CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`213801Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`RECOMMENDATION
`(cid:1800) Approval
`☐ Approval with Post-Marketing Commitment
`(cid:1798) Complete Response
`NDA 213801
`MYRBETRIQ GRANULES (mirabegron for extended-release oral
`suspension)
`
`Assessment #1
`
`MYRBETRIQ Granules (mirabegron for extended-
`release oral suspension)
`Dosage Form
`For extended-release oral suspension
`Strength
`8 mg / mL after reconstitution
`Route of Administration Oral
`Rx/OTC Dispensed
`Rx
`Applicant
`Astellas Pharma Global Development, Inc.
`US agent, if applicable Not Applicable
`
`Drug Product Name
`
`Submission(s)
`Assessed
`Original Submission
`(0001)
`Amendment (0004)
`Amendment (0005)
`Amendment (0006)
`Amendment (0007)
`Amendment (0009)
`Amendment (0014)
`Amendment (0021)
`Amendment (0024)
`Amendment (0025)
`Amendment (0026)
`Amendment (0028)
`Amendment (0030)
`Amendment (0031)
`Amendment (0032)
`Amendment (0036)
`Amendment (0037)
`Amendment (0038)
`
`Document Date
`
`Discipline(s) Affected
`
`09/28/2020
`10/29/2020
`10/30/2020
`11/06/2020
`12/11/2020
`12/15/2020
`12/22/2020
`01/15/2021
`01/26/2021
`02/05/2021
`02/09/2021
`02/19/2021
`03/04/2021
`03/04/2021
`03/05/2021
`03/17/2021
`03/19/2021
`03/23/2021
`
`All
`Drug Substance, Drug Product
`Biopharmaceutics
`OPMA
`Micro; Drug Product
`Drug Product
`Biopharmaceutics; Drug Product
`Drug Product
`OPMA; Drug Product
`Drug Product
`OPMA, Drug Product
`OPMA; Drug Product
`OPMA, Drug Product,
`Biopharmaceutics
`Drug Product
`Drug Product
`Drug Product
`Drug Product
`Drug Product
`
`OPQ-XOPQ-TEM-0001v06
`
`Page 1
`
`Effective Date: February 1, 2019
`
`Reference ID: 4772718
`
`
`
`

`

`Discipline
`Drug Substance
`Drug Product
`Manufacturing Process
`Facilities
`Microbiology
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical
`Lead
`Laboratory (OTR)
`Environmental
`Labeling
`
`
`
`
`QUALITY ASSESSMENT TEAM
`Primary Assessment
`Secondary Assessment
`Sukhamaya (Sam) Bain
`Donna Christner
`Mark Seggel
`Wendy Wilson-Lee
`Yong Wu
`Yubing Tang
`Yong Wu
`Yubing Tang
`Jason God
`Julie Nemecek
`Assadollah Noory
`Vidula Kolhatkar
`Marquita Burnett
`
`Hong Cai
`
`-
`Mark Seggel
`Mark Seggel
`
`-
`Wendy Wilson-Lee
`Wendy Wilson-Lee
`
`
`
`Reference ID: 4772718
`
`

`

`EXECUTIVE SUMMARY
`
`I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`Astellas Pharmaceuticals’ 505(b)(2) New Drug Application 213801, for
`MYRBETRIQ Granules (mirabegron for extended-release oral
`suspension), 8 mg/mL of mirabegron after reconstitution, is recommended
`for APPROVAL from the OPQ perspective.
`
`Sufficient chemistry, manufacturing and controls information and
`supporting data have been provided in accordance with 21 CFR 314.50 to
`ensure the identity, strength, quality, purity, and bioavailability of the drug
`product.
`
`The prescribing information (PI) and patient package insert (PPI) as
`submitted on March 23, 2021 (0038) and the labels as submitted on
`March 17, 2021 (0036) and March 19, 2021 (0037) are accurate,
`complete and comply with the requirements under 21 CFR 201.
`
`All drug substance and product-related manufacturing, packaging and
`testing facilities have acceptable drug CGMP status. An overall
`manufacturing inspection recommendation of APPROVE was issued on
`March 17, 2021. The recommendation remains current as of this review.
`
`The claimed categorical exclusion from the environmental assessment
`requirements under 21 CFR Part 25.31(b) is acceptable.
`
`II. SUMMARY OF QUALITY ASSESSMENTS
`
`A. Product Overview
`The proposed drug product Myrbetriq Granules (mirabegron for extended-
`release oral suspension) is a new formulation of mirabegron developed
`for the treatment of neurogenic detrusor overactivity (NDO) for the
`pediatric patients aged 3 years and older. The active ingredient
`mirabegron is a beta-3 adrenergic agonists and approved in the US under
`Myrbetriq (mirabegron extended-release tablets), 25 mg and 50 mg, in
`June 28, 2012 (NDA 202611) for the adult patients and for the treatment
`of overactive bladder (OAB) with symptoms of urge urinary incontinence,
`urgency and urinary frequency. Myrbetriq and Myrbetriq Granules are not
`substitutable on a milligram-per-milligram basis.
`
`MYRBETRIQ Granules is supplied as granules in multi-dose bottles that
`are packaged in the aluminum pouches with desiccant. 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, Myrbetriq
`Granules is pale brownish yellow to yellow oral suspension with 8 mg/mL
`of mirabegron. The oral suspension can facilitate the recommended
`OPQ-XOPQ-TEM-0001v06
`Page 3
`Effective Date: February 1, 2019
`
`Reference ID: 4772718
`
`
`
`

