Mirabegron

MYRBETRIQ is a beta-3 adrenergic agonist indicated for the treatment of:

• Overactive bladder (OAB) in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency, either alone or in combination with the muscarinic antagonist solifenacin succinate. ( 1.1 )
• Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older and weighing 35 kg or more. ( 1.2 ) MYRBETRIQ Granules is a beta-3 adrenergic agonist indicated for the treatment of NDO in pediatric patients aged 3 years and older. ( 1.2 )

1.1 Adult Overactive Bladder (OAB) MYRBETRIQ Monotherapy MYRBETRIQ ® is indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. MYRBETRIQ Combination Therapy with Solifenacin Succinate MYRBETRIQ, in combination with the muscarinic antagonist solifenacin succinate, is indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency.

1.2 Pediatric Neurogenic Detrusor Overactivity (NDO) MYRBETRIQ Granules MYRBETRIQ ® Granules is indicated for the treatment of NDO in pediatric patients aged 3 years and older. MYRBETRIQ MYRBETRIQ is indicated for the treatment of NDO in pediatric patients aged 3 years and older and weighing 35 kg or more.

MYRBETRIQ (mirabegron extended-release tablets) are supplied in two different strengths as described below:

• 25 mg oval, brown, film-coated tablet, debossed with the (Astellas logo) and “325”
• 50 mg oval, yellow, film-coated tablet, debossed with the (Astellas logo) and “355” MYRBETRIQ Granules (mirabegron for extended-release oral suspension): Each bottle is filled with approximately 8.3 g of yellowish white granules, which contain 830 mg of mirabegron. After reconstitution with 100 mL water, the oral suspension is pale brownish yellow to yellow with 8 mg/mL of mirabegron.
• Extended-release tablets: 25 mg and 50 mg ( 3 )
• For extended-release oral suspension: 8 mg/mL of mirabegron after reconstitution ( 3 ) Astellas logo Astellas logo

MYRBETRIQ/MYRBETRIQ Granules is contraindicated in patients with known hypersensitivity reactions to mirabegron or any inactive ingredients of the tablet or oral suspension [see Adverse Reactions ( 6.1 , 6.2 )] . Hypersensitivity to mirabegron or any inactive ingredients. ( 4 )

• Increases in Blood Pressure : Can increase blood pressure in adult or pediatric patients. Periodically monitor blood pressure, especially in hypertensive patients. MYRBETRIQ/MYRBETRIQ Granules are not recommended in patients with severe uncontrolled hypertension. ( 5.1 )
• Urinary Retention in Patients With Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Drugs for Overactive Bladder : Administer with caution in these patients because of risk of urinary retention. ( 5.2 )
• Angioedema : Angioedema of the face, lips, tongue, and/or larynx has been reported with mirabegron. ( 5.3 , 6.2 )

5.1 Increases in Blood Pressure Increases in Blood Pressure in Adults MYRBETRIQ/MYRBETRIQ Granules can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. MYRBETRIQ/MYRBETRIQ Granules is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology ( 12.2 )] . In two, randomized, placebo-controlled, healthy adult volunteer studies, MYRBETRIQ was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo. In contrast, in adult OAB patients in clinical trials, MYRBETRIQ, taken as monotherapy or in combination with solifenacin succinate 5 mg, the mean increase in systolic and diastolic blood pressure at the maximum recommended mirabegron dose of 50 mg was approximately 0.5 to 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in patients taking MYRBETRIQ. Increases in Blood Pressure in Pediatric Patients 3 Years and Older MYRBETRIQ/MYRBETRIQ Granules can increase blood pressure in pediatric patients. Blood pressure increases may be larger in children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Periodic blood pressure determinations are recommended. MYRBETRIQ/MYRBETRIQ Granules is not recommended for use in pediatric patients with severe uncontrolled hypertension, defined as a systolic and/or diastolic blood pressure above the 99 th percentile plus 5 mm Hg for age, sex, and stature using appropriate reference values [see Adverse Reactions ( 6.1 )] .

5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Medications for OAB In patients taking MYRBETRIQ, urinary retention has been reported to occur in patients with bladder outlet obstruction (BOO) and in patients taking muscarinic antagonist medications for the treatment of OAB. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with mirabegron; however, MYRBETRIQ should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary retention. MYRBETRIQ should also be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB, including solifenacin succinate [see Clinical Pharmacology ( 12.2 )] .

