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 percent, 0.9 percent, and 0 percent 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 percent, 1.2 percent, and 0.3 percent 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 percent 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 ≥ 2 Percent 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||Percentage 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 percent to 2 percent 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 > 3 percent of patients treated with Enablex and greater than placebo.
Table 2: Number (Percent) of Adverse Reactions, Derived from All Adverse Events Reported in > 3 Percent 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 percent)||10 (7.9 percent)|
|Dry Mouth||50 (18.7 percent)||11 (8.7 percent)|
|Headache||18 (6.7 percent)||7 (5.5 percent)|
|Dyspepsia||12 (4.5 percent)||2 (1.6 percent)|
|Nausea||11 (4.1 percent)||2 (1.6 percent)|
|Urinary Tract Infection||10 (3.7 percent)||4 (3.1 percent)|
|Accidental Injury||8 (3.0 percent)||3 (2.4 percent)|
|Flu Syndrome||8 (3.0 percent)||3 (2.4 percent)|
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
General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction
Central Nervous: confusion, hallucinations and somnolence
Cardiovascular: palpitations and syncope