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说明书

ENABLEX ®（darifenacin）缓释片
美国初步批准：2004

适应症
毒蕈碱受体拮抗剂Enablex是为膀胱过动症与急迫性尿失禁，紧迫性和频率症状的治疗表示。

剂量和用法 
建议的出发Enablex缓释片剂量为7.5毫克，每日一次。根据个人的反馈表明，剂量可增至15毫克，每天一次，如早两个星期后开始治疗。

对Enablex每日剂量不应超过7.5毫克以下患者：

中度肝功能不全患者（Child - Pugh分级乙）
患者服用烈性CYP3A4抑制剂
Enablex不建议病人使用严重肝受损（Child - Pugh分级丙）。 
Enablex可采取或没有食物。吞下的药片应整水，而不是咀嚼，分裂或挤压。
 
剂型和优势
缓释片7.5毫克和15毫克。
 
禁忌
Enablex是禁忌的患者，或在风险中，下列条件：

尿潴留，
胃潴留，或
失控的窄角型青光眼。

注意事项： 
Enablex应谨慎加以管理与临床意义膀胱由于尿潴留的风险流出阻塞的病人。
Enablex应谨慎加以管理与因胃内滞留胃肠道阻塞性疾病患者的危险。
Enablex应谨慎使用的患者正在接受治疗的窄角型青光眼，并且只有在潜在利益大于风险。

不良反应 
最常见的不良反应为Enablex（“3％）是：便秘，口干，头痛，消化不良，恶心，尿路感染，意外受伤，和流感症状。

药物相互作用
注意事项时，应采取Enablex是随之而来的是主要由CYP2D6和代谢有一个狭窄的治疗窗口，如氟卡尼，甲硫达嗪和三环类抗抑郁药，药物使用。
与其他的Enablex抗胆碱药物同时使用可能会增加的频率和/口干，便秘或严重程度，视力模糊等抗胆碱药理作用。抗胆碱药物可能会潜在地改变一些随之而来给药因肠胃蠕动影响吸收。

利用在种群 
怀孕：Enablex应该在怀孕期间使用只有在对母亲的潜在利益大于对胎儿的风险。 
哺乳母亲：这不知道是否darifenacin到人的乳汁排出，因此应谨慎前Enablex行使管理是一个哺乳妇女。
儿童用药：在安全性和有效性Enablex儿童患者尚未确定。

Emselex

Active Substance: darifenacin hydrobromide 
Common Name: darifenacin hydrobromide 
ATC Code: G04BD10
Marketing Authorisation Holder: Merus Labs Luxco II S.à R.L.
Active Substance: darifenacin hydrobromide 
Status: Authorised
Authorisation Date: 2004-10-22
Therapeutic Area: Urinary Incontinence, Urge Urinary Bladder, Overactive
Pharmacotherapeutic Group: Urinary antispasmodics

Therapeutic Indication

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in adult patients with overactive bladder syndrome.

What is Emselex?

Emselex is a medicine that contains the active substance darifenacin. It is available as prolonged-release tablets (7.5 mg and 15 mg). ‘Prolonged-release’ means that darifenacin is released slowly from the tablet over a few hours.

What is Emselex used for?

Emselex is used in adults with overactive-bladder syndrome. It is used to treat the urge incontinence (sudden lack of control over urination), increased urinary frequency (need to urinate frequently) and urgency (sudden urge to pass urine) that are associated with the syndrome.

The medicine can only be obtained with a prescription.

How is Emselex used?

The recommended starting dose of Emselex is 7.5 mg once a day. For patients requiring greater symptom relief, the dose may be increased to 15 mg. The tablets should be swallowed whole with some liquid, and not chewed, divided or crushed.

How does Emselex work?

The active substance in Emselex, darifenacin, is an anticholinergic medicine. It blocks a receptor called the ‘muscarinic M3 receptor’. In the bladder, this causes the muscles that push urine out of the bladder to relax. This leads to an increase in the capacity of the bladder and changes in the way the bladder contracts, resulting in fewer bladder contractions. This helps Emselex to prevent unwanted urination.