5.3 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with MYRBETRIQ/MYRBETRIQ Granules. In some cases, angioedema occurred after the first dose, however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema, associated with upper airway swelling, may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue MYRBETRIQ/MYRBETRIQ Granules and provide appropriate therapy and/or measures necessary to ensure a patent airway [see Adverse Reactions ( 6.2 )] .

5.4 Patients Taking Drugs Metabolized by CYP2D6 Since MYRBETRIQ/MYRBETRIQ Granules is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates is increased when coadministered with MYRBETRIQ/MYRBETRIQ Granules. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] .

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Hypertension [see Warnings and Precautions ( 5.1 )]
• Urinary Retention [see Warnings and Precautions ( 5.2 )]
• Angioedema [see Warnings and Precautions ( 5.3 )]
• Most commonly reported adverse reactions with MYRBETRIQ monotherapy in adult patients with OAB (> 2% and > placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. ( 6.1 )
• Most commonly reported adverse reactions with MYRBETRIQ, in combination with solifenacin succinate in adult patients with OAB (> 2% and > placebo and > comparator), were dry mouth, urinary tract infection, constipation, and tachycardia. ( 6.1 )
• Most commonly reported adverse reactions with MYRBETRIQ/MYRBETRIQ Granules in pediatric patients with NDO (≥ 3%) were UTI, nasopharyngitis, constipation, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 clinical practice. MYRBETRIQ Monotherapy for Adult OAB In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with OAB (Studies 1, 2, and 3), MYRBETRIQ was evaluated for safety in 2736 patients [see Clinical Studies ( 14.1 )] . Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received MYRBETRIQ 25 mg, 1375 received MYRBETRIQ 50 mg, and 929 received MYRBETRIQ 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 to 95 years). MYRBETRIQ was also evaluated for safety in 1632 patients who received MYRBETRIQ 50 mg once daily (n=812 patients) or MYRBETRIQ 100 mg (n=820 patients) in a 1-year, randomized, fixed-dose, double-blind, active-controlled, safety study in patients with OAB (Study 4). Of these patients, 731 received MYRBETRIQ in a previous 12-week study. In Study 4, 1385 patients received MYRBETRIQ continuously for at least 6 months, 1311 patients received MYRBETRIQ for at least 9 months, and 564 patients received MYRBETRIQ for at least 1 year. The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2, and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness, and tachycardia. Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo. Table 8 lists the adverse reactions, derived from all adverse events, that were reported in Studies 1, 2, and 3 at an incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of MYRBETRIQ patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. Table 8: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported in ≥ 1% of OAB Patients Treated with MYRBETRIQ 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Adverse Reaction Placebo (%) MYRBETRIQ 25 mg (%) MYRBETRIQ 50 mg (%) Number of Patients 1380 432 1375 Hypertension Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension. 7.6 11.3

7.5 Nasopharyngitis 2.5 3.5

3.9 Urinary Tract Infection 1.8 4.2

2.9 Headache 3.0 2.1

3.2 Constipation 1.4 1.6

1.6 Upper Respiratory Tract Infection 1.7 2.1

1.5 Arthralgia 1.1 1.6

1.3 Diarrhea 1.3 1.2

1.5 Tachycardia 0.6 1.6

1.2 Abdominal Pain 0.7 1.4

0.6 Fatigue 1.0 1.4

1.2 Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ in Studies 1, 2, or 3 included: Cardiac disorders : palpitations, blood pressure increased [see Clinical Pharmacology ( 12.2 )] Eye disorders : glaucoma [see Clinical Pharmacology ( 12.2 )] Gastrointestinal disorders : dyspepsia, gastritis, abdominal distension Infections and Infestations : sinusitis, rhinitis Investigations : GGT increased, AST increased, ALT increased, LDH increased Renal and urinary disorders : nephrolithiasis, bladder pain Reproductive system and breast disorders : vulvovaginal pruritus, vaginal infection Skin and subcutaneous tissue disorders : urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema Table 9 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with MYRBETRIQ 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (> 3% of MYRBETRIQ patients) were hypertension, urinary tract infection, headache, and nasopharyngitis. Table 9: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported in > 2% of OAB Patients Treated with MYRBETRIQ 50 mg Once Daily in Study 4 Adverse Reaction MYRBETRIQ 50 mg (%) Active Control (%) Number of Patients 812 812 Hypertension 9.2

