PrENABLEX * (darifenacin extended release tablets)
Muscarinic M3 selective receptor antagonist Novartis Pharmaceuticals Canada Inc. Dorval, Quebec H9S 1A9
* PrENABLEX is a registered trademark
PART I: HEALTH PROFESSIONAL INFORMATION. 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 7 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 13 DOSAGE FORMS, COMPOSITION AND PACKAGING 13 PART II SCIENTIFIC INFORMATION 14 PHARMACEUTICAL INFORMATION 14 CLINICAL TRIALS 15 DETAILED PHARMACOLOGY 18 TOXICOLOGY 19 REFERENCES 22 PART III CONSUMER INFORMATION 23
PrENABLEX *
| Route of Administration | Dosage form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Extended release tablet, 7.5 mg, 15 mg | For the 7.5 mg: Dibasic calcium phosphate anhydrous, hypromellose For the 15 mg: Dibasic calcium phosphate anhydrous, hypromellose, lactose monohydrate, FD&C yellow No 6 aluminum lake |
ENABLEX * (darifenacin) is indicated for the treatment of overactive bladder. Overactive bladder is used to describe a collection of urinary symptoms composed of urgency, with or without urge incontinence, usually with frequency and nocturia, in the absence of proven infection or other obvious pathology.
Geriatrics
> 65 Years Of Age
In clinical studies (31.4% of patients were > 65 years of age), the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 65 years are comparable to the younger population and were not affected by age.
>75 Years Of Age
In clinical studies, the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 75 years are comparable to the younger population and were not affected by age. This information is based on 75 patients over 75 years of age, that were included in the four pivotal darifenacin phase III studies (See also PRECAUTIONS).
Pediatrics
The safety and effectiveness of ENABLEX * in pediatric patients have not been established.
ENABLEX * (darifenacin) extended release tablets are contraindicated in patients with, or at risk of, urinary retention, gastric retention or uncontrolled narrow-angle glaucoma. ENABLEX * is also contraindicated in patients with known hypersensitivity to the drug or its ingredients.
Risk of Urinary Retention and Gastrointestinal Obstructive Disorders
ENABLEX * (darifenacin) should be administered with caution to the following: Patients with clinically significant bladder outflow obstruction because it may worsen symptoms of urinary retention; Patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastrointestinal obstruction; Patients with severe constipation (<=2 bowel movements per week) (see CONTRAINDICATIONS) or Patients with risk of decreased gastrointestinal motility.
Narrow-Angle Glaucoma
ENABLEX * should be used with caution in patients with narrow-angle glaucoma.
Hepatic
There are no special dosing requirements for patients with mild hepatic impairment (Child Pugh A). (For Child Pugh scores, see REFERENCES - References # 1, 2 and 4). The daily dose of ENABLEX * (darifenacin) should not exceed 7.5 mg for patients with moderate hepatic impairment (Child Pugh B). ENABLEX * has not been studied in patients with severe hepatic impairment (Child Pugh C) and therefore is not recommended for use in this patient population (see CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION).
Renal
There is insufficient evidence to determine whether a dose reduction is necessary in patients with severe renal failure.
Special Populations
Pregnant women
There are no studies of ENABLEX * in pregnant women. ENABLEX * should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.
ENABLEX * is excreted into the milk of rats. It is not known whether ENABLEX * is excreted into human milk and therefore caution should be exercised before ENABLEX * is administered to a nursing woman.
The safety and effectiveness of ENABLEX * in pediatric patients have not been established.
The recommended starting dose for the elderly is 7.5 mg daily. After 2 weeks of starting therapy, patients should be reassessed for efficacy and safety. For those patients who have an acceptable tolerability profile but require greater symptom relief, the dose may be increased to 15 mg daily, based on individual response. (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). In clinical studies, the safety and efficacy profile of darifenacin 7.5 mg and 15 mg in patients aged over 75 years is comparable to the younger population and were not affected by age. This information is based on 75 patients over 75 years of age that were included in the four pivotal darifenacin phase III studies.
