` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`213801Orig1s000
`
`
`LABELING
`
`
`
`Administration
`MYRBETRIQ:
`(cid:120)
`o
`Adult patients: Swallow MYRBETRIQ whole with water. Do not
`chew, divide, or crush. Take with or without food. (2.7)
`o
`Pediatric patients: Swallow MYRBETRIQ whole with water. Do
`not chew, divide, or crush. Take with food. (2.7)
`MYRBETRIQ Granules:
`o
`Pediatric patients: Take MYRBETRIQ Granules prepared as an
`extended-release oral suspension. Take with food. (2.7)
`
`(cid:120)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Extended-release tablets: 25 mg and 50 mg (3)
`(cid:120)
`For extended-release oral suspension: 8 mg/mL of mirabegron after
`(cid:120)
`reconstitution (3)
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`Hypersensitivity to mirabegron or any inactive ingredients. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Increases in Blood Pressure: Can increase blood pressure in adult or
`(cid:120)
`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)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`Most commonly reported adverse reactions with MYRBETRIQ
`(cid:120)
`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
`(cid:11)(cid:149) 3%) were UTI, nasopharyngitis, constipation, and headache. (6.1)
`
`(cid:120)
`
`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.
`
`------------------------------ DRUG INTERACTIONS -----------------------------
`Drugs Metabolized by CYP2D6: Mirabegron is a CYP2D6 inhibitor
`(cid:120)
`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)
`
`(cid:120)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 3/2021
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`MYRBETRIQ®/MYRBETRIQ® GRANULES safely and effectively. See
`full prescribing information for MYRBETRIQ/MYRBETRIQ
`GRANULES.
`
`MYRBETRIQ (mirabegron extended-release tablets), for oral use
`MYRBETRIQ GRANULES (mirabegron for extended-release oral
`suspension)
`Initial U.S. Approval: 2012
`
`-------------------------- RECENT MAJOR CHANGES --------------------------
`Indications and Usage (1.2)
`M/YYYY
`Dosage and Administration (2)
`M/YYYY
`Warnings and Precautions, Increase in Blood Pressure (5.1)
`M/YYYY
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`MYRBETRIQ is a beta-3 adrenergic agonist indicated for the treatment of:
`Overactive bladder (OAB) in adult patients with symptoms of urge
`(cid:120)
`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)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`MYRBETRIQ and MYRBETRIQ Granules are two different products
`(cid:120)
`and they are not substitutable on a milligram-per-milligram basis. Select
`the recommended product (MYRBETRIQ or MYRBETRIQ Granules)
`based on the indication and patient’s weight. Do not combine
`MYRBETRIQ and MYRBETRIQ Granules to achieve the total dose. A
`recommended dosage for MYRBETRIQ Granules for adults has not
`been determined. (2.1)
`OAB in Adults
`The recommended starting dose of MYRBETRIQ is 25 mg orally once
`(cid:120)
`daily, either alone or in combination with solifenacin succinate 5 mg
`orally once daily. (2.2)
`After 4 to 8 weeks, the MYRBETRIQ dose may be increased to 50 mg
`orally once daily. (2.2)
`NDO in Pediatric Patients 3 Years and Older
`Pediatric Patients weighing less than 35 kg: Use MYRBETRIQ
`(cid:120)
`Granules: The recommended starting dose of MYRBETRIQ Granules is
`weight-based and administered as an extended-release oral suspension
`once daily. After 4 to 8 weeks, increase to the lowest effective dose
`without exceeding the maximum recommended dose. (2.3)
`Pediatric Patients weighing 35 kg or more: Use MYRBETRIQ or
`MYRBETRIQ Granules:
`o
`The recommended starting dosage of MYRBETRIQ is 25 mg
`orally once daily. After 4 to 8 weeks, the MYRBETRIQ dose may
`be increased to 50 mg orally once daily. (2.3)
`The recommended starting dosage of MYRBETRIQ Granules,
`administered as an extended-release oral suspension, is 6 mL
`(48 mg) orally once daily. After 4 to 8 weeks, increase to a
`maximum dosage of MYRBETRIQ Granules 10 mL (80 mg)
`orally once daily (2.3)
`Adult or Pediatric Patients with Renal or Hepatic Impairment: Refer to the full
