Mirabegron 50 mg Tablet, Film Coated, Extended Release, 30-count — NDC 69238-2861-1 (Billing 69238-2861-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.

12.2Pharmacodynamics Urodynamics The effects of mirabegron on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of mirabegron once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, mirabegron should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2) ] .

Cardiac Electrophysiology The effect of multiple doses of mirabegron 50 mg, 100 mg, and 200 mg (four times the maximum recommended dose) once daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment arm, parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec.

For the 50 mg mirabegron dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4 to 5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec). For the mirabegron 100 mg and 200 mg dose groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4 to 5 hours post dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively.

At the mirabegron 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec). In this thorough QT study, mirabegron increased heart rate on ECG in a dose-dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 bpm, 11 bpm, and 17 bpm, respectively.

In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was approximately 1 bpm. In this thorough QT study, mirabegron also increased blood pressure in a dose-dependent manner (see Effects on Blood Pressure) . Effects on Blood Pressure In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg (four times the maximum recommended dose) of mirabegron for 10 days on the QTc interval, the maximum mean increase in supine systolic blood pressure (SBP)/diastolic blood pressure (DBP) at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo [see Warnings and Precautions (5.1)] .

The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at mirabegron doses of 50 mg, 100 mg, and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP. In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg (six times the maximum recommended dose) of mirabegron for 10 days, SBP also increased in a dose-dependent manner.

The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5, and 6.5 mm Hg for mirabegron exposures associated with doses of 50 mg, 100 mg, 200 mg, and 300 mg… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.

12.3Pharmacokinetics Absorption Mirabegron Monotherapy for Adult OAB After oral administration of mirabegron in healthy volunteers, mirabegron was absorbed to reach maximum plasma concentrations (C max ) at approximately 3.5 hours. The absolute bioavailability increased from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean C max and AUC increased more than dose proportionally.

This relationship was more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased C max and AUC tau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased C max and AUC tau by approximately 8.4- and 6.5-fold. Steady-state concentrations were achieved within 7 days of once daily dosing with mirabegron.

After once daily administration, plasma exposure of mirabegron at steady-state was approximately double that seen after a single dose. Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) The median T max of mirabegron following oral administration of a single dose of mirabegron extended-release tablets in pediatric patients under fed state was 4 to 5 hours. Population pharmacokinetic analysis predicted that the median T max of mirabegron at steady-state was 3 to 4 hours.

Effect of Food Mirabegron Monotherapy for Adult OAB There were no clinically significant differences in mirabegron pharmacokinetics when administered with or without food in adult patients. Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) In the fasted state, steady-state mirabegron AUC increased by 120% relative to the fed state in pediatric patients receiving mirabegron. Distribution Mirabegron Monotherapy for Adult OAB Mirabegron is extensively distributed in the body.

The volume of distribution at steady-state (V ss ) is approximately 1,670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes.

Based on an in vitro study, erythrocyte concentrations of 14 C-mirabegron were about 2-fold higher than in plasma. Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) Mirabegron volume of distribution was relatively large in pediatric patients (the range of mean V z /F under fed state in pediatric patients across studies: 4,895 to 13,726 L) and increased with increasing body weight. Elimination Mirabegron Monotherapy for Adult OAB The terminal elimination half-life (t 1/2 ) of mirabegron is approximately 50 hours in patients.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) The mean terminal elimination half-life (t 1/2 ) of mirabegron is approximately 26 to 31 hours in pediatric patients. Metabolism Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14 C-mirabegron.

Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although, in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination.

In healthy subjects who were genotypically poor metabolizers of CYP2D6, mean C max and AUC tau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT), and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6. Excretion Mirabegron Monotherapy for Adult OAB Total body clearance (CL tot… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Urodynamics The effects of mirabegron on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of mirabegron once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, mirabegron should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions (5.2) ] .

Cardiac Electrophysiology The effect of multiple doses of mirabegron 50 mg, 100 mg, and 200 mg (four times the maximum recommended dose) once daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment arm, parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec.

For the 50 mg mirabegron dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4 to 5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec). For the mirabegron 100 mg and 200 mg dose groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4 to 5 hours post dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively.

At the mirabegron 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec). In this thorough QT study, mirabegron increased heart rate on ECG in a dose-dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 bpm, 11 bpm, and 17 bpm, respectively.

