DARIFENACIN — darifenacin hydrobromide tablet, film coated, extended release
Aurobindo Pharma Limited
Darifenacin extended-release tablets are a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.
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.
Darifenacin extended-release tablets should be taken 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 and Precautions (5.6),Drug Interactions (7.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Darifenacin extended-release tablets 7.5 mg are white colored, round convex, film-coated tablets debossed with “Z” on one side and “22” on other side. Darifenacin extended-release tablets 15 mg are light peach colored, round convex, film-coated tablets debossed with “Z” on one side and “23” on other side.
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.
Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
Darifenacin extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Darifenacin extended-release tablets, 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.
Darifenacin extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.
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.
Darifenacin extended-release tablets are 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 darifenacin extended-release tablets affect them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
The daily dose of darifenacin extended-release tablets should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin extended-release tablets have not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore are not recommended for use in this patient population [see Dosage and Administration (2)Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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 tablets was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin extended-release tablets. 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.
|Body System||Adverse Reaction||% of Subjects|
|Darifenacin Extended-Release Tablets 7.5 mg N = 337||Darifenacin Extended-Release Tablets 15 mg N = 334||Placebo N = 388|
|Urogenital||Urinary Tract Infection||4.7||4.5||2.6|
|Body as a Whole||Asthenia||1.5||2.7||1.3|
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 tablets 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 tablets 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 darifenacin extended-release tablets and greater than placebo.
|Adverse Reaction||Darifenacin Extended-Release Tablets 7.5 mg/15 mg N = 268||Placebo N = 127|
|Constipation||56 (20.9%)||10 (7.9%)|
|Dry Mouth||50 (18.7%)||11 (8.7%)|
|Headache||18 (6.7%)||7 (5.5%)|
|Dyspepsia||12 (4.5%)||2 (1.6%)|
|Nausea||11 (4.1%)||2 (1.6%)|
|Urinary Tract Infection||10 (3.7%)||4 (3.1%)|
|Accidental Injury||8 (3%)||3 (2.4%)|
|Flu Syndrome||8 (3%)||3 (2.4%)|
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