DETROL LA — tolterodine tartrate capsule, extended release
Physicians Total Care, Inc.
FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGE
DETROL LA Capsules is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency [see CLINICAL STUDIES (14)].
2.1 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)].
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 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 less than 10 mL/min have not been studied and use of DETROL LA in this population is not recommended [see WARNINGS AND PRECAUTIONS (5.4), 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 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.
- urinary retention
- gastric retention
- uncontrolled narrow-angle glaucoma
[see WARNINGS AND PRECAUTIONS (5.1), (5.3)].
5.1 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)].
5.2 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)].
5.3 Controlled Narrow-Angle Glaucoma
Administer DETROL LA with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS (4)].
5.4 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)].
5.5 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 less than 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)].
5.6 Myasthenia Gravis
Administer DETROL LA with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.
5.7 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.
6.1 Clinical Trials Experience
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 include 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.
|Body System||Adverse Event||% DETROL LA N = 505||% PlaceboN = 507|
|Autonomic Nervous||dry mouth||23||8|
(*) 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%)].
6.2 Post-marketing Experience
The following events have been reported in association with tolterodine use in worldwide post-marketing experience:
General: anaphylactoid reactions, including 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 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 DETROL LA is 2 mg once daily [see DOSAGE AND ADMINISTRATION (2.2), 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 DETROL LA with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence and other anticholienrgic pharmacological effects.
RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.