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All about: Darifenacin

Big Image Pronouncation: (dar-ih-FEN-ah-sin)
Class: Anticholinergic

Trade Names:
Enablex
- Tablets, extended-release 7.5 mg
- Tablets, extended-release 15 mg

Mechanism of Action

Pharmacology

Competitive muscarinic receptor antagonist.

Pharmacokinetics

Absorption

Steady-state plasma levels achieved by day 6 of dosing. Steady-state bioavailability is approximately 15% and 19% for 7.5 and 15 mg dose, respectively. Darifenacin 7.5 mg in extensive metabolizers: AUC is 29.24 ng•h/mL, C max is 2.01 ng/mL, T max is 6.49 h. Darifenacin 7.5 mg in poor metabolizers: AUC is 67.56 ng•h/mL, C max is 4.27 ng/mL, T max is 5.20 h. Darifenacin 15 mg in extensive metabolizers: AUC is 88.90 ng•h/mL, C max is 5.76 ng/mL, T max is 7.61 h. Darifenacin 15 mg in poor metabolizers: AUC is 157.71 ng•h/mL, C max is 9.99 ng/mL, T max is 6.71 h.

Distribution

Approximately 98% protein bound, primarily to alpha 1 -acid-glycoprotein.

Metabolism

Metabolized by CYP2D6 and CYP3A4. The metabolic products of the hydroxylation and N-dealkylation are unlikely to contribute to the clinical effect. Approximately 7% of white patients and 2% of black patients are poor CYP2D6 metabolizers of the drug, in which case metabolism will be mediated principally by the CYP3A4 isozyme. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers.

Elimination

Approximately 60% eliminated in the urine, 40% in the feces, and 3% eliminated unchanged. Estimated clearance is 40 L/h and 32 L/h in extensive and poor metabolizers, respectively. Elimination t ½ is about 13 to 19 h. Darifenacin 7.5 mg in extensive metabolizers: t ½ is 12.43 h. Darifenacin 7.5 mg in poor metabolizers: t ½ is 19.95 h. Darifenacin 15 mg in extensive metabolizers: t ½ is 12.05 h. Darifenacin 15 mg in poor metabolizers: t ½ is 7.4 h.

Indications and Usage

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

Contraindications

Patients with or at risk of urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO Start with 7.5 mg once daily. Based on response, dose may be increased to 15 mg once daily within 2 wk of starting therapy.

Moderate Hepatic Impairment or Coadministered Potent CYP3A4 Inhibitor
Adults

PO A dose greater than 7.5 mg daily is not recommended.

General Advice

  • Administer with liquid. Advise patient to swallow tablet whole and not crush, chew, or break tablet.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Protect from light.

Drug Interactions

Anticholinergic agents

Frequency and severity of dry mouth, constipation, blurred vision, and other anticholinergic effects may be increased.

Drugs predominantly metabolized by CYP2D6 (eg, flecainide, thioridazine, tricyclic antidepressants)

Use with caution, especially with drugs with a narrow therapeutic index.

Potent CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir)

Darifenacin plasma concentrations may be elevated by these agents, increasing the pharmacologic and adverse effects.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (at least 1%).

CNS

Headache (7%); asthenia (3%); dizziness (2%).

Dermatologic

Dry skin, pruritus, rash (at least 1%).

EENT

Dry eyes (2%); abnormal vision, pharyngitis, rhinitis (at least 1%).

GI

Dry mouth (35%); constipation (21%); dyspepsia (8%); abdominal pain, nausea (4%); diarrhea (2%); vomiting (at least 1%).

Genitourinary

UTI (5%); urinary tract disorder, vaginitis (at least 1%).

Metabolic-Nutritional

Weight gain (at least 1%).

Musculoskeletal

Arthralgia, back pain (at least 1%).

Respiratory

Bronchitis, sinusitis (at least 1%).

Miscellaneous

Accidental injury, flu-syndrome (3%); pain, peripheral edema (at least 1%).

Precautions

Monitor

Identify baseline symptoms (urgency, frequency, incontinence) and monitor patient's response to therapy. Ensure therapy is periodically reviewed to determine if therapy needs to be continued without change, or if a dose change (eg, increase, decrease, discontinuation) is indicated. Monitor patient for GI, GU, OPHTH, CNS, and general body side effects. Discontinue therapy immediately if any of the following occur: severe abdominal pain, sudden eye pain, or urinary retention.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use not recommended in patients with severe hepatic impairment.

GI motility

Because GI motility may be decreased, use with caution in patients with GI obstructive disorders because of risk of gastric retention and use with caution in patients with severe constipation, ulcerative colitis, and myasthenia gravis.

Narrow-angle glaucoma

Use with caution and only if benefits outweigh risks in patients being treated for narrow-angle glaucoma.

Urinary retention

Use with caution.

Overdosage

Symptoms

Severe muscarinic effects.

Patient Information

  • Advise patient to read patient information leaflet before starting therapy and with each refill.
  • Advise patient to take prescribed dose once daily without regard to meals, but to take with food if stomach upset occurs. Advise patient to swallow tablet whole with liquid and not to crush, chew, or break tablet.
  • Advise patient that if a dose is missed to skip that dose and take the next dose at the regularly scheduled time the next day. Caution patient not to take 2 doses to catch up or to take 2 doses of medication in the same day.
  • Caution patient not to change the dose or stop taking this medicine unless advised by health care provider. Advise patient to notify health care provider if symptoms do not improve or appear to be worsening.
  • Advise patient that dry mouth, constipation, difficulty urinating, and blurred vision are common side effects of therapy and to notify health care provider if any occur and are intolerable.
  • Instruct patient to stop taking the drug and notify health care provider immediately of the following: severe abdominal pain, sudden eye pain, inability to urinate.
  • Advise patient that darifenacin can increase the risk of heat prostration and to avoid strenuous activity during periods of high temperature or humidity.
  • Advise patient to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Inform patient that medication may cause pupils to dilate, resulting in intolerance to bright lights or sunlight. Advise patient to wear dark glasses to make bright lights or sunlight tolerable.
  • Advise patient that darifenacin may cause dizziness or blurred vision and to use caution while driving or performing other potentially dangerous activities until tolerance has been determined.

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