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Tolterodine

Pronunciation

(tole TER oh deen)

Index Terms

  • Tolterodine Tartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 24 Hour, Oral, as tartrate:

Detrol LA: 2 mg, 4 mg

Generic: 2 mg, 4 mg

Tablet, Oral, as tartrate:

Detrol: 1 mg, 2 mg

Generic: 1 mg, 2 mg

Brand Names: U.S.

  • Detrol
  • Detrol LA

Pharmacologic Category

  • Anticholinergic Agent

Pharmacology

Tolterodine is a competitive antagonist of muscarinic receptors. In animal models, tolterodine demonstrates selectivity for urinary bladder receptors over salivary receptors. Urinary bladder contraction is mediated by muscarinic receptors. Tolterodine increases residual urine volume and decreases detrusor muscle pressure.

Absorption

Immediate release tablet: Rapid; ≥77%

Distribution

IV: Vd: 113 ± 27 L

Metabolism

Extensively hepatic, primarily via CYP2D6 to 5-hydroxymethyltolterodine (active) and 3A4 usually (minor pathway). In patients with a genetic deficiency of CYP2D6, metabolism via 3A4 predominates.

Excretion

Urine (77%); feces (17%); primarily as metabolites (<1% unchanged drug) of which the active 5-hydroxymethyl metabolite accounts for 5% to 14% (<1% in poor metabolizers); as unchanged drug (<1%; <2.5% in poor metabolizers)

Time to Peak

Immediate release tablet: 1-2 hours; Extended release capsule: 2-6 hours

Half-Life Elimination

Immediate release tablet: Extensive metabolizers: ~2 hours; Poor metabolizers: ~10 hours

Extended release capsule: Extensive metabolizers: ~7 hours; Poor metabolizers: ~18 hours

Protein Binding

>96% (primarily to alpha1-acid glycoprotein)

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.

Special Populations: 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.

Special Populations: Elderly

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

Use: Labeled Indications

Treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence

Contraindications

Hypersensitivity to tolterodine or fesoterodine (both are metabolized to 5-hydroxymethyl tolterodine) or any component of the formulation; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma

Dosing: Adult

Treatment of overactive bladder: Oral:

Immediate release tablet: 2 mg twice daily; the dose may be lowered to 1 mg twice daily based on individual response and tolerability

Dosing adjustment in patients concurrently taking strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir): 1 mg twice daily

Extended release capsule: 4 mg once daily; dose may be lowered to 2 mg once daily based on individual response and tolerability

Dosing adjustment in patients concurrently taking strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir): 2 mg once daily

Dosing: Geriatric

Use with caution due to its anticholinergic properties (Beers Criteria [AGS 2015]).

Dosing: Renal Impairment

Immediate release tablet: Significantly reduced renal function (studies conducted in patients with CrCl 10 to 30 mL/minute): 1 mg twice daily; use with caution

Extended release capsule:

CrCl 10 to 30 mL/minute: 2 mg once daily

CrCl <10 mL/minute: Use is not recommended; has not been studied.

Dosing: Hepatic Impairment

Immediate release tablet: Significantly reduced hepatic function: 1 mg twice daily; use with caution

Extended release capsule:

Mild to moderate impairment (Child-Pugh class A or B): 2 mg once daily

Severe impairment (Child-Pugh class C): Use is not recommended; has not been studied.

Administration

Extended release capsule: Swallow whole; do not crush, chew, or open

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Amifampridine: May diminish the anticholinergic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Amifampridine. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Opioid Analgesics: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Analgesics. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

VinBLAStine: May increase the serum concentration of Tolterodine. Management: Reduce tolterodine dose to 1 mg twice daily (regular release formulation) or 2 mg daily (extended release formulation) (adult doses) and monitor for increased levels/effects of tolterodine with initiation of vinblastine therapy. Consider therapy modification

Warfarin: Tolterodine may enhance the anticoagulant effect of Warfarin. Monitor therapy

Adverse Reactions

As reported with immediate release tablet, unless otherwise specified.

>10%: Gastrointestinal: Xerostomia (35%; extended release capsules: 23%)

1% to 10%:

Cardiovascular: Chest pain (2%)

Central nervous system: Headache (7%; extended release capsules: 6%), dizziness (5%; extended release capsules: 2%), fatigue (4%; extended release capsules: 2%), drowsiness (immediate and extended release: 3%), anxiety (extended release capsules: 1%)

Dermatologic: Xeroderma (1%)

Endocrine & metabolic: Weight gain (1%)

Gastrointestinal: Constipation (7%; extended release capsules: 6%), abdominal pain (5%; extended release capsules: 4%), diarrhea (4%), dyspepsia (4%; extended release capsules: 3%)

Genitourinary: Dysuria (2%; extended-release capsules: 1%)

Infection: Infection (1%)

Neuromuscular & skeletal: Arthralgia (2%)

Ophthalmic: Xerophthalmia (immediate and extended release: 3%), visual disturbance (2%; extended release capsules: 1%)

Respiratory: Flu-like symptoms (3%), bronchitis (2%), sinusitis (extended release capsules: 2%)

<1% (Limited to important or lfe-threatening): Anaphylaxis, angioedema, confusion, dementia (aggravated), disorientation, hallucination, memory impairment, palpitations, peripheral edema, prolonged Q-T interval on ECG, tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Cases of angioedema have been reported; some cases have occurred after a single dose. Discontinue immediately if angioedema and associated difficulty breathing, airway obstruction, or hypotension develop.

• CNS effects: May cause drowsiness, dizziness, and/or blurred vision, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Dose reduction or discontinuation should be considered if CNS effects occur.

• QT prolongation: Has been associated with QTc prolongation at high (supratherapeutic) doses. The manufacturer recommends caution in patients with congenital prolonged QT or in patients receiving concurrent therapy with QTc-prolonging drugs (class Ia or III antiarrhythmics). However, the extent of QTc prolongation even at supratherapeutic dosages was less than 15 msec. Individuals who are CYP2D6 poor metabolizers or in the presence of inhibitors of CYP2D6 and CYP3A4 may be more likely to exhibit prolongation.

Disease-related concerns:

• Alzheimer disease: Preliminary data suggests that long-term use of anticholinergics may potentially adversely affect the clinical course of Alzheimer disease in patients receiving cholinesterase inhibitors (Lu 2003; Sink 2008). Additional monitoring for decreases in cognition, functional abilities and increased problematic behaviors should be considered in patients with dementia receiving dual therapy with an anticholinesterase inhibitor and a bladder anticholinergic, such as tolterodine.

• Bladder flow obstruction: Use with caution in patients with bladder flow obstruction (eg, benign prostatic hypertrophy); may increase the risk of urinary retention.

• GI obstructive disorders: Use with caution in patients with decreased GI motility or gastrointestinal obstructive disorders (ie, pyloric stenosis); may increase the risk of gastric retention.

• Glaucoma: Use with caution in patients with controlled (treated) narrow-angle glaucoma.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment is required.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required.

Concurrent drug therapy issues:

• CYP3A4 inhibitors: Dosage adjustment is recommended in patients receiving CYP3A4 inhibitors; a lower dose of tolterodine is recommended.

Monitoring Parameters

Anticholinergic effects (ie, dry mouth, constipation, dizziness); renal function (BUN, creatinine); hepatic function; postvoid residual (PVR) urine volume prior to initiation of therapy (ACOG 2015)

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, fatigue, headache, abdominal pain, constipation, dry mouth, or dry eyes. Have patient report immediately to prescriber urinary retention, or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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