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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Angioedema [see Warnings and Precautions (5.1)] • Urinary Retention [see Warnings and Precautions (5.2)] • Decreased Gastointestinal Motility [see Warnings and Precautions (5.3)] • Most frequently reported adverse events with fesoterodine fumarate in adult patients with OAB (≥4%) were: dry mouth (placebo, 7%; fesoterodine fumarate 4 mg, 19%; fesoterodine fumarate 8 mg, 35%) and constipation (placebo, 2%; fesoterodine fumarate 4 mg, 4%; fesoterodine fumarate 8 mg, 6%). ( 6.1 ) • Most frequently reported adverse reactions with fesoterodine fumarate in pediatric patients (≥2%) with NDO were: diarrhea, urinary tract infection (UTI), dry mouth, constipation, abdominal pain, nausea, weight increased, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 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. Adult Overactive Bladder (OAB) The safety of fesoterodine fumarate was evaluated in Phase 2 and 3 controlled trials in a total of 2,859 patients with overactive bladder, of which 2,288 were treated with fesoterodine fumarate. Of this total, 782 received fesoterodine fumarate 4 mg/day, and 785 received fesoterodine fumarate 8 mg/day with treatment periods of 8-or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to fesoterodine fumarate in these trials. A total of 1,964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received fesoterodine fumarate 4 mg/day and 566 patients received fesoterodine fumarate 8 mg/day. In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, fesoterodine fumarate 4 mg, and fesoterodine fumarate 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving fesoterodine fumarate who reported one serious adverse reaction each: angina, chest pain, gastroenteritis, and QT prolongation on ECG. The most commonly reported adverse event in patients treated with fesoterodine fumarate was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, fesoterodine fumarate 4 mg, and fesoterodine fumarate 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment. The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day. Table 4 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with fesoterodine fumarate 4 mg or 8 mg once daily for up to 12-weeks. Table 4: Adverse Events With an Incidence Exceeding the Placebo Rate and Reported by ≥1% of Patients From Double-Blind, Placebo-Controlled Phase 3 Trials of 12-Weeks Treatment Duration System organ class/Preferred term Placebo N=554 % Fesoterodine fumarate 4 mg/day N=554 % Fesoterodine fumarate 8 mg/day N=566 % Gastrointestinal disorders Dry mouth 7 18.8 34.6 Constipation 2 4.2 6 Dyspepsia 0.5 1.6 2.3 Nausea 1.3 0.7 1.9 Abdominal pain upper 0.5 1.1 0.5 Infections Urinary tract infection 3.1 3.2 4.2 Upper respiratory tract infection 2.2 2.5 1.8 Eye disorders Dry eyes 0 1.4 3.7 Renal and urinary disorders Dysuria 0.7 1.3 1.6 Urinary retention 0.2 1.1 1.4 Respiratory disorders Cough 0.5 1.6 0.9 Dry throat 0.4 0.9 2.3 General disorders Edema peripheral 0.7 0.7 1.2 Musculoskeletal disorders Back pain 0.4 2 0.9 Psychiatric disorders Insomnia 0.5 1.3 0.4 Investigations ALT increased 0.9 0.5 1.2 GGT increased 0.4 0.4 1.2 Skin disorders Rash 0.5 0.7 1.1 ALT = alanine aminotransferase; GGT = gamma glutamyltransferase Patients also received fesoterodine fumarate for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received fesoterodine fumarate for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases). Pediatric Neurogenic Detrusor Overactivity (NDO) The safety of fesoterodine fumarate was evaluated in a total of 131 pediatric patients with NDO. Patients received fesoterodine fumarate 4 mg or fesoterodine fumarate 8 mg orally once daily in two clinical trials (Studies 3 and 4). Study 3 was a Phase 3 study in pediatric patients with NDO from 6 years to 17 years of age and weighing greater than 25 kg. This study consisted of a 12-week efficacy phase, in which 84 patients received fesoterodine fumarate, followed by a 12-week safety extension phase, in which 103 patients received fesoterodine fumarate. Of the 103 patients who received fesoterodine fumarate in the safety extension phase, 67 continued