Darifenacin Hydrobromide

Genitourinary antispasmodic agent; an antimuscarinic agent.1

Metabolized principally by CYP2D6 and CYP3A4.1 May inhibit CYP2D6 and CYP3A4; not expected to inhibit CYP1A2 and CYP2C9.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma darifenacin concentrations).1 7 Do not exceed 7.5 mg daily when used concomitantly with potent inhibitors of CYP3A4.1 No dosage adjustment required when used concomitantly with moderate CYP3A4 inhibitors.1 (See Specific Drugs under Interactions.)

Inhibitors of CYP2D6: Potential pharmacokinetic interaction (increased plasma darifenacin concentrations).1 However, no dosage adjustment required.1

Mixed inhibitors of CYP isoenzymes: Potential pharmacokinetic interaction (increased plasma darifenacin concentrations).1 However, no dosage adjustment required.8

Inducers of CYP3A4: Potential pharmacokinetic interaction1 (altered plasma darifenacin concentrations).1 8

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1

Substrates of CYP2D6: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1 Caution advised when used concomitantly with CYP2D6 substrates that have a narrow therapeutic index.1

Substrates of CYP1A2 or CYP2C9: Pharmacokinetic interaction not expected at therapeutic dosages.8

Drugs Affected by GI Motility

Potential pharmacokinetic interaction (altered absorption because of decreased GI motility).1 (See Decreased GI Motility under Cautions.)

Specific Drugs

Absorption

Bioavailability

Mean oral bioavailability at steady-state is approximately 15 or 19% for the 7.5- or 15-mg tablets, respectively.1 7

Peak plasma concentrations achieved approximately 7 hours after multiple dosing.1

Onset

Symptomatic improvement (i.e., reduction in number of urge incontinence episodes) observed within first 2 weeks of therapy.1 6

Food

Food does not affect darifenacin pharmacokinetics.1

Special Populations

Darifenacin exposure is 40 or 90% higher in CYP2D6 heterozygote-extensive metabolizers or poor metabolizers, respectively, and 56% lower in Japanese males.7

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 98% (mainly to α1-acid glycoprotein).1

Special Populations

In patients with moderate hepatic impairment (Child-Pugh class B), decreased protein binding resulting in increased darifenacin exposure observed.1 (See Hepatic Impairment under Dosage and Administration.)

Elimination

Metabolism

Extensively metabolized in the liver, mainly via CYP2D6 and CYP3A4.1

Elimination Route

Excreted in urine (60%) and in feces (40%); unchanged drug accounts for about 3% of recovered radioactivity.1

Half-life

Approximately 13–19 hours following long-term administration.1

Special Populations

In patients with poor metabolizer CYP2D6 phenotypes (approximately 7% of Caucasians and 2% of African Americans), darifenacin is metabolized principally via CYP3A4; decreased clearance observed.1 7 Steady-state plasma concentrations following 15-mg daily dosage approximately 1.7–1.9 times higher in poor metabolizers than in extensive metabolizers.1

In geriatric patients, possible decreased clearance (decreases about 6% per decade beginning at 44 years of age).1

In patients with renal impairment, no clear relationship between extent of impairment and darifenacin clearance observed in patients with Clcr 10–136 mL/minute.1 (See Renal Impairment under Dosage and Administration.)

Storage

Oral

25°C (may be exposed to 15–30°C).1 Protect from light.1

• Potent and selective antimuscarinic agent.1

• Inhibits binding of acetylcholine to muscarinic receptors in cholinergically innervated organs.8

• Demonstrates substantially greater binding affinity for muscarinic M3 receptors (which are involved in contraction of detrusor muscle of bladder and GI smooth muscle, saliva production, and iris sphincter function) in vitro than for other muscarinic receptor subtypes.1 3 8 Exhibits functional selectivity for urinary bladder over secretory (e.g., salivary) glands.2 3

• Increases bladder capacity and diminishes frequency of unstable contractions of detrusor muscle in patients with involuntary detrusor contractions.1