 710 pediatric patients (486 on tolterodine tartrate extended-release capsules, 224 on placebo) aged 5–10 with urinary frequency and urge incontinence were studied in two randomized, placebo-controlled, double-blind, 12-week studies. The percentage of patients with urinary tract infections was higher in patients treated with tolterodine tartrate extended-release capsules (6.6%) compared to patients who received placebo (4.5%). Aggressive, abnormal, and hyperactive behavior and attention disorders occurred in 2.9% of children treated with tolterodine tartrate extended-release capsules compared to 0.9% of children treated with placebo.

Geriatric Use

No overall differences in safety were observed between the older and younger patients treated with tolterodine.

In multiple-dose studies in which tolterodine immediate-release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine and of 5-HMT were similar in healthy elderly volunteers (aged 64 through 80 years) and healthy young volunteers (aged less than 40 years). In another clinical study, elderly volunteers (aged 71 through 81 years) were given tolterodine immediate-release 2 or 4 mg (1 or 2 mg bid). Mean serum concentrations of tolterodine and 5-HMT in these elderly volunteers were approximately 20% and 50% higher, respectively, than concentrations reported in young healthy volunteers. However, no overall differences were observed in safety between older and younger patients on tolterodine in the Phase 3, 12-week, controlled clinical studies; therefore, no tolterodine dosage adjustment for elderly patients is recommended.

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 2–3 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 (10–30 fold) in renally impaired patients as compared to the healthy volunteers. The recommended dose for patients with severe renal impairment (CCr: 10–30 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 30–80 mL/min].

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 ].

Gender

The pharmacokinetics of tolterodine immediate-release and 5-HMT are not influenced by gender. Mean Cmax of tolterodine immediate-release (1.6 µg/L in males versus 2.2 µg/L in females) and the active 5-HMT (2.2 µg/L in males versus 2.5 µg/L in females) are similar in males and females who were administered tolterodine immediate-release 2 mg. Mean AUC values of tolterodine (6.7 µgh/L in males versus 7.8 µgh/L in females) and 5-HMT (10 µgh/L in males versus 11 µgh/L in females) are also similar. The elimination half-life of tolterodine immediate-release for both males and females is 2.4 hours, and the half-life of 5-HMT is 3.0 hours in females and 3.3 hours in males.

Race

Pharmacokinetic differences due to race have not been established.

Page last updated: 2014-05-30

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