9.6 Urinary Tract Infection 5.9

6.4 Headache 4.1

2.5 Nasopharyngitis 3.9

3.1 Back Pain 2.8

1.6 Constipation 2.8

2.7 Dry Mouth 2.8

8.6 Dizziness 2.7

2.6 Sinusitis 2.7

1.5 Influenza 2.6

3.4 Arthralgia 2.1

2.0 Cystitis 2.1

2.3 In Study 4, in patients treated with MYRBETRIQ 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking MYRBETRIQ 50 mg; and these markers subsequently returned to baseline while both patients continued MYRBETRIQ. In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with MYRBETRIQ 50 mg, MYRBETRIQ 100 mg, and active control once daily, respectively. Neoplasms reported by 2 patients treated with MYRBETRIQ 100 mg included breast cancer, lung neoplasm malignant, and prostate cancer. A causal relationship between mirabegron and these reported neoplasms has not been established. In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST, and bilirubin in a patient taking MYRBETRIQ 100 mg as well as an herbal medication (Kyufu Gold). MYRBETRIQ Combination Therapy with Solifenacin Succinate for Adult OAB In three, 12-week, double-blind, randomized, active-controlled safety and efficacy studies in patients with OAB (Studies 5, 6, and 7), combination treatment of MYRBETRIQ and solifenacin succinate was evaluated for safety in 6818 patients [see Clinical Studies ( 14.2 )] . Studies 5 and 6 also included a placebo control. For the combined Studies 5, 6, and 7, 997 patients received combination treatment with MYRBETRIQ 25 mg and solifenacin succinate 5 mg, and 1706 patients received combination treatment with MYRBETRIQ 50 mg and solifenacin succinate 5 mg. In these studies, the majority of the patients were Caucasian (88%) and female (77%) with a mean age of 57 years (range 18 to 89 years). MYRBETRIQ 50 mg and solifenacin succinate 5 mg coadministration was also evaluated for safety in 1814 patients in a 52-week, double-blind, randomized, active-controlled study in patients with OAB (Study 8) [see Clinical Studies ( 14.2 )] . […]

Drug interaction studies were conducted in adult patients to investigate the effect of coadministered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of coadministered drugs (e.g., ketoconazole, rifampin, solifenacin succinate, tamsulosin, and oral contraceptives) [see Clinical Pharmacology ( 12.3 )] . No dose adjustment is recommended when these drugs are coadministered with mirabegron. The following are drug interactions for which monitoring is recommended:

• Drugs Metabolized by CYP2D6 : Mirabegron is a CYP2D6 inhibitor and, when used concomitantly with drugs metabolized by CYP2D6, especially narrow therapeutic index drugs, appropriate monitoring and possible dose adjustment of those drugs may be necessary. ( 5.4 , 7.1 , 12.3 )
• Digoxin : When initiating a combination of mirabegron and digoxin with or without solifenacin succinate, use the lowest dose of digoxin; monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect. ( 7.2 , 12.3 )

7.1 Drugs Metabolized by CYP2D6 Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme is increased when coadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when MYRBETRIQ/MYRBETRIQ Granules is coadministered with these drugs, especially with narrow therapeutic index CYP2D6 substrates [see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )] .

7.2 Digoxin When given in combination, 100 mg mirabegron increased mean digoxin C max from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Concomitant administration of 0.25 mg digoxin with a combination of 5 mg solifenacin and 50 mg mirabegron increased digoxin AUC tau and C max by approximately 10% and 14%, respectively. For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology ( 12.3 )] .

