24 HR mirabegron 8 MG/ML Extended Release Suspension

INDICATIONS AND USAGE Mirabegron extended-release tablets are beta-3 adrenergic agonists indicated for the treatment of: • Overactive bladder (OAB) in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1.1 ) • Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older and weighing 35 kg or more. ( 1.2 ) 1.1 Adult Overactive Bladder (OAB) Mirabegron Extended-Release Tablets 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. 1.2 Pediatric Neurogenic Detrusor Overactivity (NDO) Mirabegron extended-release tablets are indicated for the treatment of NDO in pediatric patients aged 3 years and older and weighing 35 kg or more.

DOSAGE AND ADMINISTRATION Mirabegron extended-release tablets and Mirabegron Granules are two different products and they are not substitutable on a milligram-per-milligram basis. Select the recommended product (Mirabegron extended-release tablets and Mirabegron Granules) based on the indication and patient's weight. OAB in Adults The recommended starting dose of mirabegron extended-release tablets is 25 mg orally once daily. ( 2.2 ) After 4 to 8 weeks, the mirabegron extended-release tablets dose may be increased to 50 mg orally once daily. ( 2.2 ) NDO in Pediatric Patients 3 Years and Older Pediatric Patients weighing 35 kg or more: Use mirabegron extended-release tablets: The recommended starting dosage of mirabegron extended-release tablets is 25 mg orally once daily. After 4 to 8 weeks, the mirabegron extended-release tablets dose may be increased to 50 mg orally once daily. ( 2.3 ) Adult or Pediatric Patients Patients with Renal or Hepatic Impairment : Refer to the full prescribing information for recommended dosage. ( 2.4 , 2.5 ) Administration Mirabegron extended-release tablets: Adult patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with or without food. ( 2.7 ) Pediatric patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with food. ( 2.7 ) 2.1 Important Dosage Information Mirabegron extended-release tablets and Mirabegron Granules are two different products and they are not substitutable on a milligram-per-milligram basis. Select the recommended product (Mirabegron extended-release tablets and Mirabegron Granules) based on the indication and patient's weight [see Indications and Usage ( 1 ) and Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )]. 2.2 Recommended Dosage for Adult Patients with OAB Mirabegron Monotherapy The recommended starting dosage of mirabegron extended-release tablets is 25 mg orally once daily. If needed, increase to the maximum dosage of mirabegron extended-release tablets 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration ( 2.7 ). 2.3 Recommended Dosage for Pediatric Patients Aged 3 Years and Older with NDO For pediatric patients 3 years of age and older, select the appropriate product (Mirabegron extended-release tablets and Mirabegron Granules) based on the patient's weight. Pediatric Patients weighing 35 kg or more: Use mirabegron extended-release tablets The recommended starting dosage of mirabegron extended-release tablets is 25 mg orally once daily. If needed, increase to a maximum dosage of mirabegron extended-release tablets 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration (2.7) . 2.4 Recommended Dosage in Adult Patients with Renal or Hepatic Impairment Dosage in Adults with Renal Impairment The recommended dosage of mirabegron extended-release tablets (administered orally once daily) in adult patients with renal impairment is described in Table 1 [see Use in Specific Populations ( 8.6 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 1: Mirabegron Extended-Release Tablets Recommended Dosage in Adult Patients with Renal Impairment (Administered Orally Once Daily) Estimated GFR 1 Starting Dose Maximum Dose eGFR 30 to 89 mL/min/1.73 m 2 25 mg 50 mg eGFR 15 to 29 mL/min/1.73 m 2 25 mg 25 mg eGFR < 15 mL/min/1.73 m 2 or requiring dialysis Not Recommended 1. Estimated GFR using the modification of diet in renal disease (MDRD) formula Dosage in Adults with Hepatic Impairment The recommended dosage of mirabegron extended-release tablets (administered orally once daily) in adult patients with hepatic impairment is described in Table 2 [see Use in Specific Populations ( 8.7 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 2: Mirabegron Recommended Dosage in Adult Patients with Hepatic Impairment (Administered Orally Once Daily) Hepatic Impairment Classification Starting Dose Maximum Dose Child-Pugh Class A ( Mild hepatic impairment 25 mg 50 mg Child-Pugh Class B ( Moderate hepatic impairment 25 mg 25 mg Child-Pugh Class C ( Severe hepatic impairment Not Recommended 2.5 Recommended Dosage in Pediatric Patients with Renal or Hepatic Impairment For pediatric patients 3 years of age and older, select the appropriate product (Mirabegron extended-release tablets and Mirabegron Granules) based on the patient's weight. Pediatric Patients weighing 35 kg or more with renal or hepatic impairment: Use Mirabegron Extended-Release Tablets Dosage in Pediatric Patients with Renal Impairment The recommended dosage of mirabegron extended-release tablets in pediatric patients with renal impairment weighing 35 kg or more (administered orally once daily) is described in Table 1 (above). Note that the dosage is the same as for adult patients with renal impairment [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] . For administration instructions, see Dosage and Administration (2.7) . Dosage in Pediatric Patients with Hepatic Impairment The recommended dosage of mirabegron extended-release tablets in pediatric patients with hepatic impairment weighing 35 kg or more (administered orally once daily) is described in Table 2 (above). Note that the dosage is the same as for adult patients with hepatic impairment [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ] . For administration instructions, see Dosage and Administration (2.7) . 2.7 Administration Instructions Mirabegron extended-release tablets Adult patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with or without food. Pediatric patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with food [see Use in Specific Populations (8.4) ] . 2.8 Missed Dose Instruct patients to take any missed doses as soon as they remember, unless more than 12 hours have passed since the missed dose. If more than 12 hours have passed, the missed dose can be skipped, and the next dose should be taken at the usual time.

WARNINGS AND PRECAUTIONS Increases in Blood Pressure : Can increase blood pressure in adult patients. Periodically monitor blood pressure, especially in hypertensive patients. Mirabegron extended-release tablets 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 Mirabegron extended-release tablets can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Mirabegron extended-release tablets are 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, mirabegron extended-release tablets were 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, mirabegron extended-release tablets, taken as monotherapy, 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 mirabegron extended-release tablets. Increases in Blood Pressure in Pediatric Patients 3 Years and Older Mirabegron extended-release tablets 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. Mirabegron extended-release tablets 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. 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. 5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Medications for OAB In patients taking mirabegron extended-release tablets, 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, mirabegron extended-release tablets should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary retention. Mirabegron extended-release tablets should also be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB [see Clinical Pharmacology ( 12.2 )] . 5.3 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with mirabegron extended-release tablets. 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 mirabegron extended-release tablets 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 mirabegron extended-release tablet is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates is increased when coadministered with mirabegron extended-release tablet. 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 )] .

CONTRAINDICATIONS Hypersensitivity to mirabegron or any inactive ingredients. ( 4 ) 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 )] .

Mechanism 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.