Darifenacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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Overview
Darifenacin is a muscarinic antagonist that is FDA approved for the {{{indicationType}}} of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Common adverse reactions include constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Overactive Bladder
- Dosing Information
- Enablex (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
- 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 (for example, 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).
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in adult patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Darifenacin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Darifenacin in pediatric patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darifenacin in pediatric patients.
Contraindications
- Enablex is contraindicated in patients with, or at risk for, the following conditions:
- urinary retention
- gastric retention, or
- uncontrolled narrow-angle glaucoma.
Warnings
Precautions
- Risk of Urinary Retention
- Enablex should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
- Decreased Gastrointestinal Motility
- Enablex should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Enablex, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis.
- Controlled Narrow-Angle Glaucoma
- Enablex should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.
- Angioedema
- Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.
- Central Nervous System Effects
- Enablex is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Enablex affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
- Patients with Hepatic Impairment
- The daily dose of Enablex 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 Dosage and Administration (2) Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Adverse Reactions
Clinical Trials Experience
- 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 [see Dosage and Administration (2)]. 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 greater than 3% of patients treated with Enablex and greater than placebo.
Postmarketing Experience
- The following adverse reactions have been reported 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 frequency or establish a causal relationship to drug exposure.
- Dermatologic: erythema multiforme, interstitial granuloma annulare
- General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction
- Central Nervous: confusion, hallucinations and somnolence
- Cardiovascular: palpitations and syncope
Drug Interactions
- CYP3A4 Inhibitors
- The systemic exposure of darifenacin from Enablex extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of Enablex should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
- CYP2D6 Inhibitors
- No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) [see Clinical Pharmacology (12.3)].
- 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 (for example, flecainide, thioridazine and tricyclic antidepressants) [see Clinical Pharmacology (12.3)].
- CYP3A4 Substrates
- Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology (12.3)].
- Combination oral contraceptives
- Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol [see Clinical Pharmacology (12.3)].
- 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. Standard therapeutic prothrombin time monitoring for warfarin should be continued.
- Digoxin
- Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued [see Clinical Pharmacology (12.3)].
- Other Anticholinergic Agents
- The concomitant use of Enablex with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility.
Use in Specific Populations
Pregnancy
- 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.
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Darifenacin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Darifenacin during labor and delivery.
Nursing Mothers
- Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before Enablex is administered to a nursing woman.
Pediatric Use
- The safety and effectiveness of Enablex in pediatric patients have not been established.
Geriatic Use
- In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Enablex were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n = 207) and younger patients less than 65 years (n = 464). No dose adjustment is recommended for elderly patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
Gender
- No dose adjustment is recommended based on gender.
Race
There is no FDA guidance on the use of Darifenacin with respect to specific racial populations.
Renal Impairment
- A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) demonstrated no clear relationship between renal function and darifenacin clearance. No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].
Hepatic Impairment
- Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Enablex is not recommended for use in these patients [see Dosage and Administration (2) and Warnings and Precautions (5.6)]. The daily dose of Enablex should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B) [see Dosage and Administration (2) and Warnings and Precautions (5.6)]. 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. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Darifenacin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Darifenacin in patients who are immunocompromised.
Administration and Monitoring
Administration
- Oral
Monitoring
There is limited information regarding Monitoring of Darifenacin in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Darifenacin in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
- Overdosage with antimuscarinic agents, including Enablex, can result in severe antimuscarinic effects. 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.
Management
- Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended.
Chronic Overdose
There is limited information regarding Chronic Overdose of Darifenacin in the drug label.
Pharmacology
Mechanism of Action
- 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.
Structure
- 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 (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:
This image is provided by the National Library of Medicine.
- 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, magnesium stearate, polyethylene glycol, talc, titanium dioxide. The 15 mg tablet also contains ferric oxide red and ferric oxide yellow.
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 treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.
- Electrophysiology
- The effect of a 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 metabolizers (PMs) and 82% extensive metabolizers (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.
Pharmacokinetics
There is limited information regarding Pharmacokinetics of Darifenacin in the drug label.
Nonclinical Toxicology
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.
Clinical Studies
There is limited information regarding Clinical Studies of Darifenacin in the drug label.
How Supplied
Storage
There is limited information regarding Darifenacin Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Patient Counseling Information of Darifenacin in the drug label.
Precautions with Alcohol
- Alcohol-Darifenacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- ®[1]
Look-Alike Drug Names
- A® — B®[2]
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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