7.3 Warfarin The mean C max of S – and R -warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary There are no studies with the use of MYRBETRIQ/MYRBETRIQ Granules in pregnant women or adolescents to inform a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. Mirabegron administration to pregnant animals during organogenesis resulted in reversible skeletal variations (in rats) at 22-fold (via AUC) the maximum recommended human dose (MRHD) of 50 mg/day and decreased fetal body weights (in rabbits) at 14-fold the MRHD. At maternally-toxic exposures in rats (96-fold), decreased fetal weight and increased fetal mortality were observed and, in rabbits (36-fold), cardiac findings (fetal cardiomegaly and fetal dilated aortae) were observed [see Data ] . The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data No embryo-fetal lethality or morphological fetal developmental abnormalities were produced in pregnant rats following daily oral administration of mirabegron during the period of organogenesis (Days 7 to 17 of gestation) at 0, 10, 30, 100, or 300 mg/kg, doses which were associated with systemic exposures (AUC) 0, 1, 6, 22, and 96-fold the MRHD. Skeletal variations (wavy ribs, delayed ossification) were observed in fetuses at doses 22-fold the systemic exposure at the MRHD and were reversible during development. Exposures 96-fold the MRHD were maternally-toxic (mortality, decreased body weight gain) and associated with fetal growth reduction. Pregnant rabbits were treated with daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg/day during the period of organogenesis (Days 6 to 20 of gestation), which resulted in plasma exposures that were 0, 1, 14, or 36-fold the MRHD based on AUC. At 10 mg/kg/day (14-fold the MRHD) and higher, fetal body weights were reduced. At 30 mg/kg/day, maternal toxicity (increased heart rate, mortality, reduced body weight gain, reduced food consumption) occurred, and fetal deaths, fetal cardiomegaly and fetal dilated aortae were observed at systemic exposure levels (AUC) 36-fold the MRHD. In a pre- and postnatal developmental study, rats were treated with daily oral doses of mirabegron at 0, 10, 30, or 100 mg/kg/day (0, 1, 6, or 22-fold the MRHD) from day 7 of gestation until day 20 after birth. Decreased maternal body weight was observed along with decreased pup survival in the first few days after birth (92.7% survival) compared to the control group (98.8% survival), at 100 mg/kg/day (22-fold the MRHD). Pup body weight gain was reduced until postnatal day 7 but not further affected throughout the remainder of the lactation period. In utero and lactational exposure did not affect developmental milestones, behavior, or fertility of offspring. No effects were observed at 30 mg/kg/day.

8.2 Lactation Risk Summary There are no data on the presence of mirabegron in human milk, the effects on the breastfed child, or the effects on milk production. Mirabegron-related material was present in rat milk and in the stomach of nursing pups following administrations of a single 10 mg/kg oral dose of 14 C-labeled mirabegron to lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MYRBETRIQ/MYRBETRIQ Granules and any potential adverse effects on the breastfed child from mirabegron or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness have been established only for the following pediatric indications:

• MYRBETRIQ: Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35 kg or more.
• MYRBETRIQ Granules: Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older. The safety and effectiveness of MYRBETRIQ/MYRBETRIQ Granules in pediatric patients aged 3 years and older have been established for the treatment of neurogenic detrusor overactivity (NDO) and the information on this use is discussed throughout the labeling. Use of MYRBETRIQ/MYRBETRIQ Granules for this indication is supported by evidence from a 52-week, open-label, baseline-controlled, multicenter, dose titration trial in pediatric patients 3 years of age and older with NDO (Study 9) [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.3 )] . Results showed an improvement from baseline in maximum cystometric (bladder) capacity (MCC) with MYRBETRIQ/MYRBETRIQ Granules use [see Clinical Studies ( 14.3 )] . The most commonly reported adverse reactions in Study 9 (≥ 3%) were UTI, nasopharyngitis, constipation, and headache. Increased mean systolic and diastolic blood pressures with use of MYRBETRIQ/MYRBETRIQ Granules occurred in patients less than 12 years of age with larger increases in patients younger than 8 years of age [see Adverse Reactions ( 6.1 )] . Take MYRBETRIQ/MYRBETRIQ Granules with food to reduce potential exposure-related risks, such as increased heart rate, as predicted by modeling of vital signs data in Study 9 [see Clinical Pharmacology ( 12.3 )] .

8.5 Geriatric Use Of 5648 patients who received MYRBETRIQ monotherapy in the phase 2 and 3 studies for OAB, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.

8.6 Renal Impairment MYRBETRIQ/MYRBETRIQ Granules have not been studied in patients with End-Stage Renal Disease (eGFR < 15 mL/min/1.73 m 2 ) or patients requiring hemodialysis and, therefore, is not recommended for use in these patient populations. No dose adjustment is necessary in patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m 2 ). In adult patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 ), the daily dose of MYRBETRIQ should not exceed 25 mg. In pediatric patients with severe renal impairment, the daily dose of MYRBETRIQ/MYRBETRIQ Granules should not exceed the recommended starting dose [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment MYRBETRIQ/MYRBETRIQ Granules have not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, is not recommended for use in this patient population. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A). In adult patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of MYRBETRIQ should not exceed 25 mg. In pediatric patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of MYRBETRIQ/MYRBETRIQ Granules should not exceed the recommended starting dose [see Clinical Pharmacology ( 12.3 )] .

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.