In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was approximately 1 bpm. In this thorough QT study, mirabegron also increased blood pressure in a dose-dependent manner (see Effects on Blood Pressure) . Effects on Blood Pressure In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg (four times the maximum recommended dose) of mirabegron for 10 days on the QTc interval, the maximum mean increase in supine systolic blood pressure (SBP)/diastolic blood pressure (DBP) at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo [see Warnings and Precautions (5.1)] .

The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at mirabegron doses of 50 mg, 100 mg, and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP. In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg (six times the maximum recommended dose) of mirabegron for 10 days, SBP also increased in a dose-dependent manner.

The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5, and 6.5 mm Hg for mirabegron exposures associated with doses of 50 mg, 100 mg, 200 mg, and 300 mg, respectively. In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2, and 3) in patients with OAB receiving mirabegron 25 mg, 50 mg, or 100 mg (two times the maximum recommended dose) once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 to 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, mirabegron 25 mg and mirabegron 50 mg patients, respectively.

Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1%, and 6.6% of placebo, mir… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Mirabegron Monotherapy for Adult OAB Mirabegron was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3-day period.

The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 to 95 years). The population included both naïve patients who had not received prior muscarinic antagonist pharmacotherapy for overactive bladder (48%) and those who had received prior muscarinic antagonist pharmacotherapy for OAB (52%). In Study 1 (NCT00689104), patients were randomized to placebo, mirabegron 50 mg, mirabegron 100 mg, or an active control once daily.

In Study 2 (NCT00662909), patients were randomized to placebo, mirabegron 50 mg or mirabegron 100 mg once daily. In Study 3 (NCT00912964), patients were randomized to placebo, mirabegron 25 mg or mirabegron 50 mg once daily. The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary.

An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition. Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 13. Table 13: Mean Baseline and Change from Baseline at Week 12 1 for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition in Patients with Overactive Bladder in Studies 1, 2, and 3 Parameter Study 1 Study 2 Study 3 Placebo Mirabegron 50 mg Placebo Mirabegron 50 mg Placebo Mirabegron 25 mg Mirabegron 50 mg Number of Incontinence Episodes per 24 Hours 2 n 291 293 325 312 262 254 257 Baseline (mean) 2.67 2.83 3.03 2.77 2.43 2.65

2.51Change from baseline (adjusted mean 3 ) -1.17 -1.57 -1.13 -1.47 -0.96 -1.36 -1.38 Difference from placebo (adjusted mean 3 ) -- -0.41 -- -0.34 -- -0.40 -0.42 95% Confidence Interval -- (-0.72, -0.09) -- (-0.66, -0.03) -- (-0.74, -0.06) (-0.76, -0.08) p-value -- 0.003 4 -- 0.026 4 -- 0.005 4 0.001 4 Number of Micturitions per 24 Hours n 480 473 433 425 415 410 426 Baseline (mean) 11.71 11.65 11.51 11.80 11.48 11.68

11.66Change from baseline (adjusted mean 3 ) -1.34 -1.93 -1.05 -1.66 -1.18 -1.65 -1.60 Difference from placebo (adjusted mean 3 ) -- -0.60 -- -0.61 -- -0.47 -0.42 95% Confidence Interval -- (-0.90, -0.29) -- (-0.98, -0.24) -- (-0.82, -0.13) (-0.76, -0.08) p-value -- < 0.001 4 -- 0.001 4 -- 0.007 4 0.015 4 Volume Voided (mL) per Micturition n 480 472 433 424 415 410 426 Baseline (mean) 156.7 161.1 157.5 156.3 164.0 165.2 159.3 Change from baseline (adjusted mean 3 ) 12.3 24.2 7.0 18.2 8.3 12.8

20.7Difference from placebo (adjusted mean 3 ) -- 11.9 -- 11.1 -- 4.6 12.4 95% Confidence Interval -- (6.3, 17.4) -- (4.4, 17.9) -- (-1.6, 10.8) (6.3, 18.6) p-value -- < 0.001 4 -- 0.001 4 -- 0.15 < 0.001 4 Week 12 is the last observation on treatment. For incontinence episodes per 24 hours, the analysis population is restricted to patients with at least 1 episode of incontinence at baseline. Least squares mean adjusted for baseline, gender, and geographical region.

Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment. Mirabegron 25 mg was effective in treating the symptoms of OAB within 8 weeks and mirabegron 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of mirabegron was maintained through the… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher than the MRHD in rats and 21 to 38-fold higher than the MRHD in mice than the human systemic exposure at the 50 mg dose.

Mutagenesis Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay. Impairment of Fertility Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22-fold the MRHD in women and 93-fold the MRHD in men.