`

`dosage which is determined based on patient weight. The liquid
`formulation will provide an alternative to the tablets for pediatric patients
`who have difficulties swallowing the tablets.
`
`
` This is considered crucial for the pediatric patients.
`Myrbetriq Granules has an extended-release profile. This is the result of
`its formulation
`
`
`
`
`
`
`
`
`The preparation of the suspension will be performed by pharmacists at
`the time of dispensing to the patients. The pharmacist should also provide
`an appropriate oral dosing device to the patient. The instructions for
`reconstitution of Myrbetriq Granules by the pharmacist and the
`instructions for patient use are driven by the physico-chemical properties
`of the drug product. From the CMC perspective, the instructions for
`pharmacists and patients in the Prescribing Information (PI) and Patient
`Package Insert (PPI) are adequate to ensure the quality of the delivered
`doses.
`
`The manufacturing, primary packaging and release testing of
`MYRBETRIQ Granules will be conducted at Astellas Pharm Tech Co.,
`Ltd. Located at Yaizu-shi, Japan. The final packaging, labeling and
`release testing will be conducted at Astellas Pharma Europe B. V.,
`Meppel, The Netherlands.
`
`The expiration dating period is 24 months when MYRBETRIQ Granules is
`stored at 20ºC to 25ºC (68°F to 77°F) with excursions permitted from
`15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
`The maximum patient use period is 28 days after reconstitution with water
`when stored at 20ºC to 25ºC.
`
`for the treatment of neurogenic detrusor overactivity
`(NDO) in pediatric patients aged 3 years and older.
`
`Proposed Indication(s)
`including Intended
`Patient Population
`Duration of Treatment As needed
`Maximum Daily Dose
`80 mg (10 mL)
`Alternative Methods of
`Not Applicable
`Administration
`
`
`
`
`
`
`
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`B. Quality Assessment Overview
`
` for
`
`
`Drug Substance: Adequate
`The drug substance mirabegron is a white crystalline powder, practically
`insoluble in water, but soluble in dimethyl sulfoxide. It melts at about 144
`°C. Its two significant pKa’s are at 4.5 (thiazol -NH2) and 8.0 (amine -NH).
`It is not hygroscopic. Two polymorphic forms have been identified, the
` form is the drug substance.
`The applicant cross-references NDA 202611 for practically all mirabegron
`drug substance information. The original NDA 202611 was approved on
`June 28, 2012. All API-related supplements to NDA 202611 have been
`approved by the Agency – the latest one was on January 22, 2021.
`The drug substance batch data submitted in the present NDA 213801 on
`October 29, 2020 are within the current specification in the cross-
`referenced NDA 202611, which includes 4 impurities which are at not
`more than the ICH M7 TTC of 30 ppm.
`There are three suppliers of the drug substance, mirabegron: Astellas
`Pharma located at Takahagi-shi, Japan; Astellas Ireland Co., Ltd. located
`at Mulhuddart, Ireland, and
`
`. The retest period is
`Mirabegron when stored at
`.
`The drug substance reviewer Dr. Sukhamaya (Sam) Bain finds the
`information on the drug substance mirabegron is adequate to support the
`approval of the NDA. See IQA Chapter Drug Substance I for details.
`
`
`Drug Product: Adequate
`MYRBETRIQ GRANULES (mirabegron for extended-release oral
`suspension) is supplied as the
` non-sterile and non-aqueous
`granules which contains the
` active ingredient
`mirabegron and
`
`diluted hydrochloric acid, xanthan gum,
`hypromellose, mannitol, magnesium stearate, acesulfame potassium,
`methylparaben, ethylparaben, simethicone, and silicon dioxide. All
`excipients are of compendial grade and acceptable from the quality
`perspective.
`
`The specification includes the tests, analytical procedures and
`acceptance criteria, necessary to ensure the identity, strength, quality,
`purity and bioavailability of the drug product.
`
`
`
`
`
`
`
`The microbiological contamination is controlled by the
`testing of microbial limit and the assays of
`
`. A within-bottle uniformity is included
`to demonstrate the suspendability and the dose accuracy for this
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`suspension packaged in the multi-dose container. The dissolution test is
`included for quality control of the extended-release formulation (see IQA
`Chapter VI Biopharmaceutics). Other tests include related substances,
`pH and
` The proposed acceptance criteria for all the
`attributes are acceptable from the quality perspective.
`
`
`
`The applicant’s proposal of not
` elemental impurities in
`including the test for the
`drug product release specification is acceptable per ICH
` and Q3D,
`respectively.
`
