Darifenacin Hydrobromide
FDA Drug Information • Also known as: Darifenacin
- Brand Names
- Darifenacin
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
Description
11 DESCRIPTION Darifenacin 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 C 28 H 30 N 2 O 2
What Is Darifenacin Hydrobromide Used For?
1 INDICATIONS AND USAGE Darifenacin extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. ( 1 ) Darifenacin extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
Dosage and Administration
2 DOSAGE AND ADMINISTRATION The recommended starting dose of darifenacin extended-release tablets 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 ( 2 ) The daily dose of darifenacin extended-release tablets should not exceed 7.5 mg in the following patients: Patients with moderate hepatic impairment (Child-Pugh B) ( 2 , 8.6 ) Patients taking potent CYP3A4 inhibitors ( 2 , 7.1 ) Darifenacin extended-release tablets are not recommended for use in patients with severe hepatic impairment (Child-Pugh C) ( 2 , 8.6 ) Darifenacin extended-release tablets may be taken with or without food. The tablet should be swallowed whole with water and not chewed, divided or crushed ( 2 ) The recommended starting dose of darifenacin extended-release tablet is 7.5 mg orally once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy. Darifenacin extended-release tablets should be taken orally once daily with water. Darifenacin extended-release tablets 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 darifenacin extended-release tablets should not exceed 7.5 mg. Darifenacin extended-release tablets are not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings & Precautions ( 5.6 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The most frequently reported adverse reactions (greater than 3%) for darifenacin extended-release tablets are: constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Limited, India at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 darifenacin extended-release tablet was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin extended-release tablet. 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 darifenacin extended-release tablets 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with darifenacin extended-release tablets for at least 24 and 52 weeks, respectively. In Studies 1, 2 and 3 combined, the serious adverse reactions to darifenacin extended-release tablets 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 darifenacin extended-release tablets 7.5 mg daily, darifenacin extended-release tablets 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with darifenacin extended-release tablets 7.5 mg daily, darifenacin extended-release tablets 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 darifenacin extended-release tablets, 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. Table 1: Incidence of Identified Adverse Reactions, Derived from All Adverse Events Reported in greater than or equal to 2% of Patients Treated with Darifenacin Extended-Release Tablets and More Frequent with Darifenacin Extended-Release Tablets than with Placebo in Studies 1, 2, and 3 Body System Adverse Reaction % of Subjects Darifenacin extended-release tablet 7.5 mg N = 337 Darifenacin extended- release tablet 15 mg N = 334 Placebo N = 338 Digestive Dry Mouth 20.2 35.3 8.2 Constipation 14.8 21.3 6.2 Dyspepsia 2.7 8.4 2.6 Abdominal Pain 2.4 3.9 0.5 Nausea 2.7 1.5 1.5 Diarrhea 2.1 0.9 1.8 Urogenital Urinary Tract Infection 4.7 4.5 2.6 Nervous Dizziness 0.9 2.1 1.3 Body as a Whole Asthenia 1.5 2.7 1.3 Eye Dry Eyes 1.5 2.1 0.5 Other adverse reactions reported by 1% to 2% of darifenacin extended-release tablets -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 darifenacin extended-release tablet was administered in accordance with dosing recommendations [see Dosage and Administration ( 2 )] . All patients initially received placebo or darifenacin extended-release tablets 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to darifenacin extended-release tablet 15 mg if needed. In this study, the most commonly reported...
Drug Interactions
7 DRUG INTERACTIONS Caution should be taken when darifenacin extended-release tablets are used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants ( 7.2 ) The concomitant use of darifenacin extended-release tablets 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 of gastrointestinal motility ( 7.3 ) 7.1 CYP3A4 Inhibitors The systemic exposure of darifenacin from darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin extended-release tablet 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 )] . 7.2 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 )] . 7.3 CYP2D6 Substrates Caution should be taken when darifenacin extended-release tablet 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 )] . 7.4 CYP3A4 Substrates Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology ( 12.3 )] . 7.5 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 )] . 7.6 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. 7.7 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 )] . 7.8 Other Anticholinergic Agents The concomitant use of darifenacin extended-release tablets 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...
Contraindications
4 CONTRAINDICATIONS Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions ( 4 ): urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions: urinary retention gastric retention, or uncontrolled narrow-angle glaucoma.
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no available data on darifenacin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 and 28 times the maximum recommended human dose (MRHD) of 15 mg, respectively. Effects on embryofetal development were observed following administration of darifenacin during pregnancy (dilated ureter and/or kidney pelvis in rabbits at about 9 times the MRHD, post-implantation loss in rabbits at about 28 times, and delayed ossification in rats at about 59 times) and during pregnancy and lactation (developmental delays in rats at about 17 times the MRHD), which was associated with maternal toxicity (see Data). Dystocia was observed in rat dams at about 17 times the MRHD. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Embryofetal development studies were conducted with oral darifenacin in female rats (0, 3, 10, and 50 mg/kg/day) and rabbits (0, 3, 10, and 30 mg/kg/day) during the period of organogenesis (gestation days 6 to 17 in the rat and gestation days 6 to 18 in the rabbit). 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 pregnant rats, there was a delay in the ossification of the sacral and caudal vertebrae (associated with a decrease in maternal and pup body weight gains) which was not observed at an exposure approximately 13 times the AUC at the MRHD. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In pregnant rabbits, an exposure of...
Overdosage
10 OVERDOSAGE Overdosage with antimuscarinic agents, including darifenacin extended-release tablets, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Darifenacin extended-release tablet 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Darifenacin extended-release tablet 7.5 mg are white to off white colored circular biconvex film coated tablet debossed with “C” on one side and “431” on the other side. Bottle of 30 ............................................................................................................... NDC 69097-431-02 Bottle of 90 ............................................................................................................... NDC 69097-431-05 Bottle of 1000 ........................................................................................................... NDC 69097-431-15 Darifenacin extended-release tablet 15 mg are light peach colored circular biconvex film coated tablet debossed with “C” on one side and “432” on the other side. Bottle of 30................................................................................................................ NDC 69097-432-02 Bottle of 90................................................................................................................ NDC 69097-432-05 Bottle of 1000 ........................................................................................................... NDC 69097-432-15 Storage Store at 25° C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep this and all drugs out of the reach of children.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.