`prescribing information for recommended dosage. (2.4, 2.5)
`Preparation for MYRBETRIQ Granules: Refer to the full prescribing
`information. (2.6)
`
`o
`
`Reference ID: 4768327
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Adult Overactive Bladder (OAB)
`1.2 Pediatric Neurogenic Detrusor Overactivity (NDO)
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Dosage Information
`2.2 Recommended Dosage for Adult Patients with OAB
`2.3 Recommended Dosage for Pediatric Patients Aged 3 Years and Older
`with NDO
`2.4 Recommended Dosage in Adult Patients with Renal or Hepatic
`Impairment
`2.5 Recommended Dosage in Pediatric Patients with Renal or Hepatic
`Impairment
`2.6 Preparation and Storage Instructions for MYRBETRIQ Granules
`2.7 Administration Instructions
`2.8 Missed Dose
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Increases in Blood Pressure
`5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in
`Patients Taking Muscarinic Antagonist Medications for OAB
`5.3 Angioedema
`5.4 Patients Taking Drugs Metabolized by CYP2D6
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Drugs Metabolized by CYP2D6
`7.2 Digoxin
`7.3 Warfarin
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 MYRBETRIQ Monotherapy for Adult OAB
`14.2 MYRBETRIQ Combination Therapy for Adult OAB
`14.3 MYRBETRIQ/MYRBETRIQ Granules for Pediatric Neurogenic
`Detrusor Overactivity (NDO)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 MYRBETRIQ (mirabegron extended-release tablets)
`16.2 MYRBETRIQ Granules (mirabegron for extended-release oral
`suspension)
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`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.
`
`Reference ID: 4768327
`
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Dosage Information
`MYRBETRIQ and MYRBETRIQ Granules are two different products and they are not substitutable on a milligram-per-
`milligram basis:
`
`(cid:120)
`
`Select the recommended product (MYRBETRIQ or MYRBETRIQ 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)].
`(cid:120) Do not combine MYRBETRIQ and MYRBETRIQ Granules to achieve the total dose.
`(cid:120) A recommended dosage for MYRBETRIQ Granules for adults has not been determined.
`
`2.2 Recommended Dosage for Adult Patients with OAB
`MYRBETRIQ Monotherapy
`The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily. If needed, increase to the maximum
`dosage of MYRBETRIQ 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and
`Administration (2.7).
`
`MYRBETRIQ Combination Therapy with Solifenacin Succinate
`The recommended starting dosage for combination treatment is MYRBETRIQ 25 mg orally once daily and solifenacin
`succinate 5 mg orally once daily. If needed, increase to the maximum dosage of MYRBETRIQ 50 mg orally once daily
`after 4 to 8 weeks. Refer to the Prescribing Information for solifenacin succinate for additional information. 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 (MYRBETRIQ or MYRBETRIQ Granules)
`based on the patient’s weight.
`
`Pediatric Patients weighing less than 35 kg: Use MYRBETRIQ Granules
`The recommended starting and maximum doses of MYRBETRIQ Granules, administered as extended-release oral
`suspension once daily [see Dosage and Administration (2.6)], are shown in Table 1. The recommended dosages are
`determined based on patient weight. Evaluate patients periodically for potential dosage adjustment. For administration
`instructions, see Dosage and Administration (2.7).
`
`Table 1: MYRBETRIQ Granules Recommended Dosage for Pediatric Patients Aged 3 Years and Older Weighing
`Less Than 35 kg as an Extended-Release Oral Suspension (Administered Orally Once Daily)
`
`Body Weight Range
`11 kg to less than 22 kg
`22 kg to less than 35 kg
`Greater than or equal to 35 kg
`
`Maximum Volume
`Starting Dose
`6 mL (48 mg)
`3 mL (24 mg)
`8 mL (64 mg)
`4 mL (32 mg)
`Refer to information in next section
`
`Pediatric Patients weighing 35 kg or more: Use MYRBETRIQ or MYRBETRIQ Granules
`The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily. If needed, increase to a maximum dosage
`of MYRBETRIQ 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and
`Administration (2.7).