During the clinical development of ENABLEX * (darifenacin), a total of 7,271 patients and healthy volunteers have been treated with doses of darifenacin from 3.75 to 60 mg once daily (recommended doses are 7.5 and 15 mg once daily) for up to one year duration of therapy, resulting in more than 2,000 patient-years exposure, for overactive bladder and other indications. Table 1 lists the adverse events (regardless of causality) reported in 3% or more patients treated with 7.5 or 15 mg ENABLEX * Extended Release Tablets in fixed-dose, placebo-controlled Phase III studies. The majority of adverse events in ENABLEX * treated subjects were mild or moderate and mostly occurred during the first two weeks of treatment. The incidence of serious adverse events was similar for 7.5 mg, 15 mg and placebo. The profile of adverse events remained consistent across all populations and dose studied. There is a tendency for adverse reactions, particularly those classified as mild to moderate, to increase with increasing dose. The most frequently reported adverse events in the pivotal trials were dry mouth and constipation. However as seen in Table 2, the patient discontinuation rates due to these events were low. Consistent with M3 muscarinic receptor selectivity, the incidence of central nervous system adverse events at all doses was similar to placebo in the population tested (see CLINICAL STUDIES). The incidence of cardiovascular adverse events, such as tachycardia, were less than 1% at all doses and did not increase with dose. No clinically significant changes in QT interval were observed in clinical trials of volunteers and patients (n= 964 treated, n= 261 placebo) with ENABLEX * up to and including doses of 60 mg (4 times the recommended dose).
Table 1 Incidence of adverse events, regardless of causality, reported in >=2% of patients treated with ENABLEX * extended release tablets in fixed-dose, placebo-controlled phase III studies
| Adverse Event | Darifenacin 7.5 mg N = 337 | Darifenacin 15 mg N = 334 | Placebo N = 388 |
| Dry mouth | 68 (20.2%) | 118 (35.3%) | 32 (8.2%) |
| Constipation | 50 (14.8%) | 71 (21.3%) | 24 (6.2%) |
| Dyspepsia | 9 (2.7%) | 28 (8.4%) | 10 (2.6%) |
| Headache | 15 (4.5%) | 17 (5.1%) | 21 (5.4%) |
| Respiratory tract infection | 9 (2.7%) | 17 (5.1%) | 26 (6.7%) |
| Urinary tract infection | 16 (4.7%) | 15 (4.5%) | 10 (2.6%) |
| Abdominal pain | 8 (2.4%) | 13 (3.9%) | 2 (0.5%) |
| Asthenia | 5 (1.5%) | 9 (2.7%) | 5 (1.3%) |
| Flu syndrome | 7 (2.1%) | 7 (2.1%) | 10 (2.6%) |
| Dizziness | 3 (0.9%) | 7 (2.1%) | 5 (1.3%) |
| Dry eyes | 5 (1.5%) | 7 (2.1%) | 2 (0.5%) |
| Back pain | 8 (2.4%) | 5 (1.5%) | 12 (3.1%) |
| Nausea | 9 (2.7%) | 5 (1.5%) | 6 (1.5%) |
| Pharyngitis | 9 (2.7%) | 4 (1.2%) | 9 (2.3%) |
Diarrhea 7 (2.1%) 3 (0.9%) 7 (1.8%)
Discontinuations due to any adverse events occurred in 1.2% and 4.5% of 7.5 mg and 15 mg ENABLEX * patients treated in fixed-dose placebo controlled trials, respectively and in 1.3% of placebo subjects. There were no discontinuations due to laboratory test abnormalities.
