CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`213801Orig1s000
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`CLINICAL REVIEW(S)
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`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`CLINICAL REVIEW
`Application Type NDA and sNDA
`Application Number(s) NDA 213801 and sNDA 202622/s-017
`Priority or Standard Priority
`Submit Date(s) September 28, 2020
`Received Date(s) September 28, 2020
`PDUFA Goal Date March 28, 2021
`Division/Office DUOG/ORPURM
`Reviewer Name(s) Elena Boley
`Review Completion Date March 18, 2021
`Established/Proper Name Mirabegron for extended-release oral suspension
`Mirabegron extended-release tablets
`(Proposed) Trade Name MYRBETRIQ® Granules
`MYRBETRIQ®
`Applicant Astellas Pharma Global Development, Inc.
`Dosage Form(s) Extended-release oral suspension 8mg/mL
`Extended-release tablets 25mg and 50mg
`Mirabegron for extended-release oral suspension:
`The recommended dose of MYRBETRIQ® Granules is determined
`based on patient weight. Treatment should be initiated at the
`recommended starting dose (see Table). After 4 to 8 weeks, based
`on individual efficacy and safety, dosage may be increased to the
`lowest effective dose, but should not exceed the maximum
`recommended dose.
`
`
`Applicant Proposed
`Dosing Regimen(s)
`
`Starting Dose1 Maximum Volume1
`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
`Greater than or equal to 35 kg2
`6 mL (48 mg)
`10 mL (80 mg)
`1MYRBETRIQ Granules for oral suspension formulation (granules were
`reconstituted with water to prepare a suspension with a concentration of 8 mg/mL
`suspension).
`2Patients ≥ 35 kg who cannot swallow tablets may take a suspension dose.
`
`Mirabegron extended-release tablets:
`For Pediatric Patients ≥ 35 kg, the recommended starting dose of
`MYRBETRIQ is 25 mg once daily. Based on individual patient
`efficacy and tolerability, the dose may be increased to 50 mg once
`daily after 4 to 8 weeks.
`Oral suspension: Neurogenic detrusor overactivity (NDO) in
`pediatric patients aged 3 years and older
`Tablets: NDO in pediatric patients aged 3 years and older and
`weighing 35 kg or more.
`Approval
`
`Applicant Proposed
`Indication(s)/Population(s)
`
`Recommendation on
`Regulatory Action
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`1
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`2
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Table of Contents
`
`
`Glossary .......................................................................................................................................... 9
`1. Executive Summary ............................................................................................................... 12
` Product Introduction ....................................................................................................... 12
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 12
` Benefit-Risk Assessment ................................................................................................ 12
` Patient Experience Data ................................................................................................. 20
`2. Therapeutic Context .............................................................................................................. 20
` Analysis of Condition..................................................................................................... 20
` Analysis of Current Treatment Options ......................................................................... 21
`3. Regulatory Background ......................................................................................................... 22
` U.S. Regulatory Actions and Marketing History ........................................................... 22
` Summary of Presubmission/Submission Regulatory Activity ....................................... 23
` Foreign Regulatory Actions and Marketing History ...................................................... 25
`4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ............................................................................................................... 25
` Office of Scientific Investigations (OSI) ....................................................................... 25
` Office of Product Quality (OPQ) ................................................................................... 25
` Clinical Microbiology .................................................................................................... 26
` Nonclinical Pharmacology/Toxicology .......................................................................... 26
` Clinical Pharmacology ................................................................................................... 26
` Devices and Companion Diagnostic Issues ................................................................... 27
` Consumer Study Reviews .............................................................................................. 27
` Division of Medication Error Prevention and Analysis (DMEPA) ............................... 27
` Division of Medical Policy Programs (DMPP) and Office of Prescription Drug
`Promotion (OPDP) .................................................................................................................... 28
` Division of Epidemiology (DEPI) .............................................................................. 28
` Division of Risk Management (DRISK) .................................................................... 28
` Division of Pharmacovigilance (DPV) ....................................................................... 28
`5. Sources of Clinical Data and Review Strategy ...................................................................... 28
` Table of Clinical Studies ................................................................................................ 28
` Review Strategy ............................................................................................................. 35
`6. Review of Relevant Individual Trials Used to Support Efficacy .......................................... 35
` Study 178-CL-206A ....................................................................................................... 35
` Study Design ........................................................................................................... 35
` Study Results .......................................................................................................... 46
`Integrated Review of Effectiveness ....................................................................................... 75
` Assessment of Efficacy Across Trials ............................................................................ 75
` Additional Efficacy Considerations ............................................................................... 76
` Considerations on Benefit in the Postmarket Setting ............................................. 76
` Other Relevant Benefits .......................................................................................... 76
`Integrated Assessment of Effectiveness ......................................................................... 76
`
`8. Review of Safety ................................................................................................................... 77
` Safety Review Approach ................................................................................................ 77
`
`7.
