Fesoterodine Fumarate 8 mg Tablet, Extended Release, 1,000-count — NDC 62332-176-91 (Billing 62332-0176-91)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine. Muscarinic receptors play a role in contractions of urinary bladder smooth muscle.

Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

12.2Pharmacodynamics In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. 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.

Cardiac Electrophysiology The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade.

Corrected QT intervals (QTc) were calculated using Fridericia’s correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.

In this study, conducted in subjects aged 44 to 65 years, fesoterodine fumarate was associated with an increase in heart rate that correlates with increasing dose. When compared to placebo, the mean increase in heart rate associated with fesoterodine 4 mg/day and fesoterodine 28 mg/day was 3 beats/minute and 11 beats/minute, respectively. In the two, phase 3, placebo-controlled studies in adult in patients with overactive bladder, the mean increases in heart rate compared to placebo were 3 to 4 beats/minute in the fesoterodine 4 mg/day group and 3 to 5 beats/minute in the fesoterodine 8 mg/day group.

12.3Pharmacokinetics Absorption: After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite is 52%.

After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after multiple-dose administration.

A Summary of pharmacokinetic parameters for the active metabolite after a single dose of fesoterodine fumarate 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 8. Table 8: Summary of Geometric Mean [CV] Pharmacokinetic Parameters for the Active Metabolite After a Single Dose of Fesoterodine Fumarate 4 mg and 8 mg in Extensive and Poor CYP2D6 Metabolizers Fesoterodine Fumarate 4 mg Fesoterodine Fumarate 8 mg Parameter EM (N=16) PM (N=8) EM (N=16) PM (N=8) C max (ng/mL) 1.89 [43%] 3.45 [54%] 3.98 [28%] 6.9 [39%] AUC 0-tz (ng*h/mL) 21.2 [38%] 40.5 [31%] 45.3 [32%] 88.7 [36%] t max (h) a 5 [2 to 6] 5 [5 to… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Fesoterodine is a competitive muscarinic receptor antagonist. After oral administration, fesoterodine is rapidly and extensively hydrolyzed by nonspecific esterases to its active metabolite, 5-hydroxymethyl tolterodine, which is responsible for the antimuscarinic activity of fesoterodine. Muscarinic receptors play a role in contractions of urinary bladder smooth muscle.

Inhibition of these receptors in the bladder is presumed to be the mechanism by which fesoterodine produces its effects.

12.3Pharmacokinetics Absorption: After oral administration, fesoterodine is well absorbed. Due to rapid and extensive hydrolysis by nonspecific esterases to its active metabolite 5-hydroxymethyl tolterodine, fesoterodine cannot be detected in plasma. Bioavailability of the active metabolite is 52%.

After single or multiple-dose oral administration of fesoterodine in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. No accumulation occurs after multiple-dose administration.

A Summary of pharmacokinetic parameters for the active metabolite after a single dose of fesoterodine fumarate 4 mg and 8 mg in extensive and poor metabolizers of CYP2D6 is provided in Table 8. Table 8: Summary of Geometric Mean [CV] Pharmacokinetic Parameters for the Active Metabolite After a Single Dose of Fesoterodine Fumarate 4 mg and 8 mg in Extensive and Poor CYP2D6 Metabolizers Fesoterodine Fumarate 4 mg Fesoterodine Fumarate 8 mg Parameter EM (N=16) PM (N=8) EM (N=16) PM (N=8) C max (ng/mL) 1.89 [43%] 3.45 [54%] 3.98 [28%] 6.9 [39%] AUC 0-tz (ng*h/mL) 21.2 [38%] 40.5 [31%] 45.3 [32%] 88.7 [36%] t max (h) a 5 [2 to 6] 5 [5 to 6] 5 [3 to 6] 5 [5 to 6] t ½ (h) 7.31 [27%] 7.31 [30%] 8.59 [41%] 7.66 [21%] EM = extensive CYP2D6 metabolizer, PM = poor CYP2D6 metabolizer, CV = coefficient of variation; C max = maximum plasma concentration, AUC 0-tz = area under the concentration time curve from zero up to the last measurable plasma concentration, t max = time to reach C max , t ½ = terminal half-life a Data presented as median (range) Effect of Food There is no clinically relevant effect of food on the pharmacokinetics of fesoterodine.

