Esmelex

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

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

Adults

The recommended starting dose is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed. For those patients requiring greater symptom relief, the dose may be increased to 15 mg daily, based on individual response.

Elderly patients (> 65 years)

The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed for efficacy and safety. For those patients who have an acceptable tolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, based on individual response.

Paediatric population

Esmelex is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

Renal impairment

No dose adjustment is required in patients with impaired renal function. However, caution should be exercised when treating this population.

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). However, there is a risk of increased exposure in this population.

Patients with moderate hepatic impairment (Child Pugh B) should only be treated if the benefit outweighs the risk, and the dose should be restricted to 7.5 mg daily. Esmelex is contraindicated in patients with severe hepatic impairment (Child Pugh C).

Patients receiving concomitant treatment with substances that are potent inhibitors of CYP2D6 or moderate inhibitors of CYP3A4

In patients receiving substances that are potent CYP2D6 inhibitors, such as paroxetine, terbinafine, quinidine and cimetidine, treatment should start with the 7.5 mg dose. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.

In patients receiving substances that are moderate CYP3A4 inhibitors, such as fluconazole, grapefruit juice and erythromycin, the recommended starting dose is 7.5 mg daily. The dose may be titrated to 15 mg daily to obtain an improved clinical response provided the dose is well tolerated. However, caution should be exercised.

Method of administration

Esmelex is for oral use. The tablets should be taken once daily with liquid. They can be taken with or without food, and must be swallowed whole and not chewed, divided or crushed.

The recommended starting dose of Esmelex 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.

Esmelex should be taken once daily with water. Esmelex 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 Esmelex should not exceed 7.5 mg. Esmelex is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

Esmelex is contraindicated in patients with:

- Hypersensitivity to the active substance or to any of the excipients.

- Urinary retention.

- Gastric retention.

- Uncontrolled narrow-angle glaucoma.

- Myasthenia gravis.

- Severe hepatic impairment (Child Pugh C).

- Severe ulcerative colitis.

- Toxic megacolon.

- Concomitant treatment with potent CYP3A4 inhibitors.

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

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

Esmelex should be administered with caution to patients with autonomic neuropathy, hiatus hernia, clinically significant bladder outflow obstruction, risk for urinary retention, severe constipation or gastrointestinal obstructive disorders, such as pyloric stenosis.

Esmelex should be used with caution in patients being treated for narrow-angle glaucoma.

Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Esmelex. If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Esmelex should be used with caution in patients with risk of decreased gastrointestinal motility, gastro-oesophageal reflux and/or who are concurrently taking medicinal products (such as oral bisphosphonates) that can cause or exacerbate oesophagitis.

Safety and efficacy have not yet been established in patients with a neurogenic cause for detrusor over activity.

Caution should be used when prescribing antimuscarinics to patients with pre-existing cardiac diseases.

As with other antimuscarinics, patients should be instructed to discontinue Esmelex and seek immediate medical attention if they experience oedema of the tongue or laropharynx, or difficulty breathing.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Urinary Retention

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

Decreased Gastrointestinal Motility

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

Esmelex 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

Esmelex 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 Esmelex 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 Esmelex should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Esmelex 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 Esmelex, 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 Esmelex are used in a hot environment. Because anticholinergics, such as Esmelex, 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 Esmelex.

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.

Esmelex 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, Esmelex 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 Esmelex is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Esmelex 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 Esmelex is not recommended for use in these patients. The daily dose of Esmelex 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.

Consistent with the pharmacological profile, the most commonly reported adverse reactions were dry mouth (20.2% and 35% for the 7.5 mg and 15 mg dose, respectively, 18.7% after flexible dose titration, and 8% - 9% for placebo) and constipation (14.8% and 21% for the 7.5 mg and 15 mg dose, respectively, 20.9% after flexible dose titration, and 5.4% - 7.9% for placebo). Anticholinergic effects, in general, are dose-dependent.

However, the patient discontinuation rates due to these adverse reactions were low (dry mouth: 0% - 0.9% and constipation: 0.6% - 2.2% for darifenacin, depending on the dose; and 0% and 0.3% for placebo, for dry mouth and constipation, respectively).

Table 1: Adverse reactions with Esmelex 7.5 mg and 15 mg prolonged-release tablets

Frequency estimate: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In the pivotal clinical trials with doses of Esmelex 7.5 mg and 15 mg, adverse reactions were reported as presented in the table above. Most of the adverse reactions were of mild or moderate intensity and did not result in discontinuation in the majority of the patients.

Treatment with Esmelex may possibly mask symptoms associated with gallbladder disease. However, there was no association between the occurrence of adverse events related to the biliary system in darifenacin-treated patients and increasing age.

The incidence of adverse reactions with the doses of Esmelex 7.5 mg and 15 mg decreased during the treatment period up to 6 months. A similar trend is also seen for the discontinuation rates.

