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Darifenacin Hydrobromide

Class: Genitourinary Smooth Muscle Relaxants
Chemical Name: (S)-1-[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-α,α-diphenyl-3-pyrrolidineacetamide
Molecular Formula: C28H30N2O2
CAS Number: 133099-04-4
Brands: Enablex

Introduction

Genitourinary antispasmodic agent; an antimuscarinic agent.1

Uses for Darifenacin Hydrobromide

Overactive Bladder

Relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency).1

Slideshow: How to Manage Your Overactive Bladder

Extended-release darifenacin (15 mg once daily) may be as effective as immediate-release oxybutynin (5 mg 3 times daily).5

Darifenacin Hydrobromide Dosage and Administration

Administration

Oral Administration

Administer orally once daily with liquids without regard to meals.1

Swallow tablets whole; do not chew, divide, or crush.1

Dosage

Available as darifenacin hydrobromide; dosage expressed in terms of darifenacin.1

Adults

Overactive Bladder
Oral

Initially, 7.5 mg once daily.1 May increase after 2 weeks to 15 mg once daily according to response.1

Prescribing Limits

Adults

Overactive Bladder
Oral

Maximum 15 mg daily.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild hepatic impairment (Child-Pugh class A).1

Maximum 7.5 mg daily in patients with moderate hepatic impairment (Child-Pugh class B).1

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 (See Distribution: Special Populations, under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required.1 8

Geriatric Patients

No dosage adjustment required.1

Cautions for Darifenacin Hydrobromide

Contraindications

  • Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma or risk of these conditions.1

  • Known hypersensitivity to darifenacin or any ingredient in the formulation.1

Warnings/Precautions

Major Toxicities

GU Effects

Severe acute urinary retention requiring treatment reported in some patients receiving higher than recommended dosages (e.g., 30 mg daily) and in patients with detrusor hyperreflexia secondary to a stroke, benign prostatic hypertrophy, or irritable bowel syndrome.1 Acute urinary retention requiring bladder catheterization for 1–2 days also reported at therapeutic dosages.1

Use with caution in patients with clinically important bladder outflow obstruction.1

General Precautions

Decreased GI Motility

May decrease GI motility; use with caution in patients with severe constipation, ulcerative colitis, or myasthenia gravis.1 Severe constipation reported.1

Risk of gastric retention; use with caution in patients with obstructive GI disorders.1

Controlled Angle-closure Glaucoma

In patients being treated for angle-closure glaucoma, use only if potential benefits outweigh risks.1 (See Contraindications under Cautions.)

Specific Populations

Pregnancy

Category C.1

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 (See Geriatric Patients under Dosage and Administration and see Elimination: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Use not evaluated and not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Dosage and Administration and see Distribution: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Dry mouth, constipation.1

Interactions for Darifenacin Hydrobromide

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

Drug

Interaction

Comments

Anticholinergic agents

Possible additive anticholinergic effects (e.g., decreased GI motility; altered absorption of other drugs)1

Antidepressants, tricyclics

Possible increased concentrations of tricyclic antidepressant1

Use concomitantly with caution1

Cimetidine

Increased plasma darifenacin concentrations1

No dosage adjustment required1

Clarithromycin

Possible increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Digoxin

Increased digoxin exposure1

Continue routine monitoring of digoxin therapy1

Diltiazem

Possible increased plasma darifenacin concentrations1

No dosage adjustment required1

Erythromycin

Increased plasma darifenacin concentrations1

No dosage adjustment required1

Flecainide

Possible increased flecainide concentrations1

Use concomitantly with caution1

Fluconazole

Increased plasma darifenacin concentrations1

No dosage adjustment required1

Hormonal contraceptives

Pharmacokinetic interaction unlikely with oral contraceptives containing ethinyl estradiol and levonorgestrel1

Imipramine

Increased plasma concentrations of imipramine and desipramine1

Itraconazole

Possible increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Ketoconazole

Increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Midazolam

Increased midazolam concentrations1

Nefazodone

Possible increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Nelfinavir

Possible increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Paroxetine

Increased plasma darifenacin concentrations1

No dosage adjustment required1

Ritonavir

Possible increased plasma darifenacin concentrations1

Do not exceed a darifenacin dosage of 7.5 mg daily1

Thioridazine

Possible increased thioridazine concentrations1

Use concomitantly with caution1

Verapamil

Possible increased plasma darifenacin concentrations1

No dosage adjustment required1

Warfarin

No substantial effect on PT1

Continue routine monitoring of PT1

Darifenacin Hydrobromide Pharmacokinetics

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.)

Stability

Storage

Oral

Extended-release Tablets

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

Actions

  • 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

Advice to Patients

  • Risk of constipation, urinary retention, blurred vision, and heat prostration (when used in a hot environment).1 4 Use caution when driving or performing dangerous activities until effects on vision are known.4

  • Importance of taking tablets with liquids and swallowing whole; do not chew, divide, or crush.1 4 If a dose is skipped, resume therapy the next day; do not take 2 doses in the same day.4

  • Importance of reading manufacturer’s patient information leaflet before initiating therapy.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Darifenacin Hydrobromide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

7.5 mg (of darifenacin)

Enablex

Novartis

15 mg (of darifenacin)

Enablex

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Enablex 15MG 24-hr Tablets (WARNER CHILCOTT PROF PROD DIV): 30/$163.99 or 90/$465.96

Enablex 7.5MG 24-hr Tablets (WARNER CHILCOTT PROF PROD DIV): 30/$164.99 or 90/$477.99

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis. Enablex (darifenacin hydrobromide) extended-release tablets prescribing information. East Hanover, NJ; 2004 Dec.

2. Miyamae K, Yoshida M, Murakami S et al. Pharmacological effects of darifenacin on human isolated urinary bladder. Pharmacology. 2003; 69:205-11. [PubMed 14624061]

3. Croom KF, Keating GM. Darifenacin in the treatment of overactive bladder. Drugs Aging. 2004; 21:885-92. [PubMed 15493952]

4. Novartis. Enablex (darifenacin hydrobromide) extended-release tablets patient information. East Hanover, NJ; 2004 Dec.

5. Zinner N, Tuttle J, and Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist, compared with oxybutynin in the treatment of patients with overactive bladder. Joint Meeting of the International Continence Society and the International Urogynecological Association. Paris: 2004. Abstract No. 378. From The International Continence Society website ()

6. Haab F, Stewart L, and Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004; 45:420-9. [PubMed 15041104]

7. Kerbusch T, Wahlby U, Milligan PA et al. Population pharmacokinetic modeling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol. 2003; 56:639-52. [IDIS 508556] [PubMed 14616424]

8. Novartis, East Hanover, NJ: Personal communication.

9. Steers W, Corcos J, Foote J et al. An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int. 2005; 95:580-6. [PubMed 15705084]

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