`
`The recommended starting dosage of MYRBETRIQ Granules is 6 mL (48 mg) orally once daily. If needed, increase to a
`maximum dosage of MYRBETRIQ Granules 10 mL (80 mg) orally once daily after 4 to 8 weeks. For administration
`instructions, see Dosage and Administration (2.7).
`
`Reference ID: 4768327
`
`
`
`2.4 Recommended Dosage in Adult Patients with Renal or Hepatic Impairment
`Dosage in Adults with Renal Impairment
`The recommended dosage of MYRBETRIQ (administered orally once daily) in adult patients with renal impairment is
`described in Table 2 [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage and
`Administration (2.7).
`
`Table 2: MYRBETRIQ Recommended Dosage in Adult Patients with Renal Impairment (Administered Orally
`Once Daily)
`
`Estimated GFR1
`eGFR 30 to 89 mL/min/1.73 m2
`eGFR 15 to 29 mL/min/1.73 m2
`eGFR < 15 mL/min/1.73 m2 or requiring dialysis
`1.
`Estimated GFR using the modification of diet in renal disease (MDRD) formula
`
`Starting Dose
`25 mg
`25 mg
`
`Maximum Dose
`50 mg
`25 mg
`
`Not recommended
`
`Dosage in Adults with Hepatic Impairment
`The recommended dosage of MYRBETRIQ (administered orally once daily) in adult patients with hepatic impairment is
`described in Table 3 [see Use in Specific Populations (8.7)]. For administration instructions, see Dosage and
`Administration (2.7).
`
`Table 3: MYRBETRIQ Recommended Dosage in Adult Patients with Hepatic Impairment (Administered Orally
`Once Daily)
`
`Hepatic Impairment Classification
`Child-Pugh Class A (Mild hepatic impairment)
`Child-Pugh Class B (Moderate hepatic impairment)
`Child-Pugh Class C (Severe hepatic impairment)
`
`Starting Dose
`25 mg
`25 mg
`
`Maximum Dose
`50 mg
`25 mg
`
`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 (MYRBETRIQ or MYRBETRIQ Granules)
`based on the patient’s weight.
`
`Pediatric Patients Weighing Less Than 35 kg with Renal or Hepatic Impairment: Use MYRBETRIQ Granules
`Dosage in Pediatric Patients with Renal Impairment
`The recommended dosage of MYRBETRIQ Granules in pediatric patients with renal impairment (administered orally
`once daily) is described in Table 4 [see Use in Specific Populations (8.6)]. For administration instructions, see Dosage
`and Administration (2.7).
`
`Table 4: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older Weighing
`Less Than 35 kg with Renal Impairment (Administered Orally Once Daily)
`
`Estimated GFR1
`eGFR 30 to 89 mL/min/1.73 m2
`
`Starting Dose Maximum Dose
`Body Weight Range
`3 mL (24 mg)
`6 mL (48 mg)
`11 kg to less than 22 kg
`4 mL (32 mg)
`8 mL (64 mg)
`22 kg to less than 35 kg
`3 mL (24 mg)
`3 mL (24 mg)
`11 kg to less than 22 kg
`eGFR 15 to 29 mL/min/1.73 m2
`4 mL (32 mg)
`4 mL (32 mg)
`22 kg to less than 35 kg
`Use is Not Recommended
`eGFR < 15 mL/min/1.73 m2 or undergoing dialysis
`1.
`Estimate GFR using a validated eGFR estimating equation for the pediatric age range of the approved indication.
`
`Reference ID: 4768327
`
`
`
`Dosage in Pediatric Patients with Hepatic Impairment
`The recommended dosage of MYRBETRIQ Granules in pediatric patients with hepatic impairment (administered orally
`once daily) is described in Table 5 [see Use in Specific Populations (8.7)]. For administration instructions, see Dosage
`and Administration (2.7).