`The batch data for the registration batches as well as supportive clinical
`batches all conform to the specifications. The analytical methods used in
`analysis of the drug product batches, at release and in stability studies,
`were suitably validated and deemed adequate for the intended purpose.
`
`MYRBETRIQ Granules is supplied as granules in bottles packaged in an
`aluminum pouch with desiccant. Each bottle is filled with approximately
`8.3 g of granules, which contain 830 mg of mirabegron. The reconstituted
`suspension will be prepared by the pharmacists and stored in the same
`bottle. The suitability of the container closure system has been
`demonstrated through the appropriate long-term, accelerated, and
`photostability studies.
`
`The stability data support the proposed expiration dating period of 24
`months when MYRBETRIQ Granules is stored at 20ºC to 25ºC with
`excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP
`Controlled Room Temperature] in the proposed container closure system.
`The applicant has provided adequate data to support the 28 days patient
`use period when stored at 20ºC to 25ºC after the reconstitution with
`water.
`
`
`The applicant has requested a categorical exclusion from the requirement
`to prepare an environmental assessment under 21 CFR § 25.31(b).
`Astellas states that there are no extraordinary circumstances associated
`with the use of mirabegron. The categorical exclusion is granted.
`
`In summary, Dr. Mark Seggel has recommended approval for this
`application from the drug product perspective. See IQA Chapter II, Drug
`Product for details.
`
`
`Labeling: Adequate
`During the initial assessment of the labeling (prescribing information (PI),
`patient package insert (PPI), and container/carton labels), several
`deficiencies were identified and conveyed to the Applicant with the
`collaboration with DMEPA and the clinical review team. All of the
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`previously identified deficiencies have been satisfactorily resolved. The
`prescribing information (PI) and patient package insert (PPI) as submitted
`on March 23, 2021 (0038) and the labels as submitted on March 17, 2021
`(0036) and March 19, 2021 (0037) are accurate, complete and comply
`with the requirements under 21 CFR 201.
`
`From the ONDP perspective, this application is deemed ready for
`approval in its present form per 314.125(b)(8). Refer to IQA Labeling
`Chapter IV for details.
`
`
` Manufacturing Integrated Assessment: Adequate
`Process: adequate
`The manufacturing process for MYRBETRIQ Granules involves the
`following steps:
`
`
`
` kg which is the same
` are proposed.
`
` The size of the registration batches is
`for the proposed commercial batch size. No
`
`The applicant has investigated the critical manufacturing process
`
`parameters (e.g.
` etc.), testing of the critical quality attributes of the drug products
`(e.g. the
` content uniformity of mirabegron,
`, pH,
`preservative assays, particle size distributions and fill weight, etc.). Proper
`acceptance criteria and the sampling plan has been established. The
`overall manufacturing process and control is deemed adequate.
`
`
`Although the assays met the acceptance criteria of the specification, it is
`noted that the variability in assays for mirabegron and
`
`
`were observed with one of the process performance
`qualification (PPQ) batches. The applicant proposed to
`
` as the
`mitigation strategy. This potential assay variability concern is further
`addressed by
`
`
`
`
`
`
`to ensure the requisite quality
`
`and performance of the finished product.
`
`The finished drug product granules are manufactured at Astellas Pharma
`Tech Co., Ltd. located at Shizuoka, Japan.
`
`Facilities: adequate
`Pre-approval inspections (PAI) were conducted via 704(a)(4) due to
`COVID-19 travel restrictions for the following three facilities: Astellas
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Pharma Tech Co., Ltd. Japan (FEI: 3002809620) for the drug product
`manufacturing; Astellas Pharma Europe B.V. (FEI: 3002808518), The
`Netherlands for the drug product packaging/labeling, release and stability
`testing and storage;
`
` for the drug substance microbiological testing. Other
`manufacturing facilities related to the commercialization of the drug
`product are acceptable based on the compliance history, acceptable
`profile codes and experience in the proposed responsibilities to support
`this application.
`
`The OPMA reviewer, Dr. Yong Wu, has concluded that the overall
`manufacturing process, controls and the facilities are adequate to support
`the approval of this NDA from OPMA perspective. See IQA OPMA
`Chapter V for manufacturing process and facilities for details.
`
`
`
`Reference ID: 4772718
`
`(b) (4)
`
`

