Pronunciation: tol-TER-oh-deen TAR-trate
Class: Anticholinergic

Trade Names

Detrol
- Tablets, oral 1 mg
- Tablets, oral 2 mg

Detrol LA
- Capsule, ER, oral 2 mg
- Capsule, ER, oral 4 mg

Unidet (Canada)

Pharmacology

Antagonizes muscarinic receptor, which mediates urinary bladder contraction.

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Pharmacokinetics

Absorption

Tolterodine is rapidly absorbed; bioavailability is at least 77%. T _max is within 1 to 2 h (immediate release) and 2 to 6 h (ER). Food increases bioavailability (approximately 53%) of immediate-release tolterodine, but has no effect on ER tolterodine.

Distribution

Tolterodine is highly protein bound, primarily to alpha-1 acid glycoprotein. Vd is approximately 113 L.

Metabolism

Tolterodine is extensively metabolized by the liver. The primary metabolic route involves oxidation of the 5-methyl group and is mediated by the CYP2D6 isoenzyme and leads to a pharmacologically active 5-hydroxymethyl tolterodine (5-HMT) metabolite.

Elimination

77% is recovered in urine and 17% is recovered in feces within 7 days. Half-life is approximately 2 h (immediate release) and 7 h (ER).

Special Populations

Renal Function Impairment

In patients with CrCl 10 to 30 mL/min, immediate-release tolterodine and metabolite levels were 2- to 3-fold higher compared with healthy patients. ER tolterodine has not been studied in patients with CrCl less than 10 mL/min.

Hepatic Function Impairment

The elimination half-life of immediate-release tolterodine was longer and Cl was substantially lower in cirrhotic patients compared with healthy patients.

Elderly

Serum concentrations of immediate-release tolterodine and 5-HMT were 20% to 50% higher in elderly patients.

Children

Pharmacokinetics of immediate-release tolterodine have not been established in pediatric patients. Dose-plasma concentration relationship was linear over the range of tolterodine ER doses assessed.

Gender

Pharmacokinetics of immediate-release tolterodine are not influenced by gender.

Race

Pharmacokinetic differences because of race have not been established.

Indications and Usage

For the treatment of overactive bladder with symptoms of urinary frequency, urgency, and urge urinary incontinence.

Contraindications

Gastric retention; hypersensitivity to any component of the product or to fesoterodine; uncontrolled narrow-angle glaucoma; urinary retention.

Dosage and Administration

Immediate Release
Adults

PO 2 mg twice daily; lower dosage to 1 mg twice daily based on individual response and tolerability.

ER
Adults

PO 4 mg once daily; lower dosage to 2 mg once daily based on individual response and tolerability.

Renal function impairment
Immediate release Significantly reduced renal function

PO 1 mg twice daily.

ER Severe renal impairment (CrCl 10 to 30 mL/min)

PO 2 mg once daily.

CrCl less than 10 mL/min

PO Use is not recommended.

Hepatic function impairment
Immediate release Significantly reduced hepatic function

PO 1 mg twice daily.

ER Mild to moderate hepatic impairment (Child-Pugh class A or B)

PO 2 mg once daily.

Severe hepatic impairment (Child-Pugh class C)

PO Use is not recommended.

Concomitant therapy

PO For patients currently taking potent inhibitors of CYP3A4 (eg, ketoconazole, clarithromycin, ritonavir), the recommended dosage is 2 mg once daily (ER) or 1 mg twice daily (immediate release).

General Advice

• ER capsules should be swallowed whole.

Storage/Stability

Store between 59° and 86°F. Protect ER capsules from light.

Drug Interactions

Anticholinergics

Coadministration may increase the frequency and/or severity of anticholinergic adverse effects (eg, blurred vision, constipation, dry mouth, somnolence).

Class IA (eg, procainamide, quinidine) or class III (eg, amiodarone, sotalol) antiarrhythmic agents

The effect of tolterodine on QT interval prolongation has been found to correlate with tolterodine plasma concentrations. The QTc interval increase appears to be greater in CYP2D6 poor metabolizers than extensive metabolizers. These observations should be considered in clinical decisions to prescribe tolterodine for patients who are taking class IA or class III antiarrhythmic agents.