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`3
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
` Review of the Safety Database ....................................................................................... 77
` Overall Exposure .................................................................................................... 78
` Relevant characteristics of the safety population .................................................... 79
` Adequacy of the safety database ............................................................................. 79
` Adequacy of Applicant’s Clinical Safety Assessments ................................................. 79
` Issues Regarding Data Integrity and Submission Quality ...................................... 79
` Categorization of Adverse Events .......................................................................... 80
` Routine Clinical Tests ............................................................................................. 80
` Safety Results ................................................................................................................. 80
` Serious Adverse Events .......................................................................................... 82
` Dropouts and/or Discontinuations Due to Adverse Effects .................................... 96
` Adverse Events ....................................................................................................... 97
` Treatment Emergent Adverse Events and Adverse Reactions ............................... 98
` Laboratory Findings .............................................................................................. 109
` Vital Signs ............................................................................................................. 110
` Electrocardiograms (ECGs) .................................................................................. 123
` QT ......................................................................................................................... 125
` Immunogenicity .................................................................................................... 125
` Urinary Tract Ultrasound and PVR ............................................................... 125
` Analysis of Submission-Specific Safety Issues ........................................................... 127
` Submission-Specific Safety Issues ....................................................................... 127
` Safety Analyses by Demographic Subgroups .............................................................. 128
` Specific Safety Studies/Clinical Trials ......................................................................... 129
` Interdisciplinary Review Team for QT Studies Consult ....................................... 129
` DPMH Consult...................................................................................................... 129
` Additional Safety Explorations .................................................................................... 129
` Human Carcinogenicity or Tumor Development ................................................. 129
` Human Reproduction and Pregnancy ................................................................... 129
` Pediatrics and Assessment of Effects on Growth ................................................. 129
` Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 131
` Safety in the Postmarket Setting .................................................................................. 131
` Safety Concerns Identified Through Postmarket Experience ............................... 131
` Expectations on Safety in the Postmarket Setting ................................................ 137
`Integrated Assessment of Safety............................................................................... 137
`
`9. Advisory Committee Meeting and Other External Consultations ....................................... 139
`10. Labeling Recommendations ................................................................................................ 139
`Prescription Drug Labeling ...................................................................................... 139
`
` Nonprescription Drug Labeling ................................................................................ 140
`11. Risk Evaluation and Mitigation Strategies (REMS)............................................................ 140
`12. Postmarketing Requirements and Commitments ................................................................ 140
`13. Appendices .......................................................................................................................... 140
`References ................................................................................................................ 140
`
`Financial Disclosure ................................................................................................. 140
`
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`4
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`Table of Tables
`
`
`Table 1 Available Treatments for Pediatric Neurogenic Detrusor Overactivity (NDO) .............. 22
`Table 2 Listing of Clinical Trials Relevant to this NDA/sNDA ................................................... 30
`Table 3 Weight-based Doses for Mirabegron Tablets or Oral Suspension ................................. 37
`Table 4 Study Flow Chart ............................................................................................................ 38
`Table 5 Schedule of Assessments ................................................................................................ 41
`Table 6 Summary of Patient Disposition and Analysis Sets, Study 178-CL-206A...................... 47
`Table 7 Protocol Deviations in Patients who Received ≥ 1 Dose of Mirabegron (All Allocated
`Set) for Study 178-CL-206A ........................................................................................................ 48
`Table 8 Summary of Demographics and Baseline Characteristics for Study 178-CL-206A (SAF)
`....................................................................................................................................................... 49
`Table 9 Neurogenic Detrusor Overactivity Diagnosis and History (SAF); Study 178-CL-206A.
