DESCRIPTION

ENABLEX® (darifenacin) is an extended-release tablet which contains 7.5mg or 15mg 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

ENABLEX (darifenacin) structural formula

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 anhyrdous, hypromellose (hydroxypropyl methylcellulose), magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains iron oxide red and iron oxide yellow.

CLINICAL PHARMACOLOGY

General

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® (darifenacin) extended-release tablet treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.

Pharmacokinetics

Absorption

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 7.5mg and 15mg extended-release tablets is depicted in Figure1.

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

Figure 1Mean (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 7.5mg and 15mg extended-release tablets in extensive (EMs) and poor (PMs) metabolizers of CYP2D6 is provided in Table1.

Table 1:Mean (SD) Steady-State Pharmacokinetic Parameters from ENABLEX® 7.5 mg and 15mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype
	ENABLEX® 7.5 mg (N = 68 EM, 5 PM)					ENABLEX® 15 mg (N = 102 EM, 17 PM)
	AUC24 (ng.h/mL)	Cmax (ng/mL)	Cavg (ng/mL)	Tmax (h)	t1/2 (h)	AUC24 (ng.h/mL)	Cmax (ng/mL)	Cavg (ng/mL)	Tmax (h)	t1/2 (h)
EM	29.24 (15.47)	2.01 (1.04)	1.22 (0.64)	6.49 (4.19)	12.43 (5.64) a	88.90 (67.87)	5.76 (4.24)	3.70 (2.83)	7.61 (5.06)	12.05 (12.37) b
PM	67.56 (13.13)	4.27 (0.98)	2.81 (0.55)	5.20 (1.79)	19.95c -	157.71 (77.08)	9.99 (5.09)	6.58 (3.22)	6.71 (3.58)	7.40d -
a N=25; b N=8; c N=2; d N=1; AUC24 = Area under the plasma concentration versus time curve for 24h;
Cmax = Maximum observed plasma concentration; Cavg = Average plasma concentration at steady state;
Tmax = Time of occurrence of Cmax; t1/2 = Terminal elimination half-life. Regarding EM and PM, see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism.

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

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

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 163L.

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:

monohydroxylation in the dihydrobenzofuran ring;
dihydrobenzofuran ring opening;
N-dealkylation of the pyrrolidine nitrogen.

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

Variability in Metabolism

A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM:EM) for Cmax and AUC following darifenacin 15mg 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 40L/h for EMs and 32L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13-19hours.