How has Emselex been studied?

Emselex has been studied in four main studies in a total of 2,078 male and female patients with symptoms of overactive bladder. Emselex was used at various doses (from 3.75 mg to 30 mg a day) and compared with placebo (a dummy treatment) or with tolterodine (another medicine used in this condition). The main measure of effectiveness was the change in the number of incontinence episodes per week.

What benefit has Emselex shown during the studies?

When the results from all four studies were combined, Emselex was more effective in reducing the number of incontinence episodes than placebo. At the start of the studies, the patients had around 16 incontinence episodes per week. After 12 weeks of treatment, patients receiving Emselex 7.5 mg or 15 mg had 8.8 (68%) or 10.6 (77%) fewer episodes of incontinence per week, respectively, and patients receiving placebo had 7 or 7.5 (54 or 58%) fewer episodes per week.

What is the risk associated with Emselex?

The most common side effects with Emselex (seen in more than 1 patient in 10) are dry mouth and constipation. For the full list of all side effects reported with Emselex, see the package leaflet.

Emselex must not be used in people who are hypersensitive (allergic) to darifenacin or any of the other ingredients. It must not be used in patients with:

· urinary retention (difficulty passing urine);

· gastric retention (when the stomach does not empty properly);

· uncontrolled narrow-angle glaucoma (increased eye pressure even with treatment);

· myasthenia gravis (a disease causing muscle weakness);

· severe liver problems;

· severe ulcerative colitis (severe inflammation of the gut causing ulcers and bleeding);

· toxic megacolon (a very serious complication of colitis).

Emselex must not be taken by patients who are also taking medicines that could affect the way that Emselex is broken down in the body, such as protease inhibitors (used to treat HIV infection, such as ritonavir), or ketoconazole or itraconazole (used to treat fungal infections).

Why has Emselex been approved?

The CHMP concluded that Emselex showed an effectiveness similar to that of other anticholinergic medicines used in overactive bladder syndrome. The Committee decided that Emselex’s benefits are greater than its risks and recommended that it be given marketing authorisation.

Other information about Emselex

The European Commission granted a marketing authorisation valid throughout the European Union for Emselex on 22 October 2004.

 

 

 

 

Drug Description

 

ENABLEX ® 
(darifenacin) Tablets

DESCRIPTION

Enablex is an extended-release tablet for oral administration which contains 7.5 mg or 15 mg darifenacin as its hydrobromide salt. The active moiety, 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 empirical formula of darifenacin hydrobromide is C28H30N2O2•HBr.

The structural formula is:

Darifenacin hydrobromide is a white to almost white, crystalline powder, with a molecular weight of 507.5.

Enablex is a once-a-day extended-release tablet and contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains ferric oxide red and ferric oxide yellow.

Indications & Dosage

INDICATIONS

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

DOSAGE AND ADMINISTRATION

The recommended starting dose of Enablex 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.

Enablex should be taken once daily with water. Enablex 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 Enablex should not exceed 7.5 mg. Enablex is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [seeWARNINGS & PRECAUTIONS, DRUG INTERACTIONS, Use in Specific Populations and CLINICAL PHARMACOLOGY].

HOW SUPPLIEDDosage Forms And Strengths

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

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

Storage And Handling

Enablex®, 7.5 mg 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 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

Storage

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

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

Manufactured by: Warner Chilcott Deutschland GmbH, D-64331 Weiterstadt, Germany. Marketed by: Warner Chilcott (US), LLC, Rockaway, NJ 07866. Revised: Oct 2013

Side Effects

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

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

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

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

Post Marketing Experience

The following adverse reactions have been reported during post-approval use of Enablex 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

Drug Interactions

DRUG INTERACTIONSCYP3A4 Inhibitors

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

CYP2D6 Inhibitors

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) [see CLINICAL PHARMACOLOGY].

