RECENT MAJOR CHANGES SECTION

Highlight: Indications and Usage (1.2) 3/2021

Dosage and Administration (2) 3/2021

Warnings and Precautions, Increase in Blood Pressure (5.1) 3/2021

RECENT MAJOR CHANGES

Indications and Usage (1.2) 3/2021

Dosage and Administration (2) 3/2021

Warnings and Precautions, Increase in Blood Pressure (5.1) 3/2021

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DESCRIPTION SECTION

11 DESCRIPTION

Mirabegron extended-release tablets for oral use is a beta-3 adrenergic agonist.

The chemical name is 2-(2-Amonothiazol-4-yl)-N-(4-(2-(2R)-hydroxy-2-phenylethylamino)ethyl)phenyl)acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is:

Mirabegron is a white powder. It is practically insoluble in water. It is soluble in methanol and dimethyl sulfoxide.

Each mirabegron extended-release tablet for oral use contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, magnesium stearate, hypromellose, ferrosoferric oxide, yellow iron oxide, and red iron oxide (25 mg tablet only).

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INDICATIONS & USAGE SECTION

Highlight: Mirabegron extended-release tablets are 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. (1.1)

1 INDICATIONS AND USAGE

1.1 Adult Overactive Bladder (OAB)

Mirabegron Monotherapy

Mirabegron extended-release tablets are indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency.

Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Extended-release tablets: 25 mg and 50 mg (3)

3 DOSAGE FORMS AND STRENGTHS

Mirabegron extended-release tablets are supplied in two different strengths as described below:

• 25 mg peach colored, oval shaped, biconvex, film-coated tablets debossed with "1159" on one side and plain on other side
• 50 mg yellow colored, oval shaped, biconvex, film-coated tablets debossed with "1160" on one side and plain on other side.

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CONTRAINDICATIONS SECTION

Highlight: Hypersensitivity to mirabegron or any inactive ingredients. (4)

4 CONTRAINDICATIONS

Mirabegron extended-release tablets are contraindicated in patients with known hypersensitivity reactions to mirabegron or any inactive ingredients of the tablet [see Adverse Reactions (6.1, 6.2)].

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USE IN SPECIFIC POPULATIONS SECTION

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no studies with the use of mirabegron 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 risks of major birth defects or miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 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 14C-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 mirabegron and any potential adverse effects on the breastfed child from mirabegron or from the underlying maternal condition.

8.4 Pediatric Use

Increased mean systolic and diastolic blood pressures with use of mirabegron occurred in patients less than 12 years of age with larger increases in patients younger than 8 years of age.

Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

Of 5,648 patients who received mirabegron monotherapy in the phase 2 and 3 studies for OAB, 2,029 (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

Mirabegron have not been studied in patients with End-Stage Renal Disease (eGFR <15 mL/min/1.73 m2) 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 m2).

In adult patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), the daily dose of mirabegron should not exceed 25 mg. [see Clinical Pharmacology (12.3)].

Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

8.7 Hepatic Impairment

Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, is not recommended for use in this patient population.

In adult patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of mirabegron should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)].

Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

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CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Mirabegron 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 5.

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 12-week treatment period.

Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours, and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2, and 3.

Figure 3: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 1

Figure 4: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours - Study 1

Figure 5: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours - Study 2

Figure 6: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours - Study 2

Figure 7: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours - Study 3

Figure 8: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours - Study 3

Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

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OVERDOSAGE SECTION

10 OVERDOSAGE

Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 beats per minute (bpm) (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.

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SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

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