`....................................................................................................................................................... 51
`Table 10 Overview of NDO Therapies Prior to Study Drug Administration in Study 178-CL-
`206A (SAF) ................................................................................................................................... 52
`Table 11 Summary of Study Drug Dosing; Study 178-CL-206A (SAF) ..................................... 53
`Table 12 Summary of Study Drug Compliance and Exposure over the Whole Treatment Period;
`Study 178-CL-206A (SAF)........................................................................................................... 53
`Table 13 Change from Baseline in Maximum Cystometric Capacity* (mL) at Week 24 – LOCF
`(FAS); Study 178-CL-206A ......................................................................................................... 54
`Table 14 Summary of Maximum Cystometric Capacity (mL) by Study Week (FAS); Study 178-
`CL-206A ....................................................................................................................................... 55
`Table 15 Results of Secondary Analyses of Change from Baseline in MCC at 24 weeks using
`different statistical approaches (without and with LOCF, BOCF) for different populations; Study
`178-CL-206A ................................................................................................................................ 56
`Table 16 Secondary Analyses of Change from Baseline to Week 24 in MCC (mL): Repeated
`Measures Analysis (FAS and PPS), Study 178-CL-206A ............................................................ 57
`Table 17 Secondary Analysis of Change from Baseline to Week 24 (With and Without LOCF)
`in MCC (mL): Wilcoxon Signed-rank Test (FAS), Study 178-CL-206A .................................... 58
`Table 18 Sensitivity Analysis of the Primary Estimand in MCC (mL): Repeated Measures
`Analysis (FAS), Study 178-CL-206A........................................................................................... 58
`Table 19 Change from Baseline in Urodynamic Endpoints at Week 4 and Week 24 (FAS); Study
`178-CL-206A ................................................................................................................................ 60
`Table 20 Change From Baseline in Secondary Efficacy Endpoints based on Urodynamic Studies
`for each Age Group at 4 and 24 Weeks (FAS); 178-CL-206A .................................................... 62
`Table 21 Change From Baseline to Weeks 4, 24, and 52 in Average Catheterized Volume per
`Catheterization (mL) (FAS); Study 178-CL-206A ....................................................................... 63
`Table 22 Change From Baseline to Weeks 4, 24, and 52 in Maximum Catheterized
`Volume per Catheterization (mL) (FAS); Study 178-CL-206A ................................................... 63
`Table 23 Change From Baseline to Weeks 4, 24, and 52 in Maximum Catheterized Daytime
`Volume (mL) (FAS); Study 178-CL-206A .................................................................................. 64
`Table 24 Change From Baseline to Weeks 4, 24 and 52 in Average Morning Catheterized
`Volume (mL) (FAS); Study 178-CL-206A .................................................................................. 65
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`5
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Table 25 Change From Baseline to Weeks 4, 24 and 52 in Mean Number of Leakage Episodes
`per Day (Day and Night Time): Ad-hoc Analysis With Imputation (FAS); Study 178-CL-206A
`....................................................................................................................................................... 66
`Table 26 Change From Baseline to Weeks 4, 24 and 52 in Mean Number of Leakage Episodes
`per Day (Day and Night Time): Ad-hoc Analysis With Imputation and Excluding 1 Child’s Data
`(FAS); Study 178-CL-206A ......................................................................................................... 67
`Table 27 Change From Baseline at Each Visit in Mean Number of Leakage Episodes per Day
`(Day and Night Time): Ad-hoc Analysis (new algorithm, version 2), excluding data from Subject
` Study 178-CL-206A................................................................................................ 68
`Table 28 Change From Baseline to Weeks 4, 24 and 52 in Number of Dry (Leakage-free) Days
`per 7 Days (Day and Night Time) (FAS), Study 178-CL-206A ................................................... 69
`Table 29 Change From Baseline to Weeks 24 and 52 in Total Patient Global Impression of
`Severity Scale Score (FAS), Study 178-CL-206A ....................................................................... 70
`Table 30 Total Clinician Global Impression of Change at Weeks 24 and 52 (FAS), Study 178-