`

` Biopharmaceutics: Adequate
`The control of the mirabegron release is based on
`. The following two step
`dissolution testing method and the acceptance criteria has been
`established for the routine quality control (QC) of the drug product
`Myrbetriq Granules at batch release and during stability testing:
`
`
`
`
`This 2-step method utilizes 500 mL of pH 6.8 USP phosphate buffer that
`contains 0.036 mol
` (step 1), which is followed by the addition of
`500 mL of 0.108 mol (step 2) to obtain almost complete release of
`mirabegron. Note that the
` concentration added in the step 2 is
`three times as that in the step 1 phosphate buffer medium. Dissolution
`data from clinical batches and registration batches support the proposed
`dissolution acceptance criteria. Different particle sizes of mirabegron or
` did not significantly affect the dissolution
`rate of mirabegron from MYRBETRIQ Granules. However, the dissolution
`profile is faster with
`
` particle size. The biopharmaceutics information
`provided in this application has been reviewed by Dr. Assadollah Noory
`and concluded the dissolution method is adequate for the quality control.
`
`
`The applicant has studied the impact of the dissolution rate of mirabegron
`from MYRBETRIQ Granules with the addition of alcohol (alcohol dose
`dumping study). The addition of alcohol (5, 10, 20, and 40%) increases
`the dissolution rate of mirabegron from MYRBETRIQ Granules at pH 6.8,
`but there is no increase at pH1.0. This study results have been
`communicated to the clinpharm review team.
`
`Dr. Assad has recommended the approval of this application from
`biopharmaceutics perspective. See IQA Biopharmaceutics Chapter VI for
`details.
`
`
` Microbiology (if applicable): Adequate
` non-sterile and
`MYRBETRIQ Granules is manufactured as a
`non-aqueous drug product. However, it is reconstituted with water as a
`suspension in the primary container closure system at the time of
`dispensing to the patient by the pharmacist.
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The applicant has provided the microbial limits testing of TAMC and
`TYMC per USP<61> and E. coli per USP<62> in mirabegron granules
`release and stability specification. The proposed microbial limits and
`testing procedures comply with regulatory expectations for a non-
`aqueous, oral product.
`
` of the
`The
`reconstituted suspension was assayed at the time of reconstitution and at
`the end of the 28 day in-use period and the results met the specification.
` effectiveness for the duration of the 28-day in-use period has
`been shown at the minimum label claim
`.
`
`The applicant has met regulatory expectations with regard to the design of
`the stability testing program to support the drug product’s microbiological
`quality throughout its shelf life. In addition, the stability data submitted to
`date support the microbiological quality of the drug product and 28-day
`patient in-use period of the reconstituted suspension when stored at the
`proposed condition in the product labeling.
`
`The microbiology information submitted in this application has been
`reviewed by the microbiology reviewer Dr. Jason God who has found the
`information provided in the application adequate to support the approval
`of this application from the microbiology perspective. See the detailed
`review from Dr. Jason God in the Microbiology Chapter VII of the IQA.
`
`
`
`
`
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`FACILITY STATUS REPORT AND OVERALL RECOMMENDATION
`As of 03/24/2021
`
`
`
`
`
`Reference ID: 4772718
`
`(b) (4)
`
`

