Data from FDA - Curated by EPG Health - Last updated 07 October 2017

Indication(s)

1 INDICATIONS AND USAGE Tolterodine tartrate extended-release capsules are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see CLINICAL STUDIES (14) ]. Tolterodine tartrate extended-release capsules are an antimuscarinic indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Tolterodine tartrate extended-release capsules are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tartrate extended-release capsules are also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tartrate extended-release capsules , are metabolized to 5-hydroxymethyl tolterodine [see WARNINGS AND PRECAUTIONS (5.2) (5.3) , (5.4) ]. Tolterodine tartrate extended-release capsules are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Tolterodine tartrate extended-release capsules are also contraindicated in patients with known hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like tolterodine tartrate extended-release capsules, are metabolized to 5-hydroxymethyl tolterodine. (4)
Adverse reactions
6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥4% and >placebo) were dry mouth, headache, constipation, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The efficacy and safety of tolterodine tartrate extended-release capsules was evaluated in 1073 patients (537 assigned to tolterodine tartrate extended-release capsules; 536 assigned to placebo) who were treated with 2, 4, 6, or 8 mg/day for up to 15 months. These included a total of 1012 patients (505 randomized to tolterodine tartrate extended-release capsules 4 mg once daily and 507 randomized to placebo) enrolled in a randomized, placebo-controlled, double-blind, 12-week clinical efficacy and safety study. Adverse events were reported in 52% (n=263) of patients receiving tolterodine tartrate extended-release capsules and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving tolterodine tartrate extended-release capsules were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with tolterodine tartrate extended-release capsules, occurring in 23.4% of patients treated with tolterodine tartrate extended-release capsules and 7.7% of placebo-treated patients. Dry mouth, constipation, abnormal vision (accommodation abnormalities), urinary retention, and dry eyes are expected side effects of antimuscarinic agents. A serious adverse event was reported by 1.4% (n=7) of patients receiving tolterodine tartrate extended-release capsules and by 3.6% (n=18) of patients receiving placebo. Table 1 lists the adverse events, regardless of causality, that were reported in the randomized, double-blind, placebo-controlled 12-week study at an incidence greater than placebo and in greater than or equal to 1% of patients treated with tolterodine tartrate extended-release capsules 4 mg once daily. Table 1. Incidencein nearest integer. (%) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with Tolterodine Tartrate Extended-Release Capsules (4 mg daily) in a 12-week, Phase 3 Clinical Trial Body System Adverse Event % Tolterodine Tartrate Extended-Release Capsules n=505 % Placebo n=507 Autonomic Nervous dry mouth 23 8 General headache 6 5 fatigue 2 1 Central/Peripheral Nervous dizziness 2 1 Gastrointestinal constipation 6 4 abdominal pain 4 2 dyspepsia 3 1 Vision xerophthalmia 3 2 vision abnormal 1 0 Psychiatric somnolence 3 2 anxiety 1 0 Respiratory sinusitis 2 1 Urinary dysuria 1 0 The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with tolterodine tartrate extended-release capsules or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving tolterodine tartrate extended-release capsules [n=12 (2.4%) vs. placebo n=6 (1.2%)]. 6.2 Post-marketing Experience The following events have been reported in association with tolterodine use in worldwide post-marketing experience: General: anaphylaxis and angioedema; Cardiovascular: tachycardia, palpitations, peripheral edema; Gastrointestinal: diarrhea; Central/Peripheral Nervous: confusion, disorientation, memory impairment, hallucinations. Reports of aggravation of symptoms of dementia (e.g., confusion, disorientation, delusion) have been reported after tolterodine therapy was initiated in patients taking cholinesterase inhibitors for the treatment of dementia. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tolterodine in their causation cannot be reliably determined.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 4 mg capsules taken orally once daily with water and swallowed whole. (2.1) 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) severe renal impairment [Creatinine Clearance (CCr) 10–30 mL/min] (2.2) drugs that are potent CYP3A4 inhibitors. (2.2) Tolterodine tartrate extended-release capsules are not recommended for use in patients with CCr <10 mL/min. (2.2) Tolterodine tartrate extended-release capsules are not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). (2.2) 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 (14) ]. 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 10–30 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 (5.6) and USE IN SPECIFIC POPULATIONS (8.6 , 8.7) ]. 2.3 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 tolterodine tartrate extended-release capsules is 2 mg once daily [see DRUG INTERACTIONS (7.2) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy and Lactation: 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. Tolterodine tartrate extended-release capsules should not be administered during nursing. (8.1, 8.3) Pediatric Use: Efficacy in the pediatric population has not been demonstrated. Safety information from a study of a total of 710 pediatric patients (486 on tolterodine tartrate extended-release capsules, 224 on placebo) is available. (8.4) 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: 10–30 mL/min). (8.6) 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) 8.1 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. 8.3 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. 8.4 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 (12.3) ]. 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. 8.5 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. 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 2–3 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 (2.2) and WARNINGS AND PRECAUTIONS (5.6) ]. Tolterodine tartrate extended-release capsules have not been studied in patients with mild to moderate renal impairment [CCr 30–80 mL/min]. 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 (2.2) and WARNINGS AND PRECAUTIONS (5.4) ]. 8.8 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 µg∙h/L in males versus 7.8 µg∙h/L in females) and 5-HMT (10 µg∙h/L in males versus 11 µg∙h/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. 8.9 Race Pharmacokinetic differences due to race have not been established.
Pregnancy and lactation
8.3 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.