Post-marketing experience

The following events have been reported in association with darifenacin use in worldwide post-marketing experience: generalised hypersensitivity reactions including angioedema, depressed mood/mood alterations, hallucination. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events cannot be estimated from the available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard

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

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

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

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

Post Marketing Experience

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

Esmelex has been administered in clinical trials at doses up to 75 mg (five times maximum therapeutic dose). The most common adverse reactions seen were dry mouth, constipation, headache, dyspepsia and nasal dryness. However, overdose with darifenacin can potentially lead to severe anticholinergic effects and should be treated accordingly. Therapy should be aimed at reversing the anticholinergic symptoms under careful medical supervision. The use of agents such as physostigmine can assist in reversing such symptoms.

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

Pharmacotherapeutic group: Urinary antispasmodic, ATC code: G04BD10.

Darifenacin is a selective muscarinic M3 receptor antagonist (M₃ SRA) in vitro. The M3 receptor is the major subtype that controls urinary bladder muscle contraction. It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.

Cystometric studies performed with darifenacin in patients with involuntary bladder contractions showed increased bladder capacity, increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions.

Treatment with Esmelex administered at dosages of 7.5 mg and 15 mg daily has been investigated in four double-blind, Phase III, randomised, controlled clinical studies in male and female patients with symptoms of overactive bladder. As seen in Table 2 below, a pooled analysis of 3 of the studies for the treatment with both Esmelex 7.5 mg and 15 mg provided a statistically significant improvement in the primary endpoint, reduction in incontinence episodes, versus placebo.

Table 2: Pooled analysis of data from three Phase III clinical studies assessing fixed doses of 7.5 mg and 15 mg Esmelex

¹ Hodges Lehmann estimate: median difference from placebo in change from baseline

² Stratified Wilcoxon test for difference from placebo.

Esmelex 7.5 mg and 15 mg doses significantly reduced both the severity and number of urinary urgency episodes and the number of micturitions, while significantly increasing the mean volume voided from baseline.

Esmelex 7.5 mg and 15 mg were associated with statistically significant improvements over placebo in some aspects of quality of life as measured by the Kings Health Questionnaire including incontinence impact, role limitations, social limitations and severity measures.

For both doses of 7.5 mg and 15 mg, the percentage median reduction from baseline in the number of incontinence episodes per week was similar between males and females. The observed differences from placebo for males in terms of percentage and absolute reductions in incontinence episodes was lower than for females.

The effect of treatment with 15 mg and 75 mg of darifenacin on QT/QTc interval was evaluated in a study in 179 healthy adults (44% male: 56% females) aged 18 to 65 for 6 days (to steady state). Therapeutic and supra-therapeutic doses of darifenacin resulted in no increase in QT/QTc interval prolongation from baseline compared to placebo at maximum darifenacin exposure.

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 Esmelex 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 Esmelex 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 Esmelex 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, Esmelex 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 Esmelex was no different from placebo.

Darifenacin is metabolised by CYP3A4 and CYP2D6. Due to genetic differences, about 7% of the Caucasians lack the CYP2D6 enzyme and are said to be poor metabolisers. A few percent of the population have increased CYP2D6 enzyme levels (ultrafast metabolisers). The information below applies to subjects who have normal CYP2D6 activity (extensive metabolisers) unless otherwise stated.

Absorption

Due to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma levels are reached approximately 7 hours after administration of the prolonged-release tablets and steady-state plasma levels are achieved by the sixth day of administration. At steady state, peak-to-trough fluctuations in darifenacin concentrations are small (PTF: 0.87 for 7.5 mg and 0.76 for 15 mg), thereby maintaining therapeutic plasma levels over the dosing interval. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets.

Distribution

Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (V_ss) is estimated to be 163 litres.

Metabolism

Darifenacin is extensively metabolised by the liver following oral administration.

Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver and by CYP3A4 in the gut wall. The three main metabolic routes are as follows:

monohydroxylation in the dihydrobenzofuran ring;

dihydrobenzofuran ring opening and

N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are major circulating metabolites but none contribute significantly to the overall clinical effect of darifenacin.

The pharmacokinetics of darifenacin at steady state are dose-dependent, due to saturation of the CYP2D6 enzyme.

Doubling the darifenacin dose from 7.5 mg to 15 mg result in a 150% increase in steady-state exposure. This dose-dependency is probably caused by saturation of the CYP2D6 catalysed metabolism possibly together with some saturation of CYP3A4-mediated gut wall metabolism.

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 faeces. Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 litres/hour. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.

Special patient population

Gender

A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females.

Elderly patients

Paediatric patients

The pharmacokinetics of darifenacin have not been established in the paediatric population.

CYP2D6 poor metabolisers

The metabolism of darifenacin in CYP2D6 poor metabolisers is principally mediated by CYP3A4. In one pharmacokinetic study the steady-state exposure in poor metabolisers was 164% and 99% higher during treatment with 7.5 mg and 15 mg once daily, respectively. However, a population pharmacokinetic analyses of Phase III data indicated that on average steady-state exposure is 66% higher in poor metabolisers than in extensive metabolisers. There was considerable overlap between the ranges of exposures seen in these two populations.

Renal insufficiency

A small study of subjects (n=24) with varying degrees of renal impairment (creatinine clearance between 10 ml/min and 136 ml/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance.

Hepatic insufficiency

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. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function.

Absorption

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

The mean oral bioavailability of Esmelex 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 Esmelex 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 Esmelex.

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.