`
`Table 5: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older Weighing
`Less Than 35 kg with Hepatic Impairment (Administered Orally Once Daily)
`
`Hepatic Impairment Classification
`Child-Pugh Class A (Mild hepatic impairment)
`
`Child-Pugh Class B (Moderate hepatic impairment)
`Child-Pugh Class C (Severe hepatic impairment)
`
`Starting Dose Maximum Dose
`Body Weight Range
`3 mL (24 mg)
`6 mL (48 mg)
`11 kg to less than 22 kg
`4 mL (32 mg)
`8 mL (64 mg)
`22 kg to less than 35 kg
`3 mL (24 mg)
`3 mL (24 mg)
`11 kg to less than 22 kg
`4 mL (32 mg)
`4 mL (32 mg)
`22 kg to less than 35 kg
`Use is Not Recommended
`
`Pediatric Patients weighing 35 kg or more with renal or hepatic impairment: Use MYRBETRIQ or MYRBETRIQ
`Granules
`Dosage in Pediatric Patients with Renal Impairment
`The recommended dosage of MYRBETRIQ in pediatric patients with renal 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
`renal impairment [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)]. For administration
`instructions, see Dosage and Administration (2.7).
`
`The recommended dosage of MYRBETRIQ Granules in pediatric patients with renal impairment weighing 35 kg or more
`(administered orally once daily) is described in Table 6 [see Use in Specific Populations (8.6)]. For administration
`instructions, see Dosage and Administration (2.7).
`
`Table 6: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older with Renal
`Impairment Weighing 35 kg or More (Administered Orally Once Daily)
`
`Maximum Dose
`Starting Dose
`Estimated GFR1
`10 mL (80 mg)
`6 mL (48 mg)
`eGFR 30 to 89 mL/min/1.73 m2
`6 mL (48 mg)
`6 mL (48 mg)
`eGFR 15 to 29 mL/min/1.73 m2
`Use is Not Recommended
`eGFR < 15 mL/min/1.73 m2 or undergoing dialysis
`1.
`Estimate GFR using a validated eGFR estimating equation for the pediatric age range of the approved indication.
`
`Dosage in Pediatric Patients with Hepatic Impairment
`The recommended dosage of MYRBETRIQ in pediatric patients with hepatic impairment weighing 35 kg or more
`(administered orally once daily) is described in Table 3 (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).
`
`The recommended dosage of MYRBETRIQ Granules in pediatric patients with hepatic impairment weighing 35 kg or
`more (administered orally once daily) is described in Table 7 [see Use in Specific Populations (8.7)]. For administration
`instructions, see Dosage and Administration (2.7).
`
`Table 7: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older with
`Hepatic Impairment Weighing 35 kg or More (Administered Orally Once Daily)
`
`Hepatic Impairment Classification
`Child-Pugh Class A (Mild hepatic impairment)
`Child-Pugh Class B (Moderate hepatic impairment)
`Child-Pugh Class C (Severe hepatic impairment)
`
`Maximum Dose
`Starting Dose
`10 mL (80 mg)
`6 mL (48 mg)
`6 mL (48 mg)
`6 mL (48 mg)
`Use is Not Recommended
`
`Reference ID: 4768327
`
`
`
`2.6 Preparation and Storage Instructions for MYRBETRIQ Granules
`The required dose for MYRBETRIQ Granules (mirabegron for extended-release oral suspension) is calculated based on
`the weight of the patient. Prepare oral suspension at the time of dispensing.
`
`Keep the bottle in the pouch up until the time of reconstitution.
`
`(cid:120) Discard the pouch and desiccant prior to reconstitution. Do not dispense.
`(cid:120) Tap the closed bottle several times to loosen the granules.
`(cid:120) Measure 100 mL of water, add the total amount to the bottle, and immediately shake vigorously for 1 minute, then
`let it stand for 10 to 30 minutes. Shake vigorously again for 1 minute.
`If granules have not dispersed, shake vigorously for another 1 minute.
`(cid:120)
`(cid:120) Record the 28-day expiration date on the container and carton based on the reconstitution date.