Interactions

7 DRUG INTERACTIONS Potent CYP3A4 Inhibitors: Coadministration may increase systemic exposure to tolterodine tartrate extended-release capsules. Reduce tolterodine tartrate extended-release capsules dose to 2 mg once daily. (7.2) Other Anticholinergics (antimuscarinics): Concomitant use with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, and other anticholinergic pharmacological effects. (7.6) 7.1 Potent CYP2D6 Inhibitors Fluoxetine, a potent inhibitor of CYP2D6 activity, significantly inhibited the metabolism of tolterodine immediate-release in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the pharmacologically active metabolite of tolterodine [see CLINICAL PHARMACOLOGY (12.1) ]. The sums of unbound serum concentrations of tolterodine and 5-HMT are only 25% higher during the interaction. No dose adjustment is required when tolterodine and fluoxetine are co-administered [see CLINICAL PHARMACOLOGY (12.3) ]. 7.2 Potent CYP3A4 Inhibitors Ketoconazole (200 mg daily), a potent CYP3A4 inhibitor, increased the mean Cmax and AUC of tolterodine by 2- and 2.5-fold, respectively, in CYP2D6 poor metabolizers. For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as itraconazole, clarithromycin, or ritonavir, the recommended dose of tolterodine tartrate extended-release capsules is 2 mg once daily [see DOSAGE AND ADMINISTRATION(2.2) and CLINICAL PHARMACOLOGY (12.3) ]. 7.3 Other Interactions No clinically relevant interactions have been observed when tolterodine was co-administered with warfarin, with a combined oral contraceptive drug containing ethinyl estradiol and levonorgestrel, or with diuretics [see CLINICAL PHARMACOLOGY (12.3) ] 7.4 Other Drugs Metabolized by Cytochrome P450 Isoenzymes In vivo drug-interaction data show that tolterodine immediate-release does not result in clinically relevant inhibition of CYP1A2, 2D6, 2C9, 2C19, or 3A4 as evidenced by lack of influence on the marker drugs caffeine, debrisoquine, S-warfarin, and omeprazole [see CLINICAL PHARMACOLOGY (12.3) ]. 7.5 Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. 7.6 Other Anticholinergics The concomitant use of tolterodine tartrate extended-release capsules with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic pharmacological effects.

More information

Category Value
Authorisation number NDA021228
Agency product number 5T619TQR3R
Orphan designation No
Product NDC 59762-0048,59762-0047
Date Last Revised 19-01-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 855189
Storage and handling Store at 20°–25°C (68°–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from light.
Marketing authorisation holder Greenstone LLC