`CL-206A ....................................................................................................................................... 71
`Table 31 Subgroup Analysis of Change from Baseline to Week 24 (LOCF) in Maximum
`Cystometric Capacity (mL): Effect of Sex (FAS), Study 178-CL-206A ..................................... 72
`Table 32 Subgroup Analysis of Maximum Cystometric Capacity (mL) at Week 24 (LOCF) by
`Race (FAS), Study 178-CL-206A................................................................................................. 73
`Table 33 Subgroup Analysis of Change from Baseline to Week 24 (LOCF) in Maximum
`Cystometric Capacity (mL) by Formulation (FAS) ...................................................................... 73
`Table 34 Pediatric Studies Safety Population in the Mirabegron Pediatric NDO Development
`Program ......................................................................................................................................... 78
`Table 35 Overview of Treatment-emergent Adverse Events (SAF); Study 178-CL-206A ......... 80
`Table 36 Overview of TEAEs and Death (SAF); Studies 178-CL-202 and 178-CL-203 ........... 81
`Table 37 Serious TEAEs (SAF); Study 178-CL-206A ................................................................. 82
`Table 38 Serious Treatment-emergent Adverse Events (SAF) .................................................... 83
`Table 39 Treatment-emergent Adverse Events Leading to Permanent Discontinuation (SAF) .. 96
`Table 40 Treatment-Emergent Adverse Events by Severity (SAF) ............................................. 98
`Table 41 TEAEs in at Least 2% of All Patients (SAF); Study 178-CL-206A ............................ 98
`Table 42 Percentages of Patients with Adverse Reactions Reported in ≥ 2% of Patients in Study
`178-CL-206A (SAF) ................................................................................................................... 100
`Table 43 Drug-related* TEAEs in Study 178-CL-206A (SAF) ................................................ 100
`Table 44 TEAEs in at Least 2% of All Patients (SAF); Study 178-CL-202 and 128-CL-203 ... 101
`Table 45 Overview of Incidence of TEAEs of Special Interest (SAF); Study 178-CL-206A .. 102
`Table 46 Cardiovascular TEAEs of Special Interest (SAF); Study 178-CL-206A ................... 103
`Table 47 TEAEs of Special Interest: Hypersensitivity Reactions (SAF); Study 178-CL-206A 104
`Table 48 TEAEs of Special Interest: Urinary Tract Infection (SAF); Study 178-CL-206A ..... 104
`Table 49 TEAEs by Time Intervals in Study 178-CL-206A (SAF) ........................................... 108
`Table 50 TEAEs by Sex, Race, Drug Formulation, and NDO Medication Use at Baseline in
`Study 178-CL-206A (SAF)......................................................................................................... 108
`Table 51 Vital Signs: Changes From Baseline in Blood Pressure (Percentiles) and Pulse Rate -
`Clinic Measurement (Clinical Practice Guidelines, 2017) (SAF) .............................................. 114
`Table 52 Potentially Clinically Relevant Values in Vital Signs – Clinic Measurements (SAF) 115
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
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`Reference ID: 4764819
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`(b) (6)
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`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Table 53 Changes in Blood Pressure Relative to Mirabegron Exposure from Clinic Visits in
`Study 178-CL-206A.................................................................................................................... 117
`Table 54 Summary of BP at Baseline and Shifts to Stage I and Stage II Hypertension†, 178-CL-
`206A ............................................................................................................................................ 120
`Table 55 Changes in Heart Rate from Study Clinic Visits in Children and Adolescents in Study
`178-CL-206A .............................................................................................................................. 121
`Table 56 Heart Rate Parameters from Study Clinic Visits in Children and Adolescents in Study
`178-CL-206A .............................................................................................................................. 122
`Table 57 Interpretation of Upper Urinary Tract Results (SAF); Study 178-CL-206A .............. 126
`Table 58 Serious Adverse Events Received for Pediatric Patients until 30 Jun 2019 ............... 132
`Table 59 SAEs reported in the 120-Day Safety Update ............................................................ 136
`
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`7
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`Reference ID: 4764819
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`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`
`No table of figures entries found.
