Summary Basis of Decision for Toviaz ™

3.3.1 Pharmacodynamics

Fesoterodine is a muscarinic receptor antagonist. Muscarinic receptors play a role in contractions of urinary bladder smooth muscle and stimulation of salivary secretion. Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

Administration of fesoterodine increased the volume at first detrusor contraction and bladder capacity in a dose-dependent manner. These findings are consistent with an antimuscarinic effect on the bladder.

The intake of fesoterodine was associated with side effects such as dry mouth, constipation, dry eyes, urinary retention, and increased heart rate. These effects are consistent with the antimuscarinic effects of fesoterodine.

The effect of fesoterodine 4 mg (therapeutic dose) and 28 mg on electrocardiogram (ECG) parameters was evaluated in a double-blind, randomized, placebo- and positive-controlled parallel group study with once daily treatment over a period of 3 days in 261 healthy subjects. Fesoterodine at doses of 4 and 28 mg/day for 3 days did not prolong the QTc interval, the QRS duration, or the PR interval in a treatment-related manner. Fesoterodine was associated with an increase in heart rate that correlated with increasing dose. On Day 3 of the study, when compared to placebo, the mean increases in heart rate associated with doses of 4 mg/day and 28 mg/day of fesoterodine were 3 beats/minute and 11 beats/minute, respectively. The maximum placebo-adjusted increases in heart rate occurred at 3 hours post-dosing and were mean 6.3 [90% confidence interval (CI) 3.0, 9.5] beats/minute for fesoterodine 4 mg and mean 15.5 (90% CI 12.6, 18.3) beats/minute for fesoterodine 28 mg/day. On Day 3 of treatment, blood pressure measurements were performed at 4-5 hours post-dosing. Systolic blood pressure was increased by mean 1.3 (90% CI -1.5, 4.1) mm Hg with fesoterodine 4 mg/day and by mean 4.1 (90% CI 0.5, 7.6) mm Hg with fesoterodine 28 mg/day. Diastolic blood pressure was increased by mean 4.3 (90% CI 1.9, 6.8) mm Hg with fesoterodine 4 mg/day and by mean 6.6 (90% CI 4.0, 9.1) mm Hg with fesoterodine 28 mg/day.

3.3.2 Pharmacokinetics

Absorption

Fesoterodine was well-absorbed after oral administration. Fesoterodine was immediately hydrolyzed to its active metabolite 5-HMT, and could not be detected in plasma. Bioavailability of 5-HMT was 52%. After single or multiple-dose oral administration of fesoterodine (4 mg to 28 mg), plasma concentrations of the active metabolite were proportional to the dose. Maximum plasma levels were reached after approximately 5 hours. No accumulation occurred after multiple-dose administration.

Distribution

Plasma protein binding of the active metabolite 5-HMT was low (approximately 50%). Following intravenous infusion of fesoterodine, the mean steady-state volume of distribution of 5-HMT was 169 L.

Metabolism

After oral administration, fesoterodine was rapidly and extensively hydrolyzed to its active metabolite 5-HMT. The active metabolite was further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4.

Excretion

Hepatic metabolism and renal excretion contributed significantly to the elimination of the active metabolite. After oral administration of fesoterodine, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%). A smaller amount of the administered dose (7%) was recovered in the faeces.

Drug Interaction and CYP2D6/CYP3A4 Metabolic Pathways

Metabolism of 5-HMT occurs via the CYP2D6 and CYP3A4 pathways. Exposure to the active metabolite 5-HMT can therefore vary based on issues such as the patient's CYP2D6 metabolizer status, concomitant medication use and co-morbid conditions. The labelling reflects these issues and also suggests limiting the dose to 4 mg in cases where a potent CYP3A4 is co-administered.

Special Populations

Urinary excretion decreased with severity of renal impairment. Subjects with mild or moderate renal impairment appeared to be able to tolerate the recommended doses of fesoterodine. However, patients with severe renal impairment (creatinine clearance of <30 mL/min) should not receive doses greater than 4 mg. This is stated in the Product Monograph, both in the Warnings and Precautions and Dosage and Administration sections.