In a study of the effects of food on the pharmacokinetics of fesoterodine in 16 healthy male volunteers, concomitant food intake increased the active metabolite of fesoterodine AUC by approximately 19% and C max by 18% [see Dosage and Administration (2.1)]. Distribution Plasma protein binding of the active metabolite is low (approximately 50%) and is primarily bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 L.

Metabolism After oral administration, fesoterodine is rapidly and extensively hydrolyzed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolites via two major pathways involving CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of fesoterodine.

Variability in CYP2D6 Metabolism A subset of individuals (approximately 7% of Caucasians and approximately 2% of African Americans) are poor metabolizers for CYP2D6. C max and AUC of the active metabolite are increased 1.7- and 2-fold, respectively, in CYP2D6 poor metabolizers, as compared to extensive metabolizers. Excretion Hepatic metabolism and renal excretion contribute 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%), and a smaller amount (7%) was recovered in feces. The terminal half-life of the active metabolite is approximately 4 hours following an intravenous administration. The apparent terminal half-life following oral administration is approximately 7 hours.

Pharmacokinetics in Specific Populations Geriatric Patients Following a single 8 mg oral dose of fesoterodine, the mean (±SD) AUC and C max for the active metabolite 5-hydroxymethyl tolterodine in 12 elderly men (mean age 67 years) were 51.8 ± 26.1 h*ng/mL and 3.8 ± 1.7 ng/mL, respectively. In the same study, the mean (±SD) AUC and C max in 12 young men (mean age 30 years) were 52 ± 31.5 h*ng/mL and… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In a urodynamic study involving patients with involuntary detrusor contractions, the effects after the administration of fesoterodine on the volume at first detrusor contraction and bladder capacity were assessed. 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.

Cardiac Electrophysiology The effect of fesoterodine 4 mg and 28 mg on the QT interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg once a day) parallel trial with once-daily treatment over a period of 3 days in 261 male and female subjects aged 44 to 65 years. Electrocardiographic parameters were measured over a 24-hour period at pre-dose, after the first administration, and after the third administration of study medication. Fesoterodine 28 mg was chosen because this dose, when administered to CYP2D6 extensive metabolizers, results in an exposure to the active metabolite that is similar to the exposure in a CYP2D6 poor metabolizer receiving fesoterodine 8 mg together with CYP3A4 blockade.

Corrected QT intervals (QTc) were calculated using Fridericia’s correction and a linear individual correction method. Analyses of 24-hour average QTc, time-matched baseline-corrected QTc, and time-matched placebo-subtracted QTc intervals indicate that fesoterodine at doses of 4 and 28 mg/day did not prolong the QT interval. The sensitivity of the study was confirmed by positive QTc prolongation by moxifloxacin.

In this study, conducted in subjects aged 44 to 65 years, fesoterodine fumarate was associated with an increase in heart rate that correlates with increasing dose. When compared to placebo, the mean increase in heart rate associated with fesoterodine 4 mg/day and fesoterodine 28 mg/day was 3 beats/minute and 11 beats/minute, respectively. In the two, phase 3, placebo-controlled studies in adult in patients with overactive bladder, the mean increases in heart rate compared to placebo were 3 to 4 beats/minute in the fesoterodine 4 mg/day group and 3 to 5 beats/minute in the fesoterodine 8 mg/day group.

14 CLINICAL STUDIES

14.1Adult Overactive Bladder The efficacy of fesoterodine fumarate extended-release tablets was evaluated in two, Phase 3, randomized, double-blind, placebo-controlled, 12-week studies for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Entry criteria required that patients have symptoms of overactive bladder for ≥6-months duration, at least 8 micturitions per day, and at least 6 urinary urgency episodes or 3 urge incontinence episodes per 3-day diary period.

Patients were randomized to a fixed dose of fesoterodine fumarate 4 or 8 mg/day or placebo. In one of these studies, 290 patients were randomized to an active control arm (an oral antimuscarinic agent). For the combined studies, a total of 554 patients received placebo, 554 patients received fesoterodine fumarate 4 mg/day, and 566 patients received fesoterodine fumarate 8 mg/day.

