Tolterodine: uses, appearance and warnings

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 )

The 2 mg capsules are opaque light green with “ ”on the cap and “132” on the body in black ink. The 4 mg capsules are opaque powder blue with “ ” on the cap and “131” on the body in black ink. Capsules: 2 mg and 4 mg ( 3 ) ink3 ink4

Tolterodine Tartrate Extended-Release Capsules, USP are supplied as follows: The 2 mg capsule with opaque light green cap and body, imprinted with “ ” on the cap and “132” on the body in black ink, containing white to off-white pellets. Bottles of 30 capsules with child-resistant closure, NDC 70436-160-04 Bottles of 90 capsules with child-resistant closure, NDC 70436-160-06 Bottles of 500 capsules, NDC 70436-160-02 The 4 mg capsule with opaque powder blue cap and body, imprinted with “ ” on the cap and “131” on the body in black ink, containing white to off-white pellets. Bottles of 30 capsules with child-resistant closure, NDC 70436-161-04 Bottles of 90 capsules with child-resistant closure, NDC 70436-161-06 Bottles of 500 capsules, NDC 70436-161-02 ink1 ink2 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure. Keep out of reach of children.

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 )

Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of tolterodine tartrate extended-release capsules. ( 5.1 ) Urinary Retention: use caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. ( 5.2 ) Gastrointestinal Disorders: use caution in patients with gastrointestinal obstructive disorders or decreased gastrointestinal motility because of the risk of gastric retention. ( 5.3 ) Controlled Narrow-Angle Glaucoma: use caution in patients being treated for narrow-angle glaucoma. ( 5.4 ) Central Nervous System Effects: Somnolence has been reported with tolterodine tartrate extended-release capsules. Advise patients not to drive or operate heavy machinery until they know how tolterodine tartrate extended-release capsules affect them ( 5.5 ). Myasthenia Gravis: use caution in patients with myasthenia gravis. ( 5.8 ) QT Prolongation: consider observations from the thorough QT study 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. ( 5.9 ) 5.1 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. 5.2 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) ] . 5.3 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) ] . 5.4 Controlled Narrow-Angle Glaucoma Administer tolterodine tartrate extended-release capsules with caution in patients being treated for narrow-angle glaucoma [see CONTRAINDICATIONS (4) ] . 5.5 Central Nervous System Effects Tolterodine tartrate extended-release capsules are 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 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 (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 tolterodine tartrate extended-release capsules should be reduced to 2 mg once daily in patients with severe renal impairment (CCr: 10 to 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 (2.2) and USE IN SPECIFIC POPULATIONS (8.7) ] . 5.8 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. 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 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 tablets or tolterodine tartrate extended-release capsules.

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 Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 1,073 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. …

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 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) ] . …