Tolterodine

Oral
Overactive bladder

Patient taking strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir): 1 mg bid (immediate-release tab); 2 mg once daily (extended-release cap).

Pharmacogenomics:

Tolterodine is mainly metabolised via oxidation by CYP2D6 to form active 5-hydroxymethyl metabolite (5-HMT). Some studies determined that individuals with reduced CYP2D6 activity, known as CYP2D6 poor metabolisers, may have significantly higher tolterodine plasma concentrations and may be at increased risk of QTc interval prolongation. Although tolterodine in normal metabolisers or poor metabolisers is not expected to cause significant QT prolongation, the degree of QT prolongation between poor metabolisers is higher than normal metabolisers. The prevalence of CYP2D6 poor metabolisers is estimated at approx 7% in Caucasians and approx 2% in African American populations.

CrCl (mL/min)	Dosage
10-30	1 mg bid (immediate-release tab); 2 mg once daily (extended-release cap).

As immediate-release tab: 1 mg bid. As extended-release cap: Mild to moderate (Child-Pugh Class A or B): 2 mg once daily. Severe (Child-Pugh Class C): Not recommended.

Urinary or gastric retention, severe ulcerative colitis, toxic megacolon, myasthenia gravis, uncontrolled narrow-angle glaucoma.

Patient at risk of QT prolongation (e.g. congenital prolonged QT, concurrent class Ia or III antiarrhythmics therapy, electrolyte imbalance, bradycardia, pre-existing cardiac disease), bladder flow obstruction (e.g. benign prostatic hypertrophy); decreased gastrointestinal motility (e.g. intestinal atony) or obstructive disorder (e.g. pyloric stenosis); controlled or treated narrow-angle glaucoma, Alzheimer's disease, autonomic neuropathy, hiatus hernia. Hepatic and renal impairment. Elderly. Pregnancy and lactation. Patient taking potent CYP3A4 inhibitors. CYP2D6 poor metabolisers.

Significant: Angioedema, QT prolongation (high doses, CYP2D6 poor metabolisers), urinary or gastric retention, decreased gastrointestinal motility, CNS effects (e.g. dizziness, drowsiness, blurred vision), anaphylaxis.
Cardiac disorders: Palpitations, tachycardia.
Eye disorders: Dry eyes, abnormal vision and accommodation.
Gastrointestinal disorders: Dry mouth, dyspepsia, constipation, abdominal pain, diarrhoea, flatulence.
General disorders and administration site conditions: Fatigue, flu-like symptoms.
Investigations: Increased weight.
Metabolism and nutrition disorders: Peripheral oedema.
Nervous system disorders: Headache, somnolence.
Renal and urinary disorders: Dysuria.
Respiratory, thoracic and mediastinal disorders: Sinusitis, chest pain.

PO: C

This drug may cause dizziness, drowsiness, or blurred vision, if affected, do not drive or operate machinery.

Monitor LFTs and renal function (e.g. BUN, creatinine); postvoid residual urine volume prior to treatment initiation. Assess for signs of anticholinergic effects (e.g. dry mouth, dizziness, constipation).

Symptoms: Accommodation disturbances, micturition difficulties, severe central anticholinergic effects (e.g. hallucinations, severe excitation), convulsions or pronounced excitation, respiratory insufficiency, tachycardia, urinary retention, mydriasis, QT prolongation. Management: Symptomatic and supportive treatment. May consider gastric lavage and administration of activated charcoal within 1 hour of ingestion. May give physostigmine for severe central anticholinergic effects; β-blockers for tachycardia; diazepam for convulsions or pronounced excitation. Place the patient in a dark room and/or administer pilocarpine eye drops for mydriasis. Consider catheterisation for urinary retention. Monitor ECG for QT prolongation and provide artificial respiration for respiratory insufficiency.

Increased risk of QT prolongation with class IA (e.g. quinidine, procainamide) and Class III (e.g. amiodarone, sotalol) antiarrhythmics. Increased serum concentrations thereby greater risk of overdosage with potent CYP3A4 inhibitors (e.g. erythromycin, clarithromycin, ketoconazole, itraconazole, protease inhibitors), especially in CYP2D6 poor metabolisers. May decrease prokinetic effects of metoclopramide and cisapride. Additive therapeutic and adverse effects with other antimuscarinic drugs. Reduced therapeutic effects with muscarinic/cholinergic receptor agonists. May increase exposure of tolterodine (immediate-release) with potent CYP2D6 inhibitor (e.g. fluoxetine), especially in CYP2D6 extensive metabolisers.

Increased bioavailability with food (immediate-release tab). May increase plasma concentration and risk of toxicity with grapefruit or grapefruit juice.

Description: Tolterodine is a competitive muscarinic receptor antagonist with selectivity for urinary bladder receptors over salivary receptors. It increases residual urine volume and decreases detrusor muscle pressure.
Pharmacokinetics:
Absorption: Rapidly absorbed (immediate-release tab). Bioavailability: Increased by approx 53% with food (immediate-release tab); 17% (extensive metabolisers); 65% (poor metabolisers). Time to peak plasma concentration: 1-2 hours (immediate-release tab); 2-6 hours (modified-release cap).
Distribution: Volume of distribution: 113±27 L. Plasma protein binding: >96%, (mainly to α₁-acid glycoprotein).
Metabolism: Extensively metabolised in the liver mainly via oxidation by CYP2D6 to 5-hydroxymethyltolterodine (active metabolite), further metabolism to form 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites. Poor CYP2D6 metabolisers: Via dealkylation by CYP3A4 into inactive N-dealkylated tolterodine metabolite. Predominantly metabolised by CYP3A4 isoenzyme in CYP2D6 poor metabolisers.
Excretion: Via urine (77%) and faeces (17%); mainly as metabolites, <1% as unchanged drug. Elimination half-life: Immediate-release tab: Approx 2 hours (extensive metabolisers); approx 10 hours (poor metabolisers). Modified-release cap: Approx 7 hours (extensive metabolisers); approx 18 hours (poor metabolisers).

Source: National Center for Biotechnology Information. PubChem Database. Tolterodine, CID=443879, https://pubchem.ncbi.nlm.nih.gov/compound/Tolterodine (accessed on Jan. 23, 2020)

Store at 25°C. Protect from light.

Drugs for Bladder & Prostate Disorders

G04BD07 - tolterodine ; Belongs to the class of urinary antispasmodics.

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