CYP2D6 Substrates

Caution should be taken when Enablex is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants) [see CLINICAL PHARMACOLOGY].

CYP3A4 Substrates

Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see CLINICAL PHARMACOLOGY].

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 [see CLINICAL PHARMACOLOGY].

Warfarin

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

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 [see CLINICAL PHARMACOLOGY].

Other Anticholinergic Agents

The concomitant use of Enablex 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.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONSRisk Of Urinary Retention

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

Decreased Gastrointestinal Motility

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

Enablex 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 airwayswelling 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

Enablex is associated with anticholinergic central nervous system (CNS) effects [see ADVERSE REACTIONS]. 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 Enablex 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 Enablex should not exceed 7.5 mg for patients with moderate hepaticimpairment (Child-Pugh B). Enablex 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, Use In Specific Populations and CLINICAL PHARMACOLOGY].

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Patients should be informed that anticholinergic agents, such as Enablex, 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 Enablex are used in a hot environment. Because anticholinergics, such as Enablex, 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 Enablex.

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.

Enablex 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 ToxicologyCarcinogenesis, 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 PopulationsPregnancyPregnancy 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, Enablex 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 Enablex is administered to a nursingwoman.

Pediatric Use

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

Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Enablex 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 [see CLINICAL PHARMACOLOGY and Clinical Studies].

Hepatic Impairment

Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Enablex is not recommended for use in these patients [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. The daily dose of Enablex 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).

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 [see CLINICAL PHARMACOLOGY].

Gender

No dose adjustment is recommended based on gender [see CLINICAL PHARMACOLOGY and Clinical Studies].

Overdosage & Contraindications

OVERDOSE

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

CONTRAINDICATIONS

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

· urinary retention

· gastric retention, or

· uncontrolled narrow-angle glaucoma.

Clinical Pharmacology

CLINICAL PHARMACOLOGYMechanism 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.

Pharmacodynamics

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 Enablex 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 Enablex 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 Enablex 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, Enablex 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 medianHR following treatment with Enablex was no different from placebo.

PharmacokineticsAbsorption

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

The mean oral bioavailability of Enablex 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 Enablex 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 Enablex.

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 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.

Drug-Drug InteractionsEffects of Other Drugs on Darifenacin

Darifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics [see DRUG INTERACTIONS].

CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Enablex was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for one PM subject (n = 1). Mean AUC increased to 143 and 939 ng•h/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of Enablex was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to 1110 and 931 ng•h/mL for EMs and for one PM subject, respectively [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88% and 84%, respectively [see DRUG INTERACTIONS].

The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor.

CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see DRUG INTERACTIONS].

Effects of Darifenacin on Other Drugs

In Vitro Studies: Based on in vitro human microsomal studies, Enablex is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations.

In Vivo Studies: The potential for clinical doses of Enablex to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies.

CYP2D6 Substrates: The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260% [see DRUG INTERACTIONS].

CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17% increase in midazolam exposure.

Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg).

Warfarin: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin30 mg was co-administered with darifenacin (30 mg daily) at steady-state [see DRUG INTERACTIONS].

Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure [see DRUG INTERACTIONS].

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 Enablex 15 mg once daily, darifenacin exposure at steady-state was approximately 12% to 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 Enablex has not been studied in the pediatric population [seeUse 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% to 79% and 61% to 73% higher in females than in males, respectively [see Use in Specific Populations].

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

Hepatic Impairment: Enablex pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given Enablex 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, WARNINGS AND PRECAUTIONS and Use in Specific Population].

Clinical Studies

Enablex extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinaryincontinence per week. The majority of patients were white (94%) and female (84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were greater than or equal to 65 years of age. These characteristics were well balanced across treatment groups. The study population was inclusive of both naïve patients who had not received prior pharmacotherapy for overactive bladder (60%) and those who had (40%).

