Enablex

*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 EMs and PMs of CYP2D6 is provided in Table 3.

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

Following single dose administration of Enablex with food, the AUC of darifenacin was not affected, while the C_max was increased by 22% and T_max was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from Enablex.

Distribution

Darifenacin is approximately 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.

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:

• (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 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 C_max 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.

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 [see Drug Interactions (7)].

CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Enablex was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin C_max 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 C_max 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 [see Dosage and Administration (2) and Drug Interactions (7.1)].

The mean C_max and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin C_max and AUC by 88% and 84%, respectively [see Drug Interactions (7.1)].

The mean C_max 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.

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 [see Drug Interactions (7.2)].

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: The mean C_max and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean C_max and AUC of desipramine, the active metabolite of imipramine, were increased by 260% [see Drug Interactions (7.3)].

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

Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg).

Warfarin: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state [see Drug Interactions (7.6)].

Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure [see Drug Interactions (7.7)].

Pharmacokinetics in Special Populations

Age: 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% to 19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations (8.5)].

Pediatric: The pharmacokinetics of Enablex has not been studied in the pediatric population [see Use in Specific Populations (8.4)].

Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin C_max and AUC at steady-state were approximately 57% to 79% and 61% to 73% higher in females than in males, respectively [see Use in Specific Populations (8.8)].

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 [see Use in Specific Populations (8.7)].

Hepatic Impairment: 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 [see Dosage and Administration (2), Warning and Precautions (5.5) and Use in Specific Population (8.6)].

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

Enablex 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 greater than or equal to 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 4 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 5 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.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Enablex^®, 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse.

Bottle of 30........................................................................ NDC 0430-0170-15

Bottle of 90........................................................................ NDC 0430-0170-23

Enablex^®, 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.

Bottle of 30........................................................................ NDC 0430-0171-15

Bottle of 90........................................................................ NDC 0430-0171-23

Storage

Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F) [see USP Controlled Room Temperature]. Protect from light.

Keep this and all drugs out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

Patients should be informed that anticholinergic agents, such as Enablex, 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 Enablex are used in a hot environment. Because anticholinergics, such as Enablex, 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 Enablex.

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.

Enablex 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.

FDA-Approved Patient Labeling

Enablex^® (ěn-ā-blěx)
(darifenacin)
extended-release tablets

Read this Patient Information leaflet about Enablex ^® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.

What is Enablex?

Enablex is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

• •Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents
• •Urgency: a strong need to urinate right away
• •Frequency: urinating often

It is unknown if Enablex is safe and effective in children.

Who should not take Enablex?

Do not take Enablex if you:

• •are not able to empty your bladder (“urinary retention”)
• •have delayed or slow emptying of your stomach (“gastric retention”)
• •have an eye problem called “uncontrolled narrow-angle glaucoma”

What should I tell my healthcare provider before starting Enablex?

Before starting Enablex, tell your doctor if you:

• •have trouble emptying your bladder or if you have a weak urine stream
• •have any stomach or intestinal problems, or problems with constipation
• •have liver problems
• •have any other medical conditions
• •are pregnant or are planning to become pregnant. It is not known if Enablex can harm your unborn baby.
• •are breastfeeding or plan to breastfeed. It is not known if Enablex passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Enablex.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Enablex and certain other medicines may affect each other, causing side effects.

Especially tell your healthcare provider if you take a:

• •antifungal medicine ketoconazole (Nizoral^®) or itraconazole (Sporanox^®)
• •antibiotic medicine clarithromycin (Biaxin^®)
• •anti-HIV medicine ritonavir (Norvir^®) or nelfinavir (Viracept^®)
• •medicine to treat depression nefazadone (Serzone^®)
• •medicine to treat an abnormal heartbeat flecainide (Tambocor™)
• •antipsychotic medicine thioridazine (Mellaril^®)
• •medicine to treat depression called a tricyclic antidepressant

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Enablex?

• •Take Enablex exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take Enablex 1 time daily with water.
• •Enablex should be swallowed whole. Do not chew, cut or crush Enablex tablet.
• •Enablex may be taken with or without food.
• •If you take too much Enablex call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking Enablex?

Enablex can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how Enablex affects you.

What are the possible side effects of Enablex?

Enablex may cause serious side effects including:

• •Serious allergic reaction. Stop taking Enablex and get medical help right away if you have:
  • ohives, skin rash or swelling
  • osevere itching
  • oswelling of your face, mouth or tongue
  • otrouble breathing

The most common side effects with Enablex are:

• •constipation
• •dry mouth
• •headache
• •heartburn
• •nausea
• •urinary tract infection
• •blurred vision
• • heat exhaustion or heat-stroke. This can happen when Enablex is used in hot environments. Symptoms of heat exhaustion may include:
  • odecreased sweating
  • odizziness
  • otiredness
  • onausea
  • oincrease body temperature

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Enablex. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Enablex?

• •Store Enablex at room temperature, between 59° F to 86° F (15° C to 30° C).
• •Keep Enablex out of the light.

Keep Enablex and all medicines out of the reach of children.

General information about Enablex.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Enablex for a condition for which it was not prescribed. Do not give Enablex to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Enablex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Enablex that is written for health professionals.

What are the ingredients in Enablex?

Active ingredient: darifenacin

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide.
The 15 mg tablet also contains ferric oxide red and ferric oxide yellow.

The brands listed are the trademarks of their respective owners and are not trademarks of Warner Chilcott.

Manufactured by:
Warner Chilcott Deutschland GmbH
D-64331 Weiterstadt
Germany

Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
1-800-521-8813

0170G0115