Table 2 Frequency of discontinuations for the most common adverse events
| Darifenacin 7.5mg N=337 | Darifenacin 15mg N = 334 | Placebo N = 388 | |
| Dry Mouth | 0 (0.0%) | 3 (0.9%) | 0 (0.0%) |
| Constipation | 2 (0.6%) | 4 (1.2%) | 1 (0.3%) |
Acute urinary retention (AUR) requiring treatment was reported in a total of 16 patients in the ENABLEX * phase I-III clinical trials. Of these 16 cases, 7 were reported as serious adverse events, including one patient with detrusor hyperreflexia secondary to a stroke, one patient with benign prostatic hypertrophy (BPH), one patient with irritable bowel syndrome (IBS) and four OAB patients taking darifenacin 30 mg daily. Of the remaining nine cases, none were reported as serious adverse events. Three occurred in OAB patients taking the recommended doses, and two of these required bladder catheterization for 1-2 days. In addition, the following adverse events were reported, regardless of causality, by less than 2% of ENABLEX * patients in either the 7.5 mg or 15 mg once daily darifenacin dose groups in the fixed-dose, placebo-controlled Phase III studies:
Body as a whole
: accidental injury; pain; face edema
Cardiovascular:
hypertension
Digestive:
vomiting; flatulence, ulcerative stomatitis
Metabolic and nutritional:
peripheral edema; weight gain; ALT increased, AST increased; edema
Musculoskeleta
l: arthralgia
NervousRespiratory: Skin and appendages: Special senses:
: insomnia; somnolence; thinking abnormal
bronchitis; rhinitis; sinusitis; cough increased
rash; dry skin; pruritus; sweating
abnormal vision; taste perversion
Urogenital:
urinary tract disorder; vaginitis; impotence; bladder pain, urinary retention
In one flexible dose titration study (n=395) evaluating the dosing regimen approved for marketing, the overall ADR profile was comparable to that observed in the pooled analysis of three pivotal fixed-dose studies, with the most relevant difference in the very common ADRs. Dry mouth was reported in 18.7% of patients treated with darifenacin and in 8.7% of those treated with placebo. Constipation was reported in 20.9% and 7.9% of patients treated with darifenacin and placebo, respectively. The discontinuation rates due to these ADRs in patients treated with darifenacin were low (dry mouth: 0.7%; constipation: 2.2%). The incidence of adverse events with the doses of ENABLEX * 7.5 mg and 15 mg decreased during the treatment period up to 6 months. A similar trend is also seen for the discontinuation rates.
Abnormal Hematologic and Clinical Chemistry Findings
There was no indication of an increased incidence of laboratory test abnormalities in subjects treated with darifenacin in long term studies.
Post-Market Adverse Drug Reactions
The following events have been reported in association with darifenacin use in worldwide post- marketing experience: Generalized Hypersensitivity reactions including angioedema. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of darifenacin in their causation cannot be reliably determined.
Drug-Drug Interactions
Effects of other drugs on darifenacin:
Darifenacin metabolism is primarily mediated by the cytrochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics.
CYP 2D6 inhibitors:
No special dosing requirements are necessary in the presence of CYP 2D6 inhibitors. Darifenacin exposure following 30 mg once daily dosing (twice the maximum recommended therapeutic dose) was 33% higher in the presence of the potent CYP 2D6 inhibitor paroxetine 20 mg.
CYP 3A4 inhibitors: The daily dose of darifenacin should not exceed 7.5 mg when co- administered with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, miconazole, troleandomycin, clarithromycin , nefazodone and ritonavir) (see DOSAGE AND ADMINISTRATION). When the 7.5 mg once-daily dose of darifenacin was given to steady- state and co-administered with the potent CYP 3A4 inhibitor ketoconazole, mean darifenacin exposure was increased 5.3 fold. No special dosing requirements are necessary in the presence of moderate CYP 3A4 inhibitors. Darifenacin exposure following 30 mg once daily dosing (twice the maximum recommended therapeutic dose) was 34%, 84% and 95% higher in the presence of cimetidine, fluconazole and erythromycin, respectively.
Effects of darifenacin on other drugs
The potential for clinical doses of darifenacin to act as inhibitors of CYP 2D6 or CYP 3A4 substrates was investigated in specific clinical interaction studies.
CYP 2D6 substrates: Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP 2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants. The mean exposure of imipramine, a CYP 2D6 substrate, was increased 70% in the presence of steady-state darifenacin 30 mg once daily (twice the maximum recommended therapeutic dose). This was accompanied by a 3.6-fold increase in the exposure of desipramine, the active metabolite of imipramine.