Cyclosporine

Tolterodine plasma concentration may be increased. The recommended dosage of immediate-release tolterodine is 1 mg twice daily during coadministration.

CYP3A4 potent inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, miconazole, nefazodone, protease inhibitors [eg, ritonavir])

May increase tolterodine plasma levels, which may increase activity and adverse effects. During coadministration with potent CYP3A4 inhibitors, the recommended dosage of immediate-release tolterodine is 1 mg twice daily and the recommended dosage of ER tolterodine is 2 mg once daily.

Fluoxetine

Plasma levels of tolterodine may be increased; no dosage adjustment is required.

Potassium chloride

All solid dosage forms of potassium chloride are contraindicated for use in any patient receiving anticholinergic agents. Arrest or delay in tablet passage through the GI tract may occur. Administration of potassium chloride as a liquid preparation is a suitable alternative.

Proton pump inhibitors (eg, omeprazole)

Plasma concentrations of tolterodine and its active metabolites may be increased, with the potential for excessive pharmacologic effects and adverse reactions. Monitor for potential adverse effects and adjust the tolterodine dose as needed.

Vinblastine

Tolterodine plasma concentrations may be increased. The recommended dosage of immediate-release tolterodine is 1 mg twice daily during coadministration.

Warfarin

The anticoagulant effect of warfarin may be increased. Monitor anticoagulant activity and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Palpitations, tachycardia (postmarketing).

CNS

Headache (7%); vertigo/dizziness (5%); fatigue (4%); somnolence (3%); anxiety (1%); confusion, disorientation, hallucinations, memory impairment (postmarketing).

Dermatologic

Dry skin (1%).

EENT

Xerophthalmia (3%); abnormal accommodation (2%); abnormal vision (1%).

GI

Dry mouth (35%); constipation (7%); abdominal pain (5%); diarrhea, dyspepsia (4%).

Genitourinary

Dysuria (2%).

Metabolic

Weight gain (1%); peripheral edema (postmarketing).

Musculoskeletal

Arthralgia (2%).

Respiratory

Sinusitis (2%).

Miscellaneous

Influenza-like symptoms (3%); chest pain (2%); infection (1%); anaphylaxis, angioedema (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined. Breast-feeding is not recommended.

Children

Safety and efficacy not established.

Renal Function

Use with caution and at reduced doses. ER tolterodine is not recommended in patients with CrCl less than 10 mL/min.

Hepatic Function

Use with caution and at reduced doses. ER tolterodine is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Special Risk Patients

Use with caution in patients with clinically significant bladder outflow obstruction, GI obstructive disorders (eg, pyloric stenosis), decreased GI motility (eg, intestinal atony), controlled narrow-angle glaucoma, or myasthenia gravis.

Anaphylaxis/Angioedema

Has occurred and required hospitalization and emergency medical treatment.

QT prolongation

Has occurred when tolterodine was used at higher than recommended doses and was more pronounced in CYP2D6 poor metabolizers. Consider this when prescribing to patients with a known history of QT prolongation or in patients taking class IA (eg, quinidine, procainamide) or class III antiarrhythmics (eg, amiodarone, sotalol).

Overdosage

Symptoms

Abdominal distension, ataxia, blurred vision, cardiac slowing followed by acceleration, CNS stimulation, coma, decreased intestinal peristalsis, delirium, dilated pupils, drowsiness, dry mouth, flushing, hallucinations, headache, hot skin, hypertension, hypotension, inhibition of sweating, palpitations, photophobia, restlessness, seizures, speech disturbances, stupor, thirst.

Patient Information

• Advise patients to swallow ER capsule whole.
• Advise patients that antimuscarinic agents, such as tolterodine, may produce side effects, including blurred vision, dizziness, and drowsiness. Advise patients to exercise caution while doing potentially dangerous activities, such as driving, until the drug's effects have been determined.

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