Prescription Drug Information: Enablex

ENABLEX — darifenacin tablet, extended release
Physicians Total Care, Inc.

DESCRIPTION

ENABLEX® (darifenacin) is an extended-release tablet 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 C28 H30 N2 O2 .HBr.

The structural formula is

ENABLEX (darifenacin) structural formula
(click image for full-size original)

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, 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

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

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 7.5 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 and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs*
(click image for full-size original)

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 extensive (EMs) and poor (PMs) metabolizers of CYP2D6 is provided in Table 1.

Table 1: 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
ENABLEX ® 7.5 mg (N = 68 EM, 5 PM) ENABLEX ® 15 mg (N = 102 EM, 17 PM)
AUC 24 (ng.h/mL) C max (ng/mL) C avg (ng/mL) T max (h) t 1/2 (h) AUC 24 (ng.h/mL) C max (ng/mL) C avg (ng/mL) T max (h) t 1/2 (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)19.95c157.71 (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 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: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 14 C-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 13-19 hours.

Pharmacokinetics in Special Populations

Age: No dose adjustment is recommended for the elderly.

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%-19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years (see PRECAUTIONS, Geriatric Use).

Pediatric: The pharmacokinetics of ENABLEX have not been studied in the pediatric population.

Gender: No dose adjustment is recommended based on gender. PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady state were approximately 57%-79% and 61%-73% higher in females than in males, respectively.

Race: The effect of race on the pharmacokinetics of ENABLEX has not been characterized.

Renal Insufficiency: No dose adjustment is recommended for patients with renal impairment. A study of subjects with varying degrees of renal impairment (creatinine clearance 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.

Hepatic Insufficiency: The daily dose of ENABLEX should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child Pugh B) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). No dose adjustment is recommended for patients with mild hepatic impairment (Child Pugh A).

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, therefore ENABLEX is not recommended for use in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Drug -Drug Interactions

Effects 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.

CYP2D6 Inhibitors: No dosing adjustments are recommended in the presence of 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.

CYP3A4 Inhibitors: The daily dose of ENABLEX should not exceed 7.5 mg when coadministered with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazodone) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). In a drug interaction study, when a 7.5 mg once-daily dose of ENABLEX was given to steady state and coadministered 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.

No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem and verapamil). 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 erythromycin. Coadministration of fluconazole and darifenacin 30 mg once daily at steady state increased darifenacin Cmax and AUC by 88% and 84%, respectively.

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.

Page 1 of 4 1 2 3 4

RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

Medication Sections

Medication Information by RSS

As a leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. RxDrugLabels.com provides the full prescription-only subset of the FDA's repository. Medication information provided here is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.