Tolterodine

Generic Name

Tolterodine tartrate

Brand Names

Detrol

Detrol LA (extended-release)

Detrunorm

Urotrol

Dextrol

Roliten

Toltam

Others vary by country and formulation

Drug Class

Antimuscarinic agent

Anticholinergic

Urinary antispasmodic

Mechanism of Action

Tolterodine is a competitive muscarinic receptor antagonist

It acts on M2 and M3 receptors in the bladder detrusor muscle

It reduces involuntary contractions of the detrusor muscle during the bladder filling phase

This leads to increased bladder capacity and reduced urgency, frequency, and incontinence episodes

Although it has affinity for muscarinic receptors throughout the body, it displays functional selectivity for the bladder over salivary glands due to metabolism to its active metabolite 5-hydroxymethyl tolterodine (5-HMT) which maintains bladder selectivity

Indications

Treatment of overactive bladder with symptoms of urge urinary incontinence urgency and frequency

Neurogenic detrusor overactivity (off-label)

Mixed urinary incontinence with urge-predominant component (adjunct)

Urgency associated with idiopathic or neurogenic bladder dysfunction

Dosage and Administration

Immediate-release tablets

Adult dose is 2 mg orally twice daily

In patients with hepatic impairment or CYP2D6 poor metabolizers or those on CYP3A4 inhibitors the dose should be reduced to 1 mg twice daily

Extended-release capsules (Detrol LA)

Adult dose is 4 mg orally once daily

Reduce to 2 mg once daily if needed due to tolerability or drug interactions

Pediatric use

Not approved for children in most regions

Investigational in pediatric neurogenic bladder

Renal impairment

Use with caution

In severe impairment reduce dose to 1 mg twice daily for immediate-release and 2 mg once daily for extended-release

Hepatic impairment

In moderate hepatic impairment reduce dose

Contraindicated in severe hepatic dysfunction

Administration

Swallow whole with liquid

Extended-release capsules should not be crushed or chewed

Pharmacokinetics

Absorption

Tolterodine is rapidly absorbed after oral administration

Immediate-release peak plasma concentration occurs within 1 to 2 hours

Extended-release peak occurs within 2 to 6 hours

Food has little effect on bioavailability

Distribution

Extensively distributed with low plasma protein binding

Crosses blood-brain barrier in animal models

Metabolism

Extensively metabolized in the liver via CYP2D6 to 5-HMT the active metabolite

In CYP2D6 poor metabolizers metabolism is primarily via CYP3A4 to inactive metabolites

Elimination

Primarily renal excretion

About 77 percent excreted in urine and 17 percent in feces

Half-life is 2 to 4 hours for immediate-release and 7 to 18 hours for extended-release

Contraindications

Urinary retention

Gastric retention

Uncontrolled narrow-angle glaucoma

Known hypersensitivity to tolterodine or formulation components

Severe hepatic impairment (Child-Pugh Class C)

Myasthenia gravis

Warnings and Precautions

Urinary retention

Use cautiously in patients with obstructive uropathy or incomplete bladder emptying

Angle-closure glaucoma

Avoid in patients with narrow-angle glaucoma unless controlled

Gastrointestinal obstruction

Use with caution in patients with decreased GI motility or obstructive disorders

CNS effects

Anticholinergic effects may include confusion hallucinations and drowsiness particularly in elderly

Hepatic and renal impairment

Reduce dose in moderate hepatic or renal dysfunction

Avoid in severe hepatic impairment

QT prolongation

Tolterodine may prolong the QT interval at high doses

Caution in patients with known QT prolongation electrolyte imbalance or those on other QT-prolonging drugs

Use in the elderly

Increased risk of cognitive impairment dry mouth constipation and falls

Monitor closely and consider dose adjustment

Adverse Effects

Very common

Dry mouth

Headache

Constipation

Common

Dizziness

Blurred vision

Dry eyes

Fatigue

Dyspepsia

Urinary tract infection

Abdominal pain

Flatulence

Somnolence

Uncommon

Palpitations

Peripheral edema

Tachycardia

Cognitive dysfunction in elderly

Confusional state

Hallucinations

Urinary retention

Rare

QT prolongation

Anaphylactic reactions

Angioedema

Stevens-Johnson syndrome

Overdose

Symptoms may include severe anticholinergic effects such as dry mouth tachycardia urinary retention dilated pupils hallucinations and seizures

Severe overdose may lead to central nervous system depression respiratory failure and cardiac arrhythmias

Treatment is supportive

In severe cases physostigmine may be considered as a reversal agent

Drug Interactions

CYP3A4 inhibitors such as ketoconazole erythromycin and clarithromycin may increase tolterodine levels especially in CYP2D6 poor metabolizers

CYP2D6 inhibitors such as fluoxetine and paroxetine may reduce conversion to active metabolite but do not necessarily affect efficacy due to compensatory pathways

Other anticholinergic agents such as oxybutynin solifenacin or diphenhydramine may increase risk of additive side effects like dry mouth constipation and confusion

Cholinesterase inhibitors such as donepezil may have reduced efficacy in dementia treatment when combined with tolterodine

QT-prolonging drugs such as amiodarone sotalol and certain antipsychotics may increase risk of torsades de pointes especially when tolterodine is administered at high doses

Prokinetic agents such as metoclopramide may have reduced efficacy due to anticholinergic effects of tolterodine

Use in Special Populations

Pregnancy

Category C

Use only if potential benefit justifies potential risk

No adequate well-controlled studies in pregnant women

Lactation

Unknown whether tolterodine is excreted in breast milk

Use caution

Pediatrics

Not approved for use in children

Safety and efficacy not established

Geriatrics

Increased susceptibility to anticholinergic side effects

Use lowest effective dose and monitor for cognitive effects

Renal impairment

Reduce dose in moderate to severe impairment

Monitor for accumulation and adverse effects

Hepatic impairment

Avoid use in severe hepatic dysfunction

Use reduced dose in moderate impairment

Monitoring Parameters

Evaluate post-void residual volume in patients at risk of urinary retention

Monitor anticholinergic adverse effects including dry mouth constipation and cognitive changes

Monitor intraocular pressure in patients with glaucoma

Monitor ECG if used in patients with risk factors for QT prolongation

Monitor hepatic and renal function in long-term therapy

Comparative Pharmacology

Compared to oxybutynin tolterodine has less dry mouth and central nervous system penetration

Compared to solifenacin and darifenacin tolterodine may have slightly less bladder selectivity but better tolerability at low doses

Extended-release tolterodine has improved tolerability profile compared to immediate-release form

Tolterodine is often used in initial therapy for overactive bladder due to its balance of efficacy and tolerability

Formulations Available

Immediate-release tablets 1 mg and 2 mg

Extended-release capsules 2 mg and 4 mg

Combination with other urinary drugs is not common

No injectable or topical forms available

Regulatory and Legal Status

Approved by FDA EMA and other health authorities

Prescription-only medication

Included in many national formularies for management of overactive bladder