Enablex

The potential for clinical doses of darifenacin to act as inhibitors of CYP 2D6 or CYP 3A4 substrates was investigated in specific clinical interaction studies.

There is no effect of food on multiple dose pharmacokinetics from extended release tablets.

The concomitant use of ENABLEX with other antimuscarinic agents may increase the frequency and/or severity of antimuscarinic pharmacological effects such as dry mouth, constipation and blurred vision.

In vitro studies: In vitro human microsomal studies have shown that darifenacin does not inhibit CYP 1A2 or CYP 2C9 up to concentrations of 1·10⁵ nM. In comparison, the average peak unbound concentration of darifenacin at steady state following 15 mg dosing is 0.24 nM.

The daily dose of darifenacin should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, miconazole, troleandomycin, clarithromycin, nefazodone and ritonavir) (see Dosage and Administration). When the 7.5 mg once-daily dose of darifenacin was given to steady-state and co-administered with the potent CYP 3A4 inhibitor ketoconazole, mean darifenacin exposure was increased 5.3 fold.

No special dosing requirements are necessary in the presence of moderate CYP 3A4 inhibitors. Darifenacin exposure following 30 mg once daily dosing (twice the maximum recommended therapeutic dose) was 34%, 84% and 95% higher in the presence of cimetidine, fluconazole and erythromycin, respectively.

Darifenacin (30 mg once daily) had no clinically relevant effect on the exposure of the CYP 3A4 substrate midazolam.

Darifenacin (30 mg once daily) had no effect on the pharmacokinetics of the oral contraceptives levonorgestrel or ethinylestradiol.

Effects on ability to drive and use machines: No studies of the effects of ENABLEX on the ability to drive and use machines have been performed. However, antimuscarinics such as ENABLEX may produce dizziness or blurred vision. Patients experiencing these side effects should not drive or use machines.

No special dosing requirements are necessary in the presence of CYP 2D6 inhibitors. Darifenacin exposure following 30 mg once daily dosing (twice the maximum recommended therapeutic dose) was 33% higher in the presence of the potent CYP 2D6 inhibitor paroxetine 20 mg.

Darifenacin metabolism is primarily mediated by the cytrochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics.

Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP 2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants.

The mean exposure of imipramine, a CYP 2D6 substrate, was increased 70% in the presence of steady-state darifenacin 30 mg once daily (twice the maximum recommended therapeutic dose). This was accompanied by a 3.6-fold increase in the exposure of desipramine, the active metabolite of imipramine.

The effect of warfarin on prothrombin time was not significantly altered when co-administered with darifenacin 30 mg/day (twice the maximum daily recommended dose).

Routine therapeutic drug monitoring for digoxin should be continued. Darifenacin 30 mg qd (twice the maximum dose) co-administered with digoxin at steady-state resulted in a small but potentially clinically significant, 16%, increase in digoxin exposure.

Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose.

There is a risk of increased exposure in this population, however, no dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). For patients with moderate hepatic impairment (Child Pugh B) or when co-administered with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, miconazole, troleandomycin and nefazodone), 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) (see Action and Clinical Pharmacology, Special Populations and Conditions).

There are no special dosing requirements for the elderly.

The safety and effectiveness of ENABLEX in pediatric patients with overactive bladder or any other condition have not been investigated.

The recommended starting dose of ENABLEX (darifenacin) Extended Release Tablets is 7.5 mg once daily. For those patients starting on 7.5 mg daily and requiring greater symptom relief, the dose may be increased to 15 mg daily as early as two weeks after starting therapy, based on individual response.

ENABLEX Extended Release Tablets should be taken once daily. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

There are no special dosing requirements for patients with renal impairment.

No special dosing requirements are necessary based on gender.

There was no indication of an increased incidence of laboratory test abnormalities in subjects treated with darifenacin in long term studies.

arthralgia.

vomiting; flatulence, ulcerative stomatitis.

urinary tract disorder; vaginitis; impotence; bladder pain.

In one flexible dose titration study (n=395) evaluating the dosing regimen approved for marketing, the overall ADR profile was comparable to that observed in the pooled analysis of three pivotal fixed-dose studies, with the most relevant difference in the very common ADRs. Dry mouth was reported in 18.7% of patients treated with darifenacin and in 8.7% of those treated with placebo. Constipation was reported in 20.9% and 7.9% of patients treated with darifenacin and placebo, respectively. The discontinuation rates due to these ADRs in patients treated with darifenacin were low (dry mouth: 0.7%; constipation: 2.2%).

The incidence of adverse events with the doses of ENABLEX 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.

Acute urinary retention (AUR) requiring treatment was reported in a total of 16 patients in the ENABLEX phase I-III clinical trials. Of these 16 cases, 7 were reported as serious adverse events, including one patient with detrusor hyperreflexia secondary to a stroke, one patient with benign prostatic hypertrophy (BPH), one patient with irritable bowel syndrome (IBS) and four OAB patients taking darifenacin 30 mg daily. Of the remaining nine cases, none were reported as serious adverse events. Three occurred in OAB patients taking the recommended doses, and two of these required bladder catheterization for 1-2 days.

In addition, the following adverse events were reported, regardless of causality, by less than 2% of ENABLEX patients in either the 7.5 mg or 15 mg once daily darifenacin dose groups in the fixed-dose, placebo-controlled Phase III studies:

abnormal vision; taste perversion.

rash; dry skin; pruritus; sweating.

accidental injury; pain; face edema.

peripheral edema; weight gain; ALT increased, AST increased; edema.

bronchitis; rhinitis; sinusitis; cough increased.

insomnia; somnolence; thinking abnormal.

hypertension.

In clinical studies, the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 75 years are comparable to the younger population and were not affected by age. This information is based on 75 patients over 75 years of age, that were included in the four pivotal darifenacin phase III studies (see also Warnings and Precautions).