`
`Table of Figures
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`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`8
`
`Reference ID: 4764819
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`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Glossary
`
`advisory committee
`
`AC
`adverse event
`
`AE
`adverse reaction
`
`AR
`bioequivalence/bioavailability
`BE/BA
`biologics license application
`BLA
`
`body mass index
`BMI
`
`baseline observation carried forward
`BOCF
`Best Pharmaceuticals for Children Act
`BPCA
`Benefit Risk Framework
`BRF
`
`Center for Biologics Evaluation and Research
`CBER
`Center for Drug Evaluation and Research
`CDER
`Center for Devices and Radiological Health
`CDRH
`Cross-Discipline Team Leader
`CDTL
`change from baseline
`CFB
`
`Code of Federal Regulations
`CFR
`
`Clinician Global Impression of Change
`CGI-C
`confidence interval
`CI
`
`continuous intermittent catheterization
`CIC
`
`chemistry, manufacturing, and controls
`CMC
`
`COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms
`CRF
`
`case report form
`CRO
`
`contract research organization
`CRT
`
`clinical review template
`CSR
`
`clinical study report
`CSS
`
`Controlled Substance Staff
`DEPI
`
`Division of Epidemiology
`DMC
`data monitoring committee
`DMEPA
`Division of Medication Error Prevention and Analysis
`DPMH
`Division of Pediatric and Maternal Health
`DPV
`
`Division of Pharmacovigilance
`DRISK
`Division of Risk Management
`EBC
`
`expected bladder capacity
`ECG
`
`electrocardiogram
`EoS
`
`end of study
`eCTD
`electronic common technical document
`eGFR
`estimated glomerular filtration rate
`ETASU
`elements to assure safe use
`FAS
`
`full analysis set
`FDA
`
`Food and Drug Administration
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`9
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`Food and Drug Administration Amendments Act of 2007
`FDAAA
`Food and Drug Administration Safety and Innovation Act
`FDASIA
`good clinical practice
`GCP
`
`good review management practice
`GRMP
`International Council for Harmonization
`ICH
`
`International Children’s Continence Society
`ICCS
`
`Investigational New Drug Application
`IND
`
`integrated summary of effectiveness
`ISE
`
`integrated summary of safety
`ISS
`
`intent to treat
`ITT
`
`last observation carried forward
`LOCF
`Marketing Authorization Holder
`MAH
`maximum cystometric capacity
`MCC
`
`Medical Dictionary for Regulatory Activities
`MedDRA
`modified intent to treat
`mITT
`NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event
`NDA
`
`new drug application
`NDO
`
`neurogenic detrusor overactivity
`NME
`
`new molecular entity
`OAB
`
`overactive bladder
`OCS
`
`Office of Computational Science
`OPDP
`Prescription Drug Promotion
`OPQ
`
`Office of Pharmaceutical Quality
`OSE
`
`Office of Surveillance and Epidemiology
`OSI
`
`Office of Scientific Investigations
`PIN-Q
`Pediatric Incontinence Questionnaire
`PBRER
`Periodic Benefit-Risk Evaluation Report
`PD
`
`pharmacodynamics or protocol deviation
`PGI-S
`Patient Global Impression of Severity Scale
`PI
`
`prescribing information or package insert
`PK
`
`pharmacokinetics
`PMC
`
`postmarketing commitment
`PMR
`
`postmarketing requirement
`PP
`
`per protocol
`PPS
`
`per protocol set
`PPI
`
`patient package insert
`PPSR
`Proposed Pediatric Study Request
`PREA