CYP 3A4 substrates:
Darifenacin (30 mg once daily) had no clinically relevant effect on the exposure of the CYP 3A4 substrate midazolam. Darifenacin (30 mg once daily) had no effect on the pharmacokinetics of the oral contraceptives levonorgestrel or ethinylestradiol.
Other Drugs:
The effect of warfarin on prothrombin time was not significantly altered when co-administered with darifenacin 30 mg/day (twice the maximum daily recommended dose).
Routine therapeutic drug monitoring for digoxin should be continued. Darifenacin 30 mg qd (twice the maximum dose) co-administered with digoxin at steady-state resulted in a small but potentially clinically significant, 16%, increase in digoxin exposure. Therapeutic drug monitoring for digoxin should be performed when initiating and ending darifenacin treatment as well as changing the darifenacin dose.
The concomitant use of ENABLEX * with other antimuscarinic agents may increase the frequency and/or severity of antimuscarinic pharmacological effects such as dry mouth, constipation and blurred vision . In vitro studies: In vitro human microsomal studies have shown that darifenacin does not inhibit CYP 1A2 or CYP 2C9 up to concentrations of 1 *105 nM. In comparison, the average peak unbound concentration of darifenacin at steady state following 15 mg dosing is 0.24 nM.
There is no effect of food on multiple dose pharmacokinetics from extended release tablets.
No studies of the effects of ENABLEX * on the ability to drive and use machines have been performed. However, antimuscarinics such as ENABLEX * may produce dizziness or blurred vision. Patients experiencing these side effects should not drive or use machines.
Dosing Considerations
Use in Children
The safety and effectiveness of ENABLEX * in pediatric patients with overactive bladder or any other condition have not been investigated.
There are no special dosing requirements for the elderly.
No special dosing requirements are necessary based on gender.
There are no special dosing requirements for patients with renal impairment.
There is a risk of increased exposure in this population, however, no dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). For patients with moderate hepatic impairment (Child Pugh B) or when co-administered with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, miconazole, troleandomycin and nefazodone), 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) (see CLINICAL PHARMACOLOGY Special Population Considerations).
Recommended Dose and Dosage Adjustment
The recommended starting dose of ENABLEX * (darifenacin) Extended Release Tablets is 7.5 mg once daily. For those patients starting on 7.5 mg daily and requiring greater symptom relief, the dose may be increased to 15 mg daily as early as two weeks after starting therapy, based on individual response. ENABLEX * Extended Release Tablets should be taken once daily. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.
For management of a suspected drug overdose, contact your regional Poison Control Centre. No cases of overdose were recorded in the ENABLEX * (darifenacin) clinical development programme that included doses as high as 60 mg daily (4 times the recommended maximum daily dose). Moreover, in a study evaluating the interaction between ketoconazole and daily doses of 30 mg darifenacin, the systemic plasma exposure exceeded the systemic exposure observed after a 60 mg dose by a factor of two, with no reported SAEs. The most commonly reported adverse events were typical of those expected from a drug with anti-muscarinic M3- receptor antagonist activity." Overdosage with antimuscarinic agents can potentially result in severe antimuscarinic effects. Treatment should be symptomatic and supportive when necessary. Treatment should be aimed at reversing the antimuscarinic symptoms under careful medical supervision.
Mechanism of Action
Darifenacin is a potent muscarinic M3 selective receptor antagonist that exhibits, in vitro, a nine to 59-fold selectivity for the human M3 receptor over human M1, M2 , M4 and M5 receptors. The M3 receptor is the major subtype that modulates urinary bladder muscle contraction. Darifenacin has a clinically significant effect on bladder function.
Pharmacodynamics
Individuals with full CYP 2D6 activity are referred to as extensive metabolizers (EMs). The estimated mean oral bioavailability of darifenacin in EMs at steady-state is 15% and 19% for 7.5 and 15 mg extended release tablets, respectively.
Pharmacokinetics
Following administration of the extended release tablets maximum plasma levels are reached approximately 7 h after dosing and steady-state plasma levels are achieved by the sixth day of dosing. At steady-state, peak to trough fluctuations in darifenacin concentrations are small (peak to trough fluctuations: 0.87 for 7.5 mg and 0.76 for 15 mg) (Figure 1), thereby maintaining therapeutic plasma levels over the dosing interval. The estimated half-life (t1/2) for the extended release tablet is 12.8 to 18.7 hours.
