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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.
Table 1: Incidence of Identified Adverse Reactions,
Derived from All Adverse Events Reported in greater than or equal to 2% of
Patients Treated with Enablex Extended-Release Tablets and More Frequent with
Enablex than with Placebo in Studies 1, 2, and 3
|Body System||Adverse Reaction||% of Subjects|
|Enablex 7.5 mg
N = 337
|Enablex 15 mg
N = 334
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 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]. 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.
Table 2: Number (%) of Adverse Reactions, Derived from
All Adverse Events Reported in greater than 3% of Patients Treated with Enablex
Extended-Release Tablets, and More Frequent with Enablex than Placebo, in Study 4
|Adverse Reaction||Enablex 7.5 mg/15 mg
N = 268
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 (3.0%)||3 (2.4%)|
|Flu Syndrome||8 (3.0%)||3 (2.4%)|
Post Marketing 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
Central Nervous: confusion, hallucinations and somnolence
Read the Enablex (darifenacin extended-release tablets) Side Effects Center for a complete guide to possible side effects
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 and CLINICAL PHARMACOLOGY].
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].
Combination Oral Contraceptives
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.
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].
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.
Read the Enablex Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/4/2016
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