Enablex Information
Enablex () Indications And Usage
Enablex () (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
Enablex () Dosage And Administration
The recommended starting dose of Enablex () is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy.
Enablex () should be taken once daily with water. Enablex () may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.
For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), 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) .
Enablex () Dosage Forms And Strengths
Enablex () extended-release tablets 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.
Enablex () extended-release tablets 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.
Enablex () Contraindications
Enablex () is contraindicated in patients with, or at risk for, the following conditions:
Enablex () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Enablex () was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with Enablex () . Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received Enablex () 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with Enablex () for at least 24 and 52 weeks, respectively.
In Studies 1, 2 and 3 combined, the serious adverse reactions to Enablex () were urinary retention and constipation.
In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with Enablex () 7.5 mg daily, Enablex () 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Enablex () 7.5 mg daily, Enablex () 15 mg daily and placebo, respectively.
Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg Enablex () , and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment.
Other adverse reactions reported by 1% to 2% of Enablex () -treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis.
Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which Enablex () was administered in accordance with dosing recommendations . All patients initially received placebo or Enablex () 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Enablex () 15 mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table 2 lists the identified adverse reactions, derived from all adverse events reported in >3% of patients treated with Enablex () and greater than placebo.
The following adverse reactions have been identified during post approval use of Enablex () extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Enablex () Use In Specific Populations
Pregnancy Category C
There are no studies of darifenacin in pregnant women.
Darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg . At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of darifenacin was shown to increase post-implantation loss, with a no effect level at nine times (10 mg/kg/day) the AUC at the MRHD). Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD).
Because animal reproduction studies are not always predictive of human response, Enablex () should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.
Enablex () Overdosage
Overdosage with antimuscarinic agents, including Enablex () , can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Enablex () has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision.
Enablex () Description
Enablex () is an extended-release tablet for oral administration 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 -2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide. The empirical formula of darifenacin hydrobromide is CHNO.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 anhydrous, hypromellose (hydroxypropyl methylcellulose), magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains iron oxide red and iron oxide yellow.
Enablex () Clinical Pharmacology
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 M receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M compared to M and M, respectively, and 59-fold greater affinity for M compared to both M and M). M 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 M receptors in these organs.
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 () treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.
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% poor metabolizer (PMs) and 82% extensive metabolizer (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 clinical efficacy and safety studies, the change in median HR following treatment with Enablex () was no different from placebo.
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*
*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.
Following single dose administration of Enablex () with food, the AUC of darifenacin was not affected, while the C was increased by 22% and T 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) 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.
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 C 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 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.
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 .
The mean C 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 and AUC by 88% and 84%, respectively .
The mean C 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
7.3
max
Enablex () 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 ≥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, b and c, 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.
Enablex () How Supplied/storage And Handling
Enablex () 7.5 mg extended-release tablets 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 0430-0170-15Bottle of 90 ...............................................................NDC 0430-0170-23
Enablex () 15 mg extended-release tablets 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 0430-0171-15Bottle of 90 ...............................................................NDC 0430-0171-23
Store at 25° C (77° F); excursions permitted to 15 - 30° C (59 - 86° F) [see USP Controlled Room Temperature]. Protect from light.
Keep this and all drugs out of the reach of children.
Enablex () 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.
Enablex ()
Enablex () Package/label Principal Display Panel - . Mg
N 0430-0170-15
30 Tablets
Enablex ()
(darifenacin)
Extended-release tablets
7.5 mg* per tablet
Enablex () Package/label Principal Display Panel - Mg
N 0430-0171-15
30 Tablets
Enablex ()
(darifenacin)
Extended-release tablets
15 mg* per tablet