7.5mg od 15mg od
Darifenacin concentration
(ng/ml)
0 2 4 6 8 10 12 14 16 18 20 22 24
Time post-dose (h)
Absorption
In healthy volunteers, darifenacin is rapidly and completely (>98%) absorbed after oral administration, although oral bioavailability is limited by first pass metabolism (see Metabolism).
Distribution
Darifenacin is a lipophilic base and is 98% bound to plasma proteins (primarily to alpha- 1- acid- glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L. Based on free drug levels in animal cerebrospinal fluid and plasma, darifenacin shows negligible concentrations in the CSF, suggesting low penetration of the blood brain barrier.
Metabolism
Darifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP 2D6 and CYP 3A4. 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 major circulating metabolites but none contributes significantly to the overall clinical effect of darifenacin. One of the hydroxylated derivatives has some anti-M3 muscarinic receptor activity. This metabolite's contribution to overall activity is negligible.
Variability in metabolism
: A subset of individuals are devoid of CYP 2D6 enzyme activity (i.e. approximately 7% of the Caucasian population). Therefore, the metabolism of darifenacin in these poor metabolizers (PMs) will be principally mediated via CYP 3A4. The darifenacin ratios (poor metabolisers: extensive metabolisers) for Cmax and AUC following darifenacin 15 mg once-daily at steady state were 1.9 and 1.7, respectively.
Population pharmacokinetic analyses of Phase 3 data indicated that on average PMs have 55% higher steady-state exposure than EMs. However, there is considerable overlap between the ranges of exposures seen in EM and PM populations and clinical experience confirms that there are no special dosing requirements for PMs.
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 (11.1 mL/s) for EMs and 32 L/h (8.9 mL/s) for PMs.
Special Populations and Considerations
The pharmacokinetics of darifenacin have not been studied in the pediatric population.
In a population pharmacokinetic study, there was a 23% per decade increase in bioavailability of darifenacin in subjects over the age of 65. However, there was considerable overlap between the ranges of exposure seen in younger and older patients, and, in the pivotal trials, no difference in safety and efficacy was observed in the elderly (>65 years of age) as compared to the overall population.
A population pharmacokinetic analysis of patient data indicated that darifenacin exposure at steady state was 28% lower in males than in females. In pivotal clinical studies, the safety and efficacy profiles of males and females were not found to be significantly different.
The effect of race on the pharmacokinetics of darifenacin has not been characterized.
The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic impairment (Child Pugh B) (see
). There are no special dosing requirements for patients with mild hepatic impairment (Child Pugh A). (See
References # 1, 2 and 5 for Child Pugh score).
Darifenacin pharmacokinetics were investigated in subjects with mild (Child Pugh A) or moderate (Child Pugh B) impairment of hepatic function given darifenacin 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, and therefore darifenacin is not recommended for use in these patients (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
A study of subjects with varying degrees of renal function [creatinine clearance between 10 and 136 mL/min (0.17 and 2.27 mL/s)] given darifenacin 15 mg once daily to steady-state demonstrated no relationship between renal function and darifenacin clearance. There is insufficient evidence to determine whether a dose reduction is necessary in patients with a greater degree of impairment.
ENABLEX * Extended Release Tablets should be stored at 15 to 30degC and protected from light.
ENABLEX * (darifenacin as darifenacin hydrobromide) 7.5 mg Extended Release Tablets: White, round shallow convex film-coated tablets, debossed with "DF" on one side and "7.5" on the reverse. Bottles of 100 tablets. Blister packs of 28 tablets (7 or 14 tablets per blister). ENABLEX * (darifenacin as darifenacin hydrobromide) 15 mg Extended Release Tablets: Light peach, round shallow convex film-coated tablets with a clear over coat, debossed with "DF" on one side and "15" on the reverse. Bottles 100 tablets. Blister packs of 28 tablets (7 or 14 tablets per blister).