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ENABLEX is a brand name for Darifenacin, supplied as a tablet (extended-release). The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: AND CLINICAL USE ..................................................................................... 3 CONTRAINDICATIONS .......................................................................................................... 3 WARNINGS AND PRECAUTIONS…
Verbatim from this product's HC label. Tap a section to expand.
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. Use in Elderly There are no special dosing requirements for the elderly.
Gender No special dosing requirements are necessary based on gender. Renal Insufficiency There are no special dosing requirements for patients with renal impairment. Hepatic 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).
g. 5 mg. ENABLEX is not recommended for use in patients with severe hepatic impairment (Child Pugh C) (see CLINICAL PHARMACOLOGY Special Population Considerations). 5 mg once daily. 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. OVERDOSAGE 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 program 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.
” Page 11 of 25 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.
ACTION AND CLINICAL PHARMACOLOGY 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).
Risk of Urinary Retention and Gastrointestinal Obstructive Disorders ENABLEX (darifenacin) should be administered with caution to patients with Clinically significant bladder outflow obstruction Risk for urinary retention in patients with or without pre-existence of this condition Gastrointestinal obstructive disorders, such as pyloric stenosis, Severe constipation (≤2 bowel movements per week) (see CONTRAINDICATIONS) Risk of decreased gastrointestinal motility.
As with other antimuscarinics, patients should be instructed to discontinue ENABLEX and seek immediate medical attention if they experience edema of the tongue or laropharynx, or difficulty breathing (see ADVERSE REACTIONS). Driving and Using Machines No studies of the effects of ENABLEX on the ability to drive and use machines have been performed.
However, ENABLEX may produce dizziness or blurred vision. Patients should not drive vehicles, use machines or perform other tasks which require alertness if they experience these adverse events. Narrow-Angle Glaucoma ENABLEX should be used with caution in patients with narrow-angle glaucoma.
Cardiovascular Caution should be used when prescribing antimuscarinics/anticholinergics to patients with pre-existing cardiac diseases. 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). 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. Page 5 of 25 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.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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.
76 for 15 mg) (Figure 1), thereby maintaining therapeutic plasma levels over the dosing interval. 7 hours. 5mg od 15mg od Page 12 of 25 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. e. approximately 7% of the Caucasian population). Therefore, the metabolism of darifenacin in these poor metabolizers (PMs) will be principally mediated via CYP 3A4. 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 […]
Nursing Women 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. Pediatrics The safety and effectiveness of ENABLEX in pediatric patients have not been established.
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). 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.
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. 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. 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.
Page 6 of 25 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). 3% of […]