Detrol La
(tolterodine tartrate)Dosage & Administration
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Detrol LA Prescribing Information
DETROL LA Capsules is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see Clinical Studies (14)].
Dosing Information
The recommended dose of DETROL LA 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 DETROL LA 2 mg [see Clinical Studies (14)].
Dosage Adjustment in Specific Populations
For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10-30 mL/min), the recommended dose of DETROL LA is 2 mg once daily. DETROL LA is 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 DETROL LA in this population is not recommended [see Warnings and Precautions (5.6) and Use in Specific Populations (8.6, 8.7)].
Dosage Adjustment in Presence of Concomitant Drugs
For patients who are taking drugs that are potent inhibitors of CYP3A4 [e.g., ketoconazole, clarithromycin, ritonavir], the recommended dose of DETROL LA is 2 mg once daily [see Drug Interactions (7.2)].
The 2 mg capsules are blue-green with symbol and 2 printed in white ink.
The 4 mg capsules are blue with symbol and 4 printed in white ink.
Pregnancy
Risk Summary
There are no available data with DETROL LA use in pregnant women to inform drug-associated risks. In animal reproduction studies, oral administration of tolterodine and its 5-HMT metabolite to pregnant mice during organogenesis did not produce adverse developmental outcomes at doses approximately 9 to 12 times the clinical exposure at a dose of 20 mg/kg/day; however, higher doses produced adverse developmental outcomes (see Data).
In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
No anomalies or malformations were observed after oral administration of tolterodine to pregnant mice during organogenesis at approximately 9-12 times the clinical exposure to the pharmacologically active components of DETROL LA (based on the AUC of tolterodine and its 5-HMT metabolite at a dose of 20 mg/kg/day). At 14-18 times the clinical exposure (doses of 30 to 40 mg/kg/day) in mice, tolterodine was embryo-lethal, caused reduced fetal weight, and increased the incidence of fetal abnormalities (cleft palate, digital abnormalities, intra‑abdominal hemorrhage, and various skeletal abnormalities, primarily reduced ossification). Pregnant rabbits administered tolterodine 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.
Lactation
Risk Summary
There is no information on the presence of tolterodine or its 5-HMT metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Based on limited data, tolterodine is excreted into the milk in mice in low amounts (see Data). The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for DETROL LA and any potential adverse effects on the breastfed infant from DETROL LA or from the underlying maternal condition.
Animal Data
The use of radiolabeled tolterodine in pregnant mice produced milk: plasma ratios that ranged between 0.0 and 0.7.
Pediatric Use
The effectiveness of DETROL LA has not been established in pediatric patients.
Efficacy was not established in two randomized, placebo-controlled, double-blind, 12-week studies that enrolled 710 pediatric patients (486 on DETROL LA, 224 on placebo) aged 5–10 years with urinary frequency and urge incontinence. The percentage of patients with urinary tract infections was higher in patients treated with DETROL LA (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 DETROL LA 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 DETROL LA 2 mg daily. Patients with CCr<10 mL/min have not been studied and use of DETROL LA in this population is not recommended [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)]. DETROL LA has 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 DETROL LA 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].
DETROL LA is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL LA is also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL LA, are metabolized to 5-hydroxymethyl tolterodine [see Warnings and Precautions (5.2, 5.3, 5.4)].
Angioedema
Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL LA. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL LA should be discontinued and appropriate therapy promptly provided.
Urinary Retention
Administer DETROL LA Capsules with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].
Gastrointestinal Disorders
Administer DETROL LA with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
DETROL LA, 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 DETROL LA with caution in patients being treated for narrow-angle glaucoma [see Contraindications (4)].
Central Nervous System Effects
Detrol LA is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)] including dizziness and somnolence [see Adverse Reactions (6.1)]. 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 DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Renal Impairment
Renal impairment can significantly alter the disposition of tolterodine and its metabolites. The dose of DETROL LA 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 DETROL LA in this population is not recommended [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)].
Myasthenia Gravis
Administer DETROL LA 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 (12.2)], 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 DETROL LA 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 DETROL or DETROL LA.