`

`
`
`CQAs
`
`C. Risk Assessment
`
`Initial Risk
`Ranking
`
`Comments
`
`Granules;
`Reconstituted
`suspension;
`drug product
`specification
`
`
`drug product
`specification
`
` via
`drug product
`specification
`
`Formulation with
`
`
`and drug
`product
`specification
`
`Formulation,
`Manufacturing
`process and
`drug product
`specification;
`In-use stability
`study
`
`
`
`
`
`
`
`Formulation,
`Manufacturing
`process and
`drug product
`specification;
`In-use stability
`study.
`
`
`
`
`
`
`
`Identification
`
`L
`
`Assay
`
`L
`
`Dose Uniformity M
`
`Related
`Substances
`
`Dosing
`Accuracy
`
`Content
`Uniformity
`
`PSD of the
`granules
`Dissolution
`
`L
`
`M
`
`M
`
`M
`
`M
`
`Reference ID: 4772718
`
`Updated Risk
`Ranking after
`Assessment
`Cycle #1
`L
`
`L
`
`L
`
`L
`
`L
`
`
`
`L
`
`L
`
`Comments
`
`
`
`
`
`Suspendability
`and uniformity of
`suspension
`demonstrated;
`IFU details steps
`to ensure
`homogeneity
`prior to dosing
`
`
`Not a narrow
`therapeutic
`index drug, but
`dosing remains
`dependent on
`user
`
`
`
`
`
`In vivo release
`rate
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`L
`
`L
`
`L
`
`L
`
`L
`
`Formulation
`primarily for
`pediatric
`patients;
`
`
`
`
`
`
`
`
`
`In vitro release
`rate increase at
`pH 6.8 but NOT
`in 0.1 N HCl;
`
`control via
`specification
`Formulation
`development
`and control via
`
` the
`drug product
`specification
`control via
`specification
`In-use stability
`study
`Risk
`assessment per
`USP<1664>;
`Oral use only.
`Long-term
`storage of solid
`granules; but
`reconstituted
`suspension
`NMT 28 days.
`
`Alcohol Dose
`Dumping
`(extended-
`release
`formulation)
`pH
`
`
`
`Assay
`
`M
`
`L
`
`M
`
`Microbial Limits
`
`L (granules)
`M (reconstituted
`suspension)
`
`Leachables
`
`M
`
`
`Lifecycle Management Considerations
`
`Any proposed change to component quality, formulation or manufacturing
`process should be carefully assessed for impact on
` and on the in vitro dissolution profile
`should be carefully addressed under both long-term storage conditions and in-
`use.
`
`
`
`
`
`
`
`Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`D. List of Deficiencies for Complete Response
`1. Overall Quality Deficiencies (Deficiencies that affect multiple sub-
`disciplines)
`na
`
`2. Drug Substance Deficiencies
`na
`
`3. Drug Product Deficiencies
`na
`
`4. Labeling Deficiencies
`na
`
`5. Manufacturing Deficiencies
`na
`
`6. Biopharmaceutics Deficiencies
`na
`
`7. Microbiology Deficiencies
`na
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8. Other Deficiencies (Specify discipline, such as Environmental)
`na
`
`
`
`
`Application Technical Lead Name and Date:
`
`Hong Cai, Ph.D.
`CMC Lead (acting)
`
`Reference ID: 4772718
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs:
`
`DMF #
`
`Type
`
`Holder
`
`Item
`Referenced
`
`Status
`
`Date
`Assessment
`Completed
`
`Comments
`
`III
`
`III
`
`III
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`
`
`
`
`
`
`N/A: There is enough data in the application, therefore the DMF did not need to
`be reviewed during the current review cycle.
`
`B. OTHER DOCUMENTS: IND, RLD, RS, Approved NDA
`Document
`Application Number
`Description
`IND submissions,
`IND 069416
`Investigational use of
`associated reviews, and
`Mirabegron for the
`communications
`treatment of an overactive
`bladder
`Myrbetriq (mirabegron
`extended-release tablets),
`25- and 50-mg; Astellas;
`AP 06/28/2012
`
`NDA 202611
`
`
`NDA application(s)
`
`2. CONSULTS
`Status
`Discipline
`na
`Biostatistics
`Pharmacology/Toxicology na
`CDRH-ODE
`na
`CDRH-OC
`na
`
`Recommendation
`
`
`
`Date
`
`
`
`Assessor
`
`
`
`
`
`
`
`
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`OPQ-XOPQ-TEM-0001v06
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`Effective Date: February 1, 2019
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`Reference ID: 4772718
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`Clinical
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`CHAPTERS: Primary Quality Assessment
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`
`CHAPTER I: Drug Substance
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`CHAPTER II: Drug Product
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`CHAPTER III: Environmental Assessment (see Chapter II)
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`CHAPTER IV: Labeling
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`CHAPTER V: Manufacturing Integrated Assessment
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`CHAPTER VI: Biopharmaceutics
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`CHAPTER VII: Microbiology
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`CHAPTER VIII: Additional Quality Disciplines Not applicable
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`Reference ID: 4772718
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`Hong
`Cai
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`Digitally signed by Hong Cai
`Date: 3/24/2021 04:03:16PM
`GUID: 55919d6500e16bdaad5825645e4f22ff
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`Reference ID: 4772718
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`40 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
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`

