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 Gastrointestinal 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) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Pediatric use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
6.1Clinical 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 7.0 18.8
34.6 Constipation 2.0 4.2
1.9 Abdominal pain upper 0.5 1.1
0.5Infections
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
3.7Renal
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
2.3 General disorders Edema peripheral 0.7 0.7
1.2 Musculoskeletal disorders Back pain 0.4 2.0
0.9 Psychiatric disorders Insomnia 0.5 1.3
0.4Investigations
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 use information is approved for Pfizer Inc.’s TOVIAZ ® (fesoterodine fumarate) extended-release tablets. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
6.2Postmarketing 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
