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 Gastrointestinal Motility [see Warnings and Precautions (5.3)]
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 Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day with treatment periods of 8- or 12-weeks. Approximately 80% of these patients had greater than 10-weeks of exposure to Toviaz in these trials.
A total of 1964 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 Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.
In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 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 Toviaz 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 Toviaz 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, Toviaz 4 mg, and Toviaz 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 Toviaz 4 mg or 8 mg once daily for up to 12-weeks.
| System organ class/Preferred term | Placebo N=554 % | Toviaz 4 mg/day N=554 % | Toviaz 8 mg/day N=566 % |
|---|---|---|---|
| ALT = alanine aminotransferase; GGT = gamma glutamyltransferase | |||
| Gastrointestinal disorders | |||
| Dry mouth | 7.0 | 18.8 | 34.6 |
| Constipation | 2.0 | 4.2 | 6.0 |
| 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 | 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 |
Patients also received Toviaz 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 Toviaz 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 Toviaz was evaluated in a total of 131 pediatric patients with NDO. Patients received Toviaz 4 mg or Toviaz 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 Toviaz, followed by a 12-week safety extension phase, in which 103 patients received Toviaz. Of the 103 patients who received Toviaz in the safety extension phase, 67 continued Toviaz from the efficacy phase and 36 switched from an active comparator in the efficacy phase to Toviaz 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 Toviaz 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.
| Preferred term | Toviaz 4 mg (N=42) % | Toviaz 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 |
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 Toviaz 4 mg or Toviaz 8 mg in Study 3 (both efficacy and safety extension phases) and Study 4. The ophthalmological adverse reactions did not result in discontinuation of Toviaz in any patient.
Increases in Heart Rate
Increases in heart rate were reported in pediatric patients with NDO who received Toviaz 4 mg and Toviaz 8 mg in Study 3. The mean heart data are described in Table 6.
| Study visit | Mean heart rate in beats per minute* (mean change from baseline) | |
|---|---|---|
| Toviaz 4 mg | Toviaz 8 mg | |
| ||
| Baseline | 88.6 | 84.2 |
| Week 4 | 93.8 (+5.2) | 94.0 (+9.8) |
| Week 12 | 94.8 (+6.2) | 94.0 (+9.8) |
| Week 24 | 90.4 (+1.8) | 90.8 (+6.5) |
The proportion of patients with heart rates greater than the 99th percentile for age also increased from baseline in patients who received Toviaz 4 mg and Toviaz 8 mg in Study 3. These data are described in Table 7.
| Study visit | Proportion of patients with heart rate >99th percentile for age | |
|---|---|---|
| Toviaz 4 mg | Toviaz 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% |
Increases from baseline in the proportion of patients with a heart rate greater than the 99th percentile for age were most pronounced in patients less than 12 years of age who received Toviaz 8 mg.
Increases in heart rate in patients who received Toviaz 4 mg and Toviaz 8 mg in Study 3 were not associated with clinical symptoms and did not result in discontinuation of therapy with Toviaz.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Toviaz. 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
General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema
Skin and subcutaneous tissue disorders: Urticaria, pruritus