`Pediatric Research Equity Act
`PRO
`
`patient reported outcome
`PSUR
`Periodic Safety Update report
`PVR
`
`post void residual
`QTc
`
`corrected QT interval
`REMS
`risk evaluation and mitigation strategy
`SAE
`
`serious adverse event
`SAF
`safety analysis set
`
`
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`10
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`
`SAP
`
`SGE
`
`SOC
`TEAE
`UTI
`
`WR
`
`
`
`statistical analysis plan
`special government employee
`standard of care or system organ class
`treatment emergent adverse event
`urinary tract infection
`Written Request
`
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`11
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-017 MYRBETRIQ® (mirabegron extended-release tablets)
`
`
`
`1. Executive Summary
`
`
`
`Product Introduction
`
`Mirabegron (MYRBETRIQ®) is a selective human beta-3 adrenoceptor agonist. Activation of
`the beta-3 adrenergic receptors residing on the bladder (detrusor smooth muscle) inhibits
`involuntary detrusor muscle contractions and increases of bladder capacity. Mirabegron, 25 mg
`and 50 mg tablets, was originally approved on June 28, 2012 under NDA 202611 for the
`treatment of adults with overactive bladder (OAB), with symptoms of urge incontinence,
`urgency and urinary frequency. In this NDA and sNDA, data for the pediatric population is
`presented to support the safety and efficacy of mirabegron oral suspension and mirabegron
`tablet, respectively, for the treatment of neurogenic detrusor overactivity (NDO) in pediatric
`patients aged 3 to less than 18 years.
`
`Treatment with mirabegron for extended-release oral suspension in children should be initiated at
`the recommended starting dose based on the patient’s weight. Thereafter, based on individual
`efficacy and safety, the dose may be increased to the maximum oral suspension dose
`(appropriate to the patient’s weight range) once daily after 4 to 8 weeks. The maximum dose for
`each weight range should not be exceeded. Mirabegron for extended-release oral suspension
`should be administered with food.
`
`Treatment with mirabegron extended-release tablets in children ≥ 35 kg should be initiated at 25
`mg once daily with food. Based on individual patient efficacy and tolerability, the dose may be
`increased to 50 mg once daily after 4 to 8 weeks.
`
`MYRBETRIQ Granules for extended-release oral suspension: 8.3 g of granules (830 mg of
`mirabegron) are yellowish white granules. After reconstitution with water, 8 mg/mL oral
`suspension is a pale yellow to brownish yellow suspension.
`
`MYRBETRIQ extended-release tablets are marketed in the US as MYRBETRIQ 25 mg and 50
`mg tablets. The 25 mg tablet is oval, brown, film coated, and debossed with the Astellas logo
`and “325.” The 50 mg tablet is yellow, film coated, and debossed with the Astellas logo and
`“355.”
`
`
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`From the Clinical perspective, the evidence presented in this NDA and sNDA is adequate to
`support the effectiveness of these products in the treatment of pediatric patients with NDO.
`
`
`
`Benefit-Risk Assessment
`
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`12
`
`Reference ID: 4764819
`
`

`

`Clinical Review
`Elena Boley
`NDA 213801 MYRBETRIQ® Granules (mirabegron for extended-release oral suspension)
`sNDA 202611/s-01