Darifenacin

Pronunciation

(dar i FEN a sin)

U.S. Brand Names

Enablex®

Synonyms

Darifenacin Hydrochloride; UK-88,525

Generic Available

No

Use

Management of symptoms of bladder overactivity (urge incontinence, urgency, and frequency)

Pregnancy Risk Factor

C

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women; should be used only if potential benefit outweighs possible risk to the fetus.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Hypersensitivity to darifenacin or any component of the formulation; uncontrolled narrow-angle glaucoma; paralytic ileus, GI or GU obstruction

Warnings/Precautions

Use with caution with hepatic impairment; dosage limitation is required in moderate hepatic impairment (Child-Pugh Class B). Not recommended for use in severe hepatic impairment (Child-Pugh Class C). Use with caution in patients with clinically-significant bladder outlet obstruction, prostatic hyperplasia (nonobstructive), or urinary retention. Use caution in patients with decreased GI motility, constipation, hiatal hernia, reflux esophagitis, and ulcerative colitis. Use caution in patients with myasthenia gravis. In patients with controlled narrow angle glaucoma, darifenacin should be used with extreme caution and only when the potential benefit outweighs risks of treatment. Safety and efficacy have not been established in pediatric patients.

Adverse Reactions

>10%: Gastrointestinal: Xerostomia (19% to 35%), constipation (15% to 21%)

1% to 10%:

Central nervous system: Headache (7%), dizziness (1% to 2%)

Gastrointestinal: Dyspepsia (3% to 8%), abdominal pain (2% to 4%), nausea (2% to 4%), diarrhea (1% to 2%)

Genitourinary: Urinary tract infection (4% to 5%)

Neuromuscular & skeletal: Asthenia (2% to 3%)

Ocular: Dry eyes (2%)

Miscellaneous: Flu-like syndrome (<1% to 3%), accidental injury (<1% to 3%)

<1%: Abnormal vision, acute urinary retention, arthralgia, back pain, bronchitis, dry skin, flu-like syndrome, hypertension, pain, peripheral edema, pharyngitis, rash, rhinitis, sinusitis, weight gain, urinary tract disorder, vaginitis, vomiting

Drug Interactions

Substrate of CYP2D6 (minor), CYP3A4 (major); Inhibits CYP2D6 (moderate), 3A4 (weak)

Anticholinergic agents: Adverse anticholinergic effects may be additive with other anticholinergic agents (includes tricyclic antidepressants, antihistamines, and phenothiazines).

CYP2D6 substrates: Darifenacin may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Darifenacin may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: May decrease the levels/effects of darifenacin. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of darifenacin. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. The dosage of darifenacin should not exceed 7.5 mg daily in patients receiving potent CYP3A4 inhibitors.

Stability

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

Mechanism of Action

Selective antagonist of the M3 muscarinic (cholinergic) receptor subtype. Blockade of the receptor limits bladder contractions, reducing the symptoms of bladder irritability/overactivity (urge incontinence, urgency and frequency).

Pharmacodynamics/Kinetics

Distribution: Vd: 163 L

Protein binding: 98%

Metabolism: Hepatic, via CYP3A4 (major) and CYP2D6 (minor)

Bioavailability: 15% to 19%

Half-life elimination: 13-19 hours

Time to peak, plasma: 7 hours

Excretion: As metabolites (inactive); urine (60%), feces (40%)

Dosage

Oral: Adults: Initial: 7.5 mg once daily. If response is not adequate after a minimum of 2 weeks, dosage may be increased to 15 mg once daily. Dosage should not be increased in patients with hepatic impairment or in those receiving potent inhibitors of CYP3A4.

Dosage adjustment in renal impairment: No adjustment required.

Dosage adjustment in hepatic impairment:

Moderate impairment (Child-Pugh Class B): Daily dosage should not exceed 7.5 mg/day

Severe impairment (Child-Pugh Class C): Has not been evaluated; use is not recommended

Administration

Tablet should be swallowed whole; may be taken without regard to food.

Dietary Considerations

May be taken without regard to meals, with or without food.

Dosage Forms

Tablet, extended release: 7.5 mg, 15 mg