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`CHAPTER IV: LABELING
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`1.0 PRESCRIBING INFORMATION
`
`Assessment of Product Quality Related Aspects of the Prescribing
`Information:
`
`MYRBETRIQ Granules (mirabegron for extended-release oral suspension) is
`supplied as granules in multi-dose bottles that are packaged in aluminum
`pouches with desiccant. After reconstitution with 100 mL of water by the
`pharmacist, the oral suspension has 8 mg/mL mirabegron. Unused suspension
`should be discarded after 28 days. This labeling review covers the CMC-related
`sections of the prescribing information (PI), the carton label, bottle label, and the
`aluminum pouch label.
`
`Note that the prescribing information has been designed to cover both
`MYRBETRIQ Granules (mirabegron for extended-release oral suspension) and
`MYRBETRIQ (mirabegron extended-release tablets). (MYBETRIQ was
`approved under NDA 202611; see also efficacy supplement S-017, which is
`currently under review for the treatment of NDO in pediatric patients, and the
`associated CMC review.)
`
`This assessment is based on the revised PI submitted on March 23, 2021
`(SN0038). The labeling review team (ONDP, OPPQ, DMEPA and clinical) has
`provided the comments to the applicant on January 29, 2021, February 23 and
`24, 2021, and March 17, 18, and 22, 2021. The following submissions were
`reviewed:
`
`Labeling Submissions Assessed
`Original Submission (SN0001)
`Amendment (SN0009)
`Amendment (SN0031)
`Amendment (SN0032)
`Amendment (SN0036)
`Amendment (SN0037)
`Amendment (SN0038)
`
`
`Document Date
`September 28, 2020
`December 15, 2020
`March 04, 2021
`March 05, 2021
`March 17, 2021
`March 19, 2021
`March 23, 2021
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`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`Item
`Product Title in Highlights
`Proprietary name
`Established name(s)
`
`Information Provided in
`the NDA
`
`MYRBETRIQ GRANULES
`(mirabegron for extended-
`release oral suspension)
`
`oral
`Route(s) of administration
`Dosage Forms and Strengths Heading in Highlights
`Summary of the dosage
`For extended-release
`form(s) and strength(s)
`oral suspension: 8
`mg/mL of mirabegron
`in metric system.
`after reconstitution
`na
`
`Assess if the tablet is
`scored. If product meets
`guidelines and criteria for a
`scored tablet, state
`“functionally scored”
`
`Assessor’s Comments
`
`Satisfactory
`Satisfactory
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`Satisfactory
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`Satisfactory
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`For injectable drug
`products for parental
`administration, use
`appropriate package type
`term (e.g., single-dose,
`multiple-dose, single-
`patient-use). Other
`package terms include
`pharmacy bulk package
`and imaging bulk package.
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`1.2 FULL PRESCRIBING INFORMATION
`1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)
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`Information Provided in
`Item
`the NDA
`DOSAGE AND ADMINISTRATION section
`Special instructions for
`See proposed Section
`product preparation (e.g.,
`“2.6
`
`” above
`reconstitution and resulting
`copied from the proposed
`concentration, dilution,
`PI.
`compatible diluents,
`storage conditions needed
`to maintain the stability of
`the reconstituted or diluted
`product)
`
`
`Assessor’s Comments
`
`Satisfactory
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`1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)
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`Reference ID: 4772718
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`Item
`
`Information
`Provided
`in the NDA
`DOSAGE FORMS AND STRENGTHS section
`Available dosage form(s)
`for extended-
`release oral
`suspension
`8 mg/mL of
`mirabegron
`na
`
`Assessor’s Comments
`
`Satisfactory
`
`
`Satisfactory
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`na