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Darifenacin Extended-Release Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Darifenacin is a potent muscarinic receptor antagonist. Chemically, darifenacin hydrobromide is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide. The structural formula is

Molecular formula: C28H30N2O2 • HBr - Molecular weight: 507.5

Darifenacin hydrobromide is a white to almost white, crystalline powder.

Darifenacin hydrobromide extended-release (ER) tablet for oral administration which contains 7.5 mg or 15 mg darifenacin as its hydrobromide salt.

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose (hydroxypropyl methylcellulose), magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains iron oxide red and iron oxide yellow.

2. INDICATIONS AND USAGE

Darifenacin is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

3. DOSAGE AND ADMINISTRATION

The recommended starting dose of darifenacin is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy.

Darifenacin should be taken once daily with water. Darifenacin may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of darifenacin should not exceed 7.5 mg. Darifenacin is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings & Precautions, Drug Interactions, Use in Specific Populations].

4. CONTRAINDICATIONS

Darifenacin is contraindicated in patients with, or at risk for, the following conditions:

• Urinary retention

• Gastric retention, or

• Uncontrolled narrow-angle glaucoma.

5. MECHANISM OF ACTION

Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion.

In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no studies of darifenacin in pregnant women.

Darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg . At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of darifenacin was shown to increase post-implantation loss, with a no effect level at nine times (10 mg/kg/day) the AUC at the MRHD). Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD).

Because animal reproduction studies are not always predictive of human response, darifenacin should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

6.2 Nursing Mothers

Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before darifenacin is administered to a nursing woman.

6.3 Pediatric Use

The safety and effectiveness of darifenacin in pediatric patients have not been established.

6.4 Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with darifenacin were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n=207) and younger patients < 65 years (n=464). No dose adjustment is recommended for elderly patients.

6.5 Hepatic Impairment

Subjects with severe hepatic impairment (Child Pugh C) have not been studied, therefore darifenacin is not recommended for use in these patients [see Dosage and Administration and Warnings and Precautions]. The daily dose of darifenacin should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child Pugh B) [see Dosage and Administration and Warnings and Precautions]. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment (Child Pugh A).

6.6 Renal Impairment

A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) demonstrated no clear relationship between renal function and darifenacin clearance. No dose adjustment is recommended for patients with renal impairment.

6.7 Gender

No dose adjustment is recommended based on gender.

7. WARNINGS AND PRECAUTIONS

7.1 Risk of Urinary Retention

Darifenacin should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

7.2 Decreased Gastrointestinal Motility

Darifenacin should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Darifenacin, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis.

7.3 Controlled Narrow-Angle Glaucoma

Darifenacin should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.

7.4 Angioedema

Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

7.5 Central Nervous System Effects

Darifenacin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how darifenacin affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

7.6 Patients with Hepatic Impairment

The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population [see Dosage and Administration, and Use in Specific Populations].

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of darifenacin was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin. Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received darifenacin 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with darifenacin for at least 24 and 52 weeks, respectively.

In Studies 1, 2 and 3 combined, the serious adverse reactions to darifenacin were urinary retention and constipation.

In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with darifenacin 7.5 mg daily, darifenacin 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with darifenacin 7.5 mg daily, darifenacin 15 mg daily and placebo, respectively.

Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg darifenacin, and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment.

Table 1: Incidence of Identified Adverse Reactions, Derived from All Adverse Events Reported in ≥2% of Patients Treated with Darifenacin Extended-Release Tablets and More Frequent with Darifenacin than with Placebo in Studies 1, 2, and 3

Other adverse reactions reported by 1% to 2% of darifenacin-treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis.

Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which darifenacin was administered in accordance with dosing recommendations [see Dosage and Administration (2)]. All patients initially received placebo or darifenacin 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to darifenacin 15 mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table 2 lists the identified adverse reactions, derived from all adverse events reported in >3% of patients treated with darifenacin and greater than placebo.

Table 2: Number (%) of Adverse Reactions, Derived from All Adverse Events Reported in >3% of Patients Treated with Darifenacin Extended-Release Tablets, and More Frequent with Darifenacin than Placebo, in Study 4

8.2 Post Marketing Experience

The following adverse reactions have been identified during post approval use of darifenacin extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: hypersensitivity reactions, including angioedema with airway obstruction

Central Nervous: confusion and hallucinations

Cardiovascular: palpitations

9. OVERDOSAGE

Overdosage with antimuscarinic agents, including darifenacin, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Darifenacin has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision.

10. DRUG INTERACTIONS

10.1 CYP3A4 Inhibitors

The systemic exposure of darifenacin from darifenacin extended release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g. erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration].

10.2 CYP2D6 Inhibitors

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine and duloxetine).

10.3 CYP2D6 Substrates

Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (e.g. flecainide, thioridazine and tricyclic antidepressants).

10.4 CYP3A4 Substrates

Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics.

10.5 Combination oral contraceptives

Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol.

10.6 Warfarin

Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was coadministered with darifenacin (30 mg daily) at steady state. Standard therapeutic prothrombin time monitoring for warfarin should be continued.

10.7 Digoxin

Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued.

10.8 Other Anticholinergic Agents

The concomitant use of darifenacin with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility.

11. PHARMACOKINETICS

Absorption

After oral administration of darifenacin to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.

Figure 1: Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs*

* Includes 95 EMs and 6 PMs for 7.5 mg; 104 EMs and 10 PMs for 15 mg.

A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3.

Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype

aN = 25; bN = 8; cN = 2; dN = 1; AUC24 = Area under the plasma concentration versus time curve for 24h;

Cmax = Maximum observed plasma concentration; Cavg = Average plasma concentration at steady-state;

Tmax = Time of occurrence of Cmax; t½ = Terminal elimination half-life.

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The mean oral bioavailability of darifenacin in EMs at steady state is estimated to be 15% and 19% for 7.5-mg and 15-mg tablets, respectively.

Effect of Food

Following single dose administration of darifenacin with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22% and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from darifenacin.

Distribution

Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L.

Metabolism

Darifenacin is extensively metabolized by the liver following oral dosing.

Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows:

(i) monohydroxylation in the dihydrobenzofuran ring;

(ii) dihydrobenzofuran ring opening;

(iii) N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin.

Variability in Metabolism

A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM:EM) for Cmax and AUC following darifenacin 15 mg once daily at steady state were 1.9 and 1.7, respectively.

Excretion

Following administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.

Pharmacokinetics in Special Populations

Age: A population pharmacokinetic analysis of patient data indicated a trend for clearance of darifenacin to decrease with age (6% per decade relative to a median age of 44). Following administration of darifenacin 15 mg once daily, darifenacin exposure at steady state was approximately 12%-19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations].

Pediatric: The pharmacokinetics of darifenacin has not been studied in the pediatric population [see Use in Specific Populations].

Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady state were approximately 57%-79% and 61%-73% higher in females than in males, respectively [see Use in Specific Populations].

Race: The effect of race on the pharmacokinetics of darifenacin has not been characterized [see Warnings and Precautions].

Renal Impairment: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given darifenacin 15 mg once daily to steady state demonstrated no clear relationship between renal function and darifenacin clearance [see Use in Specific Populations].

Hepatic Impairment: Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or moderate (Child Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. Subjects with severe hepatic impairment (Child Pugh C) have not been studied [see Dosage and Administration, Warning and Precautions and Use in Specific Population].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names: ENABLEX, by Warner Chilcott.

International trade name: VESIGARD, by Cipla (India).

b) Generic drugs: None.

2) How Supplied:

Enablex 7.5 mg extended-release tablets are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse.

Bottle of 30 ....................................................... NDC 0430-0170-15

Bottle of 90 ....................................................... NDC 0430-0170-23

Enablex 15 mg extended-release tablets are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.

Bottle of 30 ....................................................... NDC 0430-0171-15

Bottle of 90 ....................................................... NDC 0430-0171-23

3) Storage:

Store at 25°C (77°F); excursions permitted to 15 - 30° C (59 - 86° F) [see USP Controlled Room Temperature]. Protect from light.

Keep this and all drugs out of the reach of children.

Rx only

Rev 03/12