In subjects with moderate hepatic impairment, the maximum plasma concentrations of 5-HMT were increased by 1.4-fold. Therefore no dose adjustment is necessary for patients with mild to moderate hepatic impairment. Subjects with severe hepatic impairment were not studied, and therefore Toviaz is not recommended for this population.

Factors such as age, gender, and race were not shown to significantly impact exposure to the active metabolite 5-HMT.

3.3.3 Clinical Efficacy

The efficacy of Toviaz 4 mg and 8 mg taken orally once daily was evaluated in two Phase III randomized, double-blind, placebo-controlled, 12-week studies. The co-primary endpoints were the change from Baseline to Week 12 in the average number of micturitions per 24 hours and the change from Baseline to Week 12 in the average number of urge urinary incontinence (UUI) episodes per 24 hours, as well as treatment response derived from the Treatment Benefit Scale. Micturition was defined as a patient voluntarily passing urine (not including UUI episodes). Secondary endpoints included change in mean voided volume, daytime micturitions, urgency episodes per 24 hours, number of continent days per week, and change in severity of urgency episodes. Sustained efficacy was evaluated in a 3-year open-label extension of one Phase II study and two Phase III studies. A total of 2,288 patients were administered Toviaz in the Phase II and Phase III studies.

In the two Phase III studies, Toviaz 4 and 8 mg administered once daily for 12 weeks improved all three primary variables (change in the average number of micturitions per 24 hours, change in the average number of UUI episodes per 24 hours, and treatment response) in a statistically significant manner compared to placebo treatment. The mean changes from baseline in the average number of micturitions per 24 hours for Toviaz 4 mg and 8 mg were -1.74 and -1.94, respectively, for Study 1; and -1.86 and -1.94, respectively, for Study 2; compared to -1.02 for placebo (in both studies). The change in the average number of UUI episodes per 24 hours for Toviaz 4 mg and 8 mg were -2.06 and -2.27, respectively, for Study 1; and -1.77 and -2.42, respectively, for Study 2; compared to -1.20 for placebo in Study 1 and -1.00 for placebo in Study 2. The treatment response for Toviaz 4 mg and 8 mg were 74.7% and 79.0%, respectively, for Study 1; and 63.7% and 74.2%, respectively, for Study 2; compared to 53.4% for placebo in Study 1 and 45.1% for placebo in Study 2. Dose-dependent responses to Toviaz 4 and 8 mg/day were observed for all three primary efficacy variables and improvements in all three primary variables were observed as early as 2 weeks after commencement of treatment, at the first efficacy evaluation. In addition to improvements in all primary endpoints, Toviaz improved the signs and symptoms of overactive bladder for all secondary endpoints in a dose-dependent manner.

Prior drug treatment for overactive bladder, age, or gender did not affect the efficacy of Toviaz in a medically-relevant manner.

3.3.4 Clinical Safety

The safety of Toviaz was primarily evaluated in the Phase II and Phase III studies in a total of 2,859 patients with overactive bladder of which 2,288 were treated with Toviaz. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase II or Phase III studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks of exposure to Toviaz.

In the Phase II and Phase III placebo-controlled studies 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 event each: angina; chest pain; gastroenteritis; and QT prolongation on the ECG.

The most frequently reported adverse events were those typical for antimuscarinic drugs. The adverse events were generally mild or moderate in intensity, and included dry mouth; constipation; urinary tract infection; dry eyes; and urinary retention. The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in patients taking 8 mg/day (35%) and in patients taking 4 mg/day (19%), as compared to placebo (7%). The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in patients taking placebo, 4% in patients taking Toviaz 4 mg/day, and 6% in those taking Toviaz 8 mg/day.

Patients also received Toviaz for up to three years in open-label extension phases of one Phase II and two Phase III controlled studies. In all of the open-label studies 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 the 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 QTc interval prolongation (2 cases).

Toviaz was associated with an increase in heart rate that correlated with increasing dose. In the placebo-controlled Phase III studies in patients with overactive bladder, the mean increases in heart rate compared to placebo were approximately 3-4 beats/minute in the 4 mg/day group and 3-5 beats/minute in the 8 mg/day group.