DETROL LA Capsule Ref.[10552] Active ingredients: Tolterodine

5.1 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.

5.2 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)].

5.3 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)].

5.4 Controlled Narrow-Angle Glaucoma

Administer DETROL LA with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS (4)].

5.5 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.

5.6 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)].

5.7 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)].

5.8 Myasthenia Gravis

Administer DETROL LA with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

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 (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.

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 efficacy and safety of DETROL LA Capsules was evaluated in 1073 patients (537 assigned to DETROL LA; 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 DETROL LA 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 DETROL LA and in 49% (n=247) of patients receiving placebo. The most common adverse events reported by patients receiving DETROL LA were dry mouth, headache, constipation, and abdominal pain. Dry mouth was the most frequently reported adverse event for patients treated with DETROL LA, occurring in 23.4% of patients treated with DETROL LA 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 DETROL LA 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 DETROL LA 4 mg once daily.

Table 1. Incidence^* ( % ) of Adverse Events Exceeding Placebo Rate and Reported in ≥1% of Patients Treated with DETROL LA (4 mg daily) in a 12-week, Phase 3 Clinical Trial:

^* in nearest integer

The frequency of discontinuation due to adverse events was highest during the first 4 weeks of treatment. Similar percentages of patients treated with DETROL LA or placebo discontinued treatment due to adverse events. Dry mouth was the most common adverse event leading to treatment discontinuation among patients receiving DETROL LA [n=12 (2.4%) vs. placebo n=6 (1.2%)].

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.

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 C_max 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 C_max 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 DETROL LA 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< em>[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 DETROL LA with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence, and other anticholinergic pharmacological effects.

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.

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.

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.

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 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].

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)].