Adult: For the symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency: Initially, 7.5 mg once daily. After 2 weeks, doses may be increased to 15 mg once daily if needed.
Special Patient Group
Patients taking potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine, quinidine, cimetidine) or moderate CYP3A4 inhibitors (e.g. fluconazole, erythromycin): Initially, 7.5 mg once daily. If needed, doses may be titrated to 15 mg once daily, provided that the doses is well tolerated.
Pharmacogenomics:
Darifenacin is mainly metabolised by the CYP3A4 and CYP2D6 isoenzymes. The metabolism of CYP2D6 poor metabolisers will be mainly mediated by the CYP3A4 isoenzyme. The prevalence of CYP2D6 poor metabolisers is estimated at approx 7% in Caucasians and 2% in African Americans. Studies have shown that CYP2D6 poor metabolisers experienced a steady-state exposure 164% and 99% higher during therapy with 7.5 mg and 15 mg doses, respectively. Another population study has noted that CYP2D6 poor metabolisers may experience an increased darifenacin Max plasma concentrations and exposure (66% higher) as compared to CYP2D6 extensive metabolisers. Current product specific information and professional society practice guidelines have no recommendations on the clinical significance of these increased concentrations. Hence, there is insufficient evidence for a recommendation on genetic testing and no dosage adjustment has been recommended for specific CYP2D6 genotypes.
Hepatic Impairment
Moderate (Child-Pugh class B): Max: 7.5 mg daily. Severe (Child-Pugh class C): Contraindicated.
Administration
May be taken with or without food. Swallow whole, do not chew/crush/divide.
Contraindications
Urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, myasthenia gravis, severe ulcerative colitis, toxic megacolon. Severe (Child-Pugh class C) hepatic impairment. Concomitant use with potent CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole) and potent P-gp inhibitors (e.g. ciclosporin, verapamil).
Special Precautions
Patient with autonomic neuropathy, hiatus hernia, clinically significant bladder outflow obstruction, predisposition for urinary retention, gastrointestinal obstructive disorders (e.g. pyloric stenosis), decreased gastrointestinal motility (e.g. severe constipation, mild to moderate ulcerative colitis), GERD; controlled narrow-angle glaucoma; other causes of frequent urination (e.g. heart failure), UTI, pre-existing cardiac diseases. Patient exposed to hot weather and/or undergoing exercise. Patients taking potent CYP2D6 inhibitors or moderate CYP3A4 inhibitors. Moderate (Child-Pugh class B) hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Significant: CNS effect (e.g. headache, confusion, hallucinations, somnolence); heat prostration (may occur in increased environmental temperature). Eye disorders: Dry eye, visual disturbance (including blurred vision). Gastrointestinal disorders: Dry mouth, constipation, abdominal pain, nausea, dyspepsia, dysgeusia, diarrhoea, flatulence, mouth ulceration. General disorders and administration site conditions: Peripheral oedema, asthenia. Investigations: Increased AST/ALT, weight gain. Nervous system disorders: Dizziness. Psychiatric disorders: Insomnia, thinking abnormal. Renal and urinary disorders: UTI, urinary retention, urinary tract disorder, bladder pain. Reproductive system and breast disorders: Vaginitis, erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Nasal dryness, cough, dyspnoea, rhinitis. Skin and subcutaneous tissue disorders: Dry skin, rash, pruritus, hyperhidrosis. Vascular disorders: Hypertension. Potentially Fatal: Angioedema (involving the face, lips, tongue, larynx).
This drug may cause dizziness, blurred vision, insomnia, or somnolence; if affected, do not drive or operate machinery.
Monitoring Parameters
Obtain and monitor LFTs. Evaluate postvoid residual urine volume at baseline and as necessary thereafter. Assess for anticholinergic effects and hypersensitivity reactions.
Overdosage
Symptoms: Dry mouth, constipation, headache, dyspepsia, nasal dryness, severe anticholinergic effects. Management: Symptomatic treatment. May give physostigmine to reverse anticholinergic effects.
Drug Interactions
May exacerbate oesophagitis with oral bisphosphonates. Increased exposure with potent CYP2D6 inhibitors (e.g. paroxetine, terbinafine, cimetidine, quinidine) and moderate CYP3A4 inhibitors (e.g. erythromycin, clarithromycin, fluconazole). Significantly increased exposure with potent CYP3A4 inhibitors (e.g. protease inhibitors, ketoconazole, itraconazole) and potent P-gp inhibitors (e.g. ciclosporin, verapamil). May decrease plasma concentration with CYP3A4 inducers (e.g. rifampicin, carbamazepine, barbiturates). Increased plasma concentrations of CYP2D6 substrates with narrow therapeutic index (e.g. flecainide, TCAs, thioridazine). May increase exposures of midazolam and digoxin. Increased risk of adverse effects with other antimuscarinic agents (e.g. oxybutynin, tolterodine, flavoxate).
Food Interaction
Increased exposure with grapefruit juice. May decrease exposure with St. John's wort.
Action
Description: Mechanism of Action: Darifenacin is a selective antagonist of the muscarinic (cholinergic) M3 subtype receptors. These receptors are involved in bladder contraction; therefore, blockade of these receptors limits bladder contractions, which results in reduced symptoms of bladder irritability or overactivity (e.g. urge incontinence, urgency, and frequency). Pharmacokinetics: Absorption: Bioavailability: Approx 15-19%. Time to peak plasma concentration: Approx 7 hours. Distribution: Plasma protein binding: Approx 98%, particularly to α1-acid glycoprotein. Metabolism: Metabolised in the liver by the CYP3A4 and CYP2D6 isoenzymes. Undergoes extensive first-pass metabolism. Excretion: Via urine (approx 60%) and faeces (approx 40%) as inactive metabolites. Elimination half-life: Approx 13-19 hours.
Chemical Structure
Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 444031, Darifenacin. https://pubchem.ncbi.nlm.nih.gov/compound/Darifenacin. Accessed Nov. 23, 2023.
Storage
Store between 15-30°C. Protect from light and moisture.
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