The majority of patients were Caucasian (91%) and female (79%) with a mean age of 58 years (range 19 to 91 years). The primary efficacy endpoints were the mean change in the number of urge urinary incontinence episodes per 24 hours and the mean change in the number of micturitions (frequency) per 24 hours. An important secondary endpoint was the mean change in the voided volume per micturition.

Results for the primary endpoints and for mean change in voided volume per micturition from the two 12-week clinical studies of fesoterodine fumarate are reported in Table 10. Table 10: Mean Baseline and Change From Baseline to Week 12 for Urge Urinary Incontinence Episodes, Number of Micturitions, and Volume Voided per Micturition Study 1 Study 2 Parameter Placebo N=279 Fesoterodine Fumarate 4mg/day N=265 Fesoterodine Fumarate 8mg/day N=276 Placebo N=266 Fesoterodine Fumarate 4mg/day N=267 Fesoterodine Fumarate 8mg/day N=267 Number of urge incontinence episodes per 24 hours a Baseline 3.7 3.8 3.7 3.7 3.9

3.9Change from baseline -1.2 -2.06 -2.27 -1 -1.77 -2.42 p-value vs. placebo - 0.001 <0.001 - <0.003 <0.001 Number of micturitions per 24 hours Baseline 12 11.6 11.9 12.2 12.9 12 Change from baseline -1.02 -1.74 -1.94 -1.02 -1.86 -1.94 p-value vs. placebo - <0.001 <0.001 - 0.032 <0.001 Voided volume per micturition (mL) Baseline 150 160 154 159 152 156 Change from baseline 10 27 33 8 17 33 p-value vs. placebo - <0.001 <0.001 - 0.150 <0.001 vs. = versus a Only those patients who were urge incontinent at baseline were included for the analysis of number of urge incontinence episodes per 24 hours: In Study 1, the number of these patients was 211, 199, and 223 in the placebo, fesoterodine fumarate 4 mg/day and fesoterodine fumarate 8 mg/day groups, respectively.

In Study 2, the number of these patients was 205, 228, and 218, respectively. Figures 1 to 4: The following figures show change from baseline over time in number of micturitions and urge urinary incontinence episodes per 24 h in the two studies. A reduction in number of urge urinary incontinence episodes per 24 hours was observed for both doses as compared to placebo as early as two weeks after starting fesoterodine fumarate therapy. fesoterodine-figure1.jpg fesoterodine-figure2.jpg fesoterodine-figure3.jpg fesoterodine-figure4.jpg

14.2Pediatric Neurogenic Detrusor Overactivity The efficacy of fesoterodine fumarate was evaluated in Study 3 (NCT01557244), a Phase 3, randomized, open-label study consisting of a 12-week efficacy phase followed by a 12-week safety extension phase in pediatric patients from 6 years to 17 years of age. Two cohorts were studied. Cohort 1 (patients weighing greater than 25 kg) received a fixed dose of fesoterodine fumarate 4 mg or fesoterodine fumarate 8 mg tablets orally once daily, or once daily.

In the safety extension phase, patients randomized to the active comparator were switched to fesoterodine fumarate 4 mg or fesoterodine fumarate 8 mg once daily. For study inclusion, patients were required to have stable neurological disease and c… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis,Mutagenesis,Impairment of Fertility Carcinogenicity No evidence of drug-related carcinogenicity was found in 24-month studies with oral administration to mice and rats. The highest tolerated doses in mice (females 45 to 60 mg/kg/day, males 30 to 45 mg/kg/day) correspond to 11 to 19 times (females) and 4 to 9 times (males) the estimated human AUC values reached with fesoterodine 8 mg, which is the Maximum Recommended Human Dose (MRHD). In rats, the highest tolerated dose (45 to 60 mg/kg/day) corresponds to 3 to 8 times (females) and 3 to 14 times (males) the estimated human AUC at the MRHD.

Mutagenesis Fesoterodine was not mutagenic or genotoxic in vitro (Ames tests, chromosome aberration tests) or in vivo (mouse micronucleus test). Impairment of Fertility Fesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day in mice. At 45 mg/kg/day, a lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2-weeks prior to mating and continuing through day 7 of gestation.

The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. At the NOEL, the systemic exposure, based on AUC, was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher.