Энаблекс

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

The recommended starting dose of Энаблекс 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.

Энаблекс should be taken once daily with water. Энаблекс 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 (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of Энаблекс should not exceed 7.5 mg. Энаблекс is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

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

• urinary retention
• gastric retention, or
• uncontrolled narrow-angle glaucoma.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Urinary Retention

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

Decreased Gastrointestinal Motility

Энаблекс should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Энаблекс, 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.

Controlled Narrow-Angle Glaucoma

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

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.

Central Nervous System Effects

Энаблекс is associated with anticholinergic central nervous system (CNS) effects. 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 Энаблекс affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Patients With Hepatic Impairment

The daily dose of Энаблекс should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Энаблекс has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Patients should be informed that anticholinergic agents, such as Энаблекс, may produce clinically significant adverse effects related to anticholinergic pharmacological activity including constipation, urinary retention and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as Энаблекс are used in a hot environment. Because anticholinergics, such as Энаблекс, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined. Patients should read the patient information leaflet before starting therapy with Энаблекс.

Patients should be informed that darifenacin may produce clinically significant angioedema that may result in airway obstruction. Patients should be advised to promptly discontinue darifenacin therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.

Энаблекс extended-release tablets should be taken once daily with water. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated free plasma AUC reached at the maximum recommended human dose (the AUC at the MRHD) of 15 mg and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at the MRHD in female rats and approximately eight times the AUC at the MRHD in male rats.

Darifenacin was not genotoxic in the bacterial mutation assay (Ames test), the Chinese hamster ovary assay, the human lymphocyte assay, or the in vivo mouse bone marrow cytogenetics assay.

There was no evidence for effects on fertility in male or female rats treated at oral doses up to approximately 78 times (50 mg/kg/day) the AUC at the MRHD.

Use In Specific Populations

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, Энаблекс should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

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 Энаблекс is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Энаблекс 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 less than 65 years (n = 464). No dose adjustment is recommended for elderly patients.

Hepatic Impairment

Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Энаблекс is not recommended for use in these patients. The daily dose of Энаблекс should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B). 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).

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.

Gender

No dose adjustment is recommended based on gender.

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 Энаблекс was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with Энаблекс. 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 Энаблекс 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with Энаблекс for at least 24 and 52 weeks, respectively.

In Studies 1, 2 and 3 combined, the serious adverse reactions to Энаблекс 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 Энаблекс 7.5 mg daily, Энаблекс 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Энаблекс 7.5 mg daily, Энаблекс 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 Энаблекс, 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 greater than or equal to 2% of Patients Treated with Энаблекс Extended-Release Tablets and More Frequent with Энаблекс than with Placebo in Studies 1, 2, and 3

Other adverse reactions reported by 1% to 2% of Энаблекс-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 Энаблекс was administered in accordance with dosing recommendations. All patients initially received placebo or Энаблекс 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Энаблекс 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 greater than 3% of patients treated with Энаблекс and greater than placebo.

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

Post Marketing Experience

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

Dermatologic: erythema multiforme, interstitial granuloma annulare

General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction

Central Nervous: confusion, hallucinations and somnolence

Cardiovascular: palpitations and syncope

Overdosage with antimuscarinic agents, including Энаблекс, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Энаблекс 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.

In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after Энаблекс treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.

Electrophysiology

The effect of a six-day treatment of 15 mg and 75 mg Энаблекс on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65. Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg Энаблекс dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, Энаблекс did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with Энаблекс was no different from placebo.

Absorption

After oral administration of Энаблекс 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 Энаблекс 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 Энаблекс 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 Энаблекс 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 Энаблекс 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype

The mean oral bioavailability of Энаблекс 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 Энаблекс 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 Энаблекс.

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:

1. monohydroxylation in the dihydrobenzofuran ring;
2. dihydrobenzofuran ring opening;
3. 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 versus 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 to 19 hours.