fesoterodine fumarate from the efficacy phase and 36 switched from an active comparator in the efficacy phase to fesoterodine fumarate in the safety extension phase. Study 4 (N=11) was an 8-week, Phase 2 pharmacokinetic (PK) and safety study in pediatric patients with NDO from 8 years to 17 years of age. The most commonly reported adverse reactions in pediatric patients with NDO who received fesoterodine fumarate 4 mg or 8 mg in Study 3 (≥2%) were diarrhea, UTI, dry mouth, constipation, abdominal pain, nausea, weight increased and headache. Table 5 lists the adverse reactions reported at an incidence greater than or equal to 2% in either treatment group in the Study 3 efficacy phase. Table 5: Adverse Reactions Reported in ≥2% of Patients With NDO Aged 6 Years to 17 Years in the 12-Week Efficacy Phase of Study 3 Preferred term Fesoterodine Fumarate 4 mg (N=42) % Fesoterodine Fumarate 8 mg (N=42) % Diarrhea 11.9 7.1 Urinary tract infection 9.5 2.4 Dry mouth 7.1 9.5 Constipation 7.1 7.1 Abdominal pain † 7.1 4.8 Nausea 4.8 2.4 Weight increased 4.8 0 Headache 4.8 7.1 † Includes abdominal pain and abdominal pain upper Ophthalmological Adverse Reactions Ophthalmological adverse reactions, including myopia, accommodation disorder and blurred vision, were reported in 8 of 131 (6.1%) pediatric patients with NDO who received fesoterodine fumarate 4 mg or fesoterodine fumarate 8 mg in Study 3 (both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result in discontinuation of fesoterodine fumarate in any patient. Increases in Heart Rate Increases in heart rate were reported in pediatric patients with NDO who received fesoterodine fumarate 4 mg and fesoterodine fumarate 8 mg in Study 3. The mean heart data are described in Table 6. Table 6: Mean Baseline and Mean Changes From Baseline in Heart Rate in Pediatric Patients Weighing Greater Than 25 kg in Study 3 Study visit Mean heart rate in beats per minute 1 (mean change from baseline) Fesoterodine Fumarate 4 mg Fesoterodine Fumarate 8 mg Baseline 88.6 84.2 Week 4 93.8 (+5.2) 94 (+9.8) Week 12 94.8 (+6.2) 94 (+9.8) Week 24 90.4 (+1.8) 90.8 (+6.5) 1 Heart rate expressed as the mean of the baseline measurement and the mean at each study visit and mean changes from baseline at each study visit by original treatment group in patients with complete follow-up at all study visits. The proportion of patients with heart rates greater than the 99 th percentile for age also increased from baseline in patients who received fesoterodine fumarate 4 mg and fesoterodine fumarate 8 mg in Study 3. These data are described in Table 7. Table 7: Proportion of Pediatric Patients With Heart Rate Greater Than the 99 th Percentile for Age and Weighing Greater Than 25 kg in Study 3 Study visit Proportion of patients with heart rate >99 th percentile for age Fesoterodine Fumarate 4 mg Fesoterodine Fumarate 8 mg Baseline 2.4% 2.4% Week 4 8.1% 12.2% Week 12* 7.5% 11.5% Week 24 3.3% 2.7% * Week 12 comprises patients who received fesoterodine fumarate for 12 weeks after being originally randomized to fesoterodine fumarate 4 mg and 8 mg and patients originally randomized to active comparator and subsequently transitioned to fesoterodine fumarate 4 mg and 8 mg for 12 weeks. Increases from baseline in the proportion of patients with a heart rate greater than the 99 th percentile for age were most pronounced in patients less than 12 years of age who received fesoterodine fumarate 8 mg. Increases in heart rate in patients who received fesoterodine fumarate 4 mg and fesoterodine fumarate 8 mg in Study 3 were not associated with clinical symptoms and did not result in discontinuation of therapy with fesoterodine fumarate. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fesoterodine fumarate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders : Palpitations Central nervous system disorders : Dizziness, headache, somnolence Eye disorders : Blurred vision Gastrointestinal disorders: Hypoaesthesia oral General disorders and administrative site conditions : Hypersensitivity reactions, including angioedema with airway obstruction, face edema Psychiatric disorders: Confusional state Skin and subcutaneous tissue disorders : Urticaria, pruritus