Toviaz

Pharmacotherapeutic group: Urologicals, Urinary antispasmodics, ATC code: G04BD11. Mechanism of action Fesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolysed by non-specific plasma esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the main active pharmacological principle of fesoterodine. Clinical efficacy and safety The efficacy of fixed doses of fesoterodine 4 mg and 8 mg was evaluated in two Phase 3 randomised, double-blind, placebo-controlled, 12-week studies. Female (79%) and male (21%) patients with a mean age of 58 years (range 19-91 years) were included. A total of 33% of patients were ≥65 years of age and 11% were ≥75 years of age. Fesoterodine treated patients had statistically significant mean reductions in the number of micturitions per 24 hours and in the number of urge incontinence episodes per 24 hours at the end of treatment compared to placebo. Likewise, the response rate (% of patients reporting that their condition has been “greatly improved” or “improved” using a 4-point Treatment Benefit Scale) was significantly greater with fesoterodine compared to placebo. Furthermore, fesoterodine improved the mean change in the voided volume per micturition, and the mean change in the number of continent days per week (see Table 1 below). Table 1: Mean changes from Baseline to end of treatment for primary and selected secondary endpoints Study 1 Study 2 Parameter Placebo Fesoterodine 4 mg Fesoterodine 8 mg Active comparator Placebo Fesoterodine 4 mg Fesoterodine 8 mg Number of micturitions per 24 hours# N=279 N=265 N=276 N=283 N=266 N=267 N=267 Baseline 12.0 11.6 11.9 11.5 12.2 12.9 12.0 Change from baseline -1.02 -1.74 -1.94 -1.69 -1.02 -1.86 -1.94 p-value <0.001 <0.001 0.032 <0.001 Responder rate (treatment response)# N=279 N=265 N=276 N=283 N=266 N=267 N=267 Responder rate 53.4% 74.7% 79.0% 72.4% 45.1% 63.7% 74.2% p-value <0.001 <0.001 <0.001 <0.001 Number of urge incontinence episodes per 24 hours N=211 N=199 N=223 N=223 N=205 N=228 N=218 Baseline 3.7 3.8 3.7 3.8 3.7 3.9 3.9 Change from baseline -1.20 -2.06 -2.27 -1.83 -1.00 -1.77 -2.42 p-value 0.001 <0.001 0.003 <0.001 Number of continent days per week N=211 N=199 N=223 N=223 N=205 N=228 N=218 Baseline 0.8 0.8 0.6 0.6 0.6 0.7 0.7 Change from baseline 2.1 2.8 3.4 2.5 1.4 2.4 2.8 p-value 0.007 <0.001 <0.001 <0.001 Voided volume per micturition (ml) N=279 N=265 N=276 N=283 N=266 N=267 N=267 Baseline 150 160 154 154 159 152 156 Change from baseline 10 27 33 24 8 17 33 p-value <0.001 <0.001 0.150 <0.001 # primary end points Cardiac electrophysiology The effect of fesoterodine 4 mg and 28 mg on the QT interval was thoroughly evaluated in a double- blind, randomised, placebo- and positive-controlled (moxifloxacin 400 mg) parallel group study with once-daily treatment over a period of 3 days in 261 male and female subjects aged 45 to 65 years. Change from baseline in QTc based on the Fridericia correction method did not show any differences between the active treatment and placebo group. Paediatric population Fesoterodine was evaluated in a randomised, open-label study consisting of a 12-week efficacy phase study followed by a 12-week safety extension phase in paediatric patients from 6 years to 17 years of age with neurogenic detrusor overactivity. Two cohorts were studied. In the Cohort 1, 124 patients weighing > 25 kg received a fixed dose of fesoterodine 4 mg or 8 mg tablets once-daily or active comparator oxybutynin XL tablets. In the safety extension phase, patients randomised to active comparator tablets were switched to fesoterodine 4 mg or 8 mg tablets (allocated by the investigator). In the Cohort 2, 57 patients weighing ≤ 25 kg received a fixed dose of fesoterodine 2 mg or 4 mg investigational beads-in-capsule (BIC) formulation once daily. In the safety extension phase, patients continued on the dose of fesoterodine to which they had been randomised. For study inclusion, patients were required to have stable neurological disease and clinically or urodynamically-demonstrated neurogenic detrusor overactivity (see section 4.2). The primary efficacy endpoint for both Cohorts was the mean change from baseline in maximum cystometric bladder capacity (MCBC) at Week 12. Treatment with fesoterodine 4 mg or 8 mg tablets resulted in improvements from baseline to Week 12 in the primary efficacy endpoint, MCBC, for paediatric patients in Cohort 1, with numerically higher changes from baseline for fesoterodine 8 mg tablets than for fesoterodine 4 mg tablets. Treatment with fesoterodine 2 mg and 4 mg BIC resulted in improvements from baseline to Week 12 in the primary efficacy endpoint, MCBC, for paediatric patients in Cohort 2, with numerically higher changes from baseline for fesoterodine 4 mg BIC than for fesoterodine 2 mg BIC. Table 2: Mean baseline and change from baseline to week 12 maximum cystometric bladder capacity (mL) Cohort 1 (body weight > 25 kg) Cohort 2 (body weight ≤ 25 kg Feso 4 mg tablet Feso 8 mg tablet Oxybutynin XL Feso 2 mg BIC Feso 4 mg BIC N = 41 N = 41 N = 38 N = 25 N = 28 Baseline 195.1 173.3 164.1 131.4 126.7 Change from baseline (95% CI) a 58.12 (28.84, 87.39) 83.36 (54.22,112.49) 87.17 (56.82,117.53) 23.49 (3.03, 43.95) 40.17 (20.84, 59.50) p-value vs. baseline a 0.0001 <.0001 <.0001 -- b -- b Abbreviations: BIC = beads-in-capsule; CI = confidence interval; Feso = fesoterodine, N = number of patients with a non-missing baseline measurement; vs. = versus. Baseline is defined as the last available measurement prior to the start of treatment. a. Based on an analysis of covariance model with terms for treatment group, baseline maximum cystometric bladder capacity and baseline weight. Last observation carried forward/baseline observation was used for imputing missing values. b. No hypothesis testing was planned for Cohort 2; therefore, no p-values are presented. Secondary endpoints Treatment with fesoterodine 4 mg or 8 mg tablets resulted in statistically significant improvements in the urodynamic measure secondary endpoint bladder volume at first involuntary detrusor contraction. The most commonly reported adverse reactions in the efficacy phase were diarrhoea, dry mouth, constipation, abdominal pain (including upper abdominal pain) and headache. These mild to moderate adverse reactions are consistent with the pharmacological, antimuscarinic properties of fesoterodine. Increases in heart rate were observed in patients who received Fesoterodine which were not associated with clinical symptoms. Overall, the safety profile in paediatric patients with neurogenic detrusor overactivity was similar to that observed in adults with overactive bladder syndrome.