Table 4 shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily Enablex for 12 weeks. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies. Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition.

Table 4: Difference Between Enablex (7.5 mg, 15 mg) and Placebo for the Week 12 Change from Baseline (Studies 1, 2 and 3)

Table 5 shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg Enablex or placebo daily with the option to increase to 15 mg Enablex or placebo daily after two weeks.

Table 5: Difference between Enablex (7.5 mg/15 mg) and Placebo for the Week 12 Change from Baseline (Study 4)

As seen in Figures 2 a, 2b and 2c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with Enablex 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period.

Figures 2a, 2b, 2c. Median Change from Baseline at Weeks 2, 6, 12 for Number of Urge Incontinence Episodes per Week (Studies 1, 2 and 3)

Medication Guide

PATIENT INFORMATION

Enablex® 
(en-a-blex)
(darifenacin) Extended-release Tablets

Read this Patient Information leaflet about Enablex® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.

What is Enablex?

Enablex is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

· Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents

· Urgency: a strong need to urinate right away

· Frequency: urinating often

It is unknown if Enablex is safe and effective in children.

Who should not take Enablex?

Do not take Enablex if you:

· are not able to empty your bladder (“urinary retention”)

· have delayed or slow emptying of your stomach (“gastric retention”)

· have an eye problem called “uncontrolled narrow-angle glaucoma”

What should I tell my healthcare provider before starting Enablex?

Before starting Enablex, tell your doctor if you:

· have trouble emptying your bladder or if you have a weak urine stream

· have any stomach or intestinal problems, or problems with constipation

· have liver problems

· have any other medical conditions

· are pregnant or are planning to become pregnant. It is not known if Enablex can harm your unborn baby.

· are breastfeeding or plan to breastfeed. It is not known if Enablex passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Enablex.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Enablex and certain other medicines may affect each other, causing side effects.

Especially tell your healthcare provider if you take a:

· antifungal medicine ketoconazole (Nizoral®) or itraconazole (Sporanox®)

· antibiotic medicine clarithromycin (Biaxin®)

· anti-HIV medicine ritonavir (Norvir®) or nelfinavir (Viracept®)

· medicine to treat depression nefazadone (Serzone®)

· medicine to treat an abnormal heartbeat flecainide (Tambocor™)

· antipsychotic medicine thioridazine (Mellaril®)

· medicine to treat depression called a tricyclic antidepressant

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacisteach time you get a new medicine.

How should I take Enablex?

· Take Enablex exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take Enablex 1 time daily with water.

· Enablex should be swallowed whole. Do not chew, cut or crush Enablex tablet.

· Enablex may be taken with or without food.

· If you take too much Enablex call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking Enablex?

Enablex can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how Enablex affects you.

What are the possible side effects of Enablex?

Enablex may cause serious side effects including:

· Serious allergic reaction. Stop taking Enablex and get medical help right away if you have:

o hives, skin rash or swelling

o severe itching

o swelling of your face, mouth or tongue

o trouble breathing

o The most common side effects with Enablex are:

o constipation

o dry mouth

o headache

o heartburn

o nausea

o urinary tract infection

o blurred vision

o heat exhaustion or heat-stroke. This can happen when Enablex is used in hot environments. Symptoms of heat exhaustion may include:

§ decreased sweating

§ dizziness

§ tiredness

§ nausea

§ increase body temperature

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Enablex. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Enablex?

· Store Enablex at room temperature, between 59° F to 86° F (15° C to 30° C).

· Keep Enablex out of the light.

Keep Enablex and all medicines out of the reach of children.

General information about Enablex.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Enablex for a condition for which it was not prescribed. Do not give Enablex to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Enablex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Enablex that is written for health professionals.

What are the ingredients in Enablex?

Active ingredient: darifenacin

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide.

The 15 mg tablet also contains ferric oxide red and ferric oxide yellow.