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

In clinical studies (31.4% of patients were >65 years of age), the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 65 years are comparable to the younger population and were not affected by age.

Each once-a-day extended release, white, round, shallow, convex film-coated tablet for oral use, debossed with “DF” on one side and “7.5” on the reverse contains darifenacin 7.5 mg as darifenacin hydrobromide. Nonmedicinal ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, PEG 400, talc and titanium dioxide. Blister packs of 28 (7 or 14 tablets per blister).

Each once-a-day extended release, light peach, round, shallow, convex film-coated tablet for oral use, debossed with “DF” on one side and “15” on the reverse contains: darifenacin 15 mg as darifenacin hydrobromide. Nonmedicinal ingredients: dibasic calcium phosphate anhydrous, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, PEG 400, talc and titanium dioxide. Blister packs of 28 (7 or 14 tablets per blister).

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. (See Action and Clinical Pharmacology, Special Populations and Conditions.)

In clinical studies, the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 75 years is comparable to the younger population and were not affected by age. This information is based on 75 patients over 75 years of age that were included in the four pivotal darifenacin phase III studies.

There is insufficient evidence to determine whether a dose reduction is necessary in patients with severe renal failure.

There are no special dosing requirements for patients with mild hepatic impairment (Child Pugh A). The daily dose of ENABLEX (darifenacin) should not exceed 7.5 mg for patients with moderate hepatic impairment (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 Action and Clinical Pharmacology and Dosage and Administration).

ENABLEX (darifenacin) should be administered with caution to the following:

• Patients with clinically significant bladder outflow obstruction because it may worsen symptoms of urinary retention;

  
  

• Patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastrointestinal obstruction;

  
  

• Patients with severe constipation (≤2 bowel movements per week) (see Contraindications) or

  
  

• Patients with risk of decreased gastrointestinal motility.

ENABLEX should be used with caution in patients with narrow-angle glaucoma.

There are no studies of ENABLEX in pregnant women. ENABLEX should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

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

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

The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic impairment (Child Pugh B) (see Warnings and Precautions, Dosage and Administration). There are no special dosing requirements for patients with mild hepatic impairment (Child Pugh A).

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, and therefore darifenacin is not recommended for use in these patients (see Warnings and Precautions, Dosage and Administration).

In a population pharmacokinetic study, there was a 23% per decade increase in bioavailability of darifenacin in subjects over the age of 65. However, there was considerable overlap between the ranges of exposure seen in younger and older patients, and, in the pivotal trials, no difference in safety and efficacy was observed in the elderly (>65 years of age) as compared to the overall population.

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 L. Based on free drug levels in animal cerebrospinal fluid and plasma, darifenacin shows negligible concentrations in the CSF, suggesting low penetration of the blood brain barrier.

Following administration of the extended release tablets maximum plasma levels are reached approximately 7 h after dosing and steady-state plasma levels are achieved by the sixth day of dosing. At steady-state, peak to trough fluctuations in darifenacin concentrations are small (peak to trough fluctuations: 0.87 for 7.5 mg and 0.76 for 15 mg) (Figure 1), thereby maintaining therapeutic plasma levels over the dosing interval. The estimated half-life (t_1/2) for the extended release tablet is 12.8 to 18.7 hours.

In healthy volunteers, darifenacin is rapidly and completely (>98%) absorbed after oral administration, although oral bioavailability is limited by first pass metabolism (see Metabolism).

Darifenacin is a potent muscarinic M₃ selective receptor antagonist that exhibits, in vitro, a nine to 59-fold selectivity for the human M₃ receptor over human M₁, M₂ , M₄ and M₅ receptors. The M₃ receptor is the major subtype that modulates urinary bladder muscle contraction.

Darifenacin has a clinically significant effect on bladder function.

A subset of individuals are devoid of CYP 2D6 enzyme activity (i.e. approximately 7% of the Caucasian population). Therefore, the metabolism of darifenacin in these poor metabolizers (PMs) will be principally mediated via CYP 3A4. The darifenacin ratios (poor metabolisers: extensive metabolisers) for C_max and AUC following darifenacin 15 mg once-daily at steady state were 1.9 and 1.7, respectively.

Population pharmacokinetic analyses of Phase 3 data indicated that on average PMs have 55% higher steady-state exposure than EMs. However, there is considerable overlap between the ranges of exposures seen in EM and PM populations and clinical experience confirms that there are no special dosing requirements for PMs.

The effect of race on the pharmacokinetics of darifenacin has not been characterized.

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 (11.1 mL/s) for EMs and 32 L/h (8.9 mL/s) for PMs.

A study of subjects with varying degrees of renal function [creatinine clearance between 10 and 136 mL/min (0.17 and 2.27 mL/s)] given darifenacin 15 mg once daily to steady-state demonstrated no relationship between renal function and darifenacin clearance. There is insufficient evidence to determine whether a dose reduction is necessary in patients with a greater degree of impairment.

A population pharmacokinetic analysis of patient data indicated that darifenacin exposure at steady state was 28% lower in males than in females. In pivotal clinical studies, the safety and efficacy profiles of males and females were not found to be significantly different.

Darifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP 2D6 and CYP 3A4. 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 major circulating metabolites but none contributes significantly to the overall clinical effect of darifenacin. One of the hydroxylated derivatives has some anti-M₃ muscarinic receptor activity. This metabolite's contribution to overall activity is negligible.

Individuals with full CYP 2D6 activity are referred to as extensive metabolizers (EMs). The estimated mean oral bioavailability of darifenacin in EMs at steady-state is 15% and 19% for 7.5 and 15 mg extended release tablets, respectively.

The pharmacokinetics of darifenacin have not been studied in the pediatric population.