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Enablex (Darifenacin) - Description and Clinical Pharmacology

 
 



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 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 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 7.5 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*

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)
19.95c 
-
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 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 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 13-19 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.

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:  Caution should be taken when ENABLEX is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants (see PRECAUTIONS, Drug Interactions).

The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. This was accompanied by a 3.6-fold increase in the mean Cmax and AUC of desipramine, the active metabolite of imipramine.

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

Darifenacin (10 mg t.i.d.) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinylestradiol.

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

Routine therapeutic drug monitoring for digoxin should be continued. Darifenacin (30 mg daily) coadministered with digoxin (0.25 mg) at steady state resulted in a 16% increase in digoxin exposure.

Electrophysiology

The effect of 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% PMs and 82% 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 Phase II/III clinical studies, the change in median HR following treatment with ENABLEX was no different from placebo.

CLINICAL STUDIES

ENABLEX® (darifenacin) 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 urinary incontinence 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 > 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 2 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 2:       Difference Between ENABLEX® (7.5 mg, 15 mg) and Placebo for the Week 12 Change from Baseline (Studies 1, 2 and 3)
Study 1 Study 2 Study 3
ENABLEX ®
7.5 mg
ENABLEX ®
15 mg
Placebo ENABLEX ®
7.5 mg
ENABLEX ®
15 mg
Placebo ENABLEX ®
15 mg
Placebo
No. of Patients Entered
229

115

164

108

107

109

112

115
Incontinence Episodes per Week
Median Baseline 16.3 17.0 16.6 14.0 17.3 16.1 16.2 15.5
Median Change
from Baseline

-9.0

-10.4

-7.6

-8.1

-10.4

-5.9

-11.4

-9.0
Median
Difference to
Placebo

-1.5*

-2.1*

-

-2.8*

-4.3*

-

-2.4*

-
Micturitions per Day
Median Baseline 10.1 10.1 10.1 10.3 11.0 10.1 10.5 10.4
Median Change
from Baseline

-1.6

-1.7

-0.8

-1.7

-1.9

-1.1

-1.9

-1.2
Median
Difference to
Placebo

-0.8*

-0.9*

-

-0.5

-0.7*

-

-0.5

-
Volume of Urine Passed per Void (mL)
Median Baseline 160.2 151.8 162.4 161.7 157.3 162.2 155.0 147.1
Median Change
from Baseline

14.9

30.9

7.6

16.8

23.6

7.1

26.7

4.6
Median
Difference to
Placebo

9.1*

20.7*

-

9.2

16.6*

-

20.1*

-
* Indicates statistically significant difference versus placebo (p<0.05, Wilcoxon rank-sum test)

Table 3 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 3:       Difference Between ENABLEX® (7.5 mg/15 mg) and Placebo for the Week 12 Change from Baseline (Study 4)
ENABLEX ®
7.5 mg /15 mg
Placebo
No. of Patients Treated 268 127
Incontinence Episodes per Week
Median Baseline 16.0 14.0
Median Change from Baseline -8.2 -6.0
Median Difference to Placebo -1.4* -
Micturitions per Day
Median Baseline 9.9 10.4
Median Change from Baseline -1.9 -1.0
Median Difference to Placebo -0.8* -
Volume of Urine Passed per Void (mL)
Median Baseline 173.7 177.2
Median Change from Baseline 18.8 6.6
Median Difference to Placebo 13.3 * -
* Indicates statistically significant difference versus placebo (p<0.05, Wilcoxon rank-sum test)

      As seen in Figures 2 a, b and c, reductions in the number of 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 2 a,b,c.
		     
	Median Change from Baseline at Weeks 2, 6, 12 for Number of Incontinence Episodes per Week (Studies 1, 2 and 3) Figure 2a, Study 1

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

Figure 2b, Study 2

Figure 2b, Study 2

Figure 2c, Study 3

Figure 2c, Study 3

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