`(cid:120) Give the patient an appropriate dosing device.
`Store the reconstituted suspension at 20°C to 25°C (68°F to 77°F) for up to 28 days.
`(cid:120)
`(cid:120) Discard the unused portion after 28 days [see How Supplied/Storage and Handling (16.2)].
`
`After reconstitution with 100 mL water, the suspension contains 8 mg/mL of mirabegron.
`
`2.7 Administration Instructions
`Administration instructions for MYRBETRIQ and MYRBETRIQ Granules differ based on the patient population.
`
`MYRBETRIQ
`Adult patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with or without food.
`Pediatric patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with food [see Use in
`Specific Populations (8.4)].
`
`MYRBETRIQ Granules
`Adult patients: A recommended dosage for MYRBETRIQ Granules for adults has not been determined.
`Pediatric patients: Take MYRBETRIQ Granules prepared as an extended-release oral suspension [see Dosage and
`Administration (2.6)]. Take with food to reduce potential exposure-related risks [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.
`3 DOSAGE FORMS AND STRENGTHS
`
`MYRBETRIQ (mirabegron extended-release tablets) are supplied in two different strengths as described below:
`
`(cid:120)
`(cid:120)
`
`25 mg oval, brown, film-coated tablet, debossed with the
`50 mg oval, yellow, film-coated tablet, debossed with the
`
`(Astellas logo) and “325”
`(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.
`4 CONTRAINDICATIONS
`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)].
`
`Reference ID: 4768327
`
`
`
`5 WARNINGS AND PRECAUTIONS
`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
`99th 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)].
`
`Reference ID: 4768327
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`
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`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in more detail in other sections of the labeling.
`
`(cid:120) Hypertension [see Warnings and Precautions (5.1)]
`(cid:120) Urinary Retention [see Warnings and Precautions (5.2)]
`(cid:120) Angioedema [see Warnings and Precautions (5.3)]
`
`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.
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`Reference ID: 4768327
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`
`
`Table 8: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo
`(cid:53)(cid:68)(cid:87)(cid:72) (cid:68)(cid:81)(cid:71) (cid:53)(cid:72)(cid:83)(cid:82)(cid:85)(cid:87)(cid:72)(cid:71) (cid:76)(cid:81) (cid:149) 1% of OAB Patients Treated with MYRBETRIQ 25 mg or 50 mg Once Daily in Studies 1,
`2, and 3
`
`MYRBETRIQ 50 mg
`MYRBETRIQ 25 mg
`Placebo
`Adverse Reaction
`(%)
`(%)
`(%)
`1375
`432
`1380
`Number of Patients
`7.5
`11.3
`7.6
`Hypertension1
`3.9
`3.5
`2.5
`Nasopharyngitis
`2.9
`4.2
`1.8
`Urinary Tract Infection
`3.2
`2.1
`3.0
`Headache
`1.6
`1.6
`1.4
`Constipation
`Upper Respiratory Tract
`1.5
`2.1
`1.7
`Infection
`1.3
`1.6
`1.1
`Arthralgia
`1.5
`1.2
`1.3
`Diarrhea
`1.2
`1.6
`0.6
`Tachycardia
`0.6
`1.4
`0.7
`Abdominal Pain
`1.2
`1.4
`1.0
`Fatigue
`Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline
`hypertension.
`
`1.
`
`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
`Number of Patients
`Hypertension
`Urinary Tract Infection
`Headache
`Nasopharyngitis
`Back Pain
`Constipation
`Dry Mouth
`Dizziness
`Sinusitis
`Influenza
`Arthralgia
`Cystitis
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`Reference ID: 4768327
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`MYRBETRIQ 50 mg
`(%)
`812
`9.2
`5.9
`4.1
`3.9
`2.8
`2.8
`2.8
`2.7
`2.7
`2.6
`2.1
`2.1
`
`Active Control
`(%)
`812
`9.6
`6.4
`2.5
`3.1
`1.6
`2.7
`8.6
`2.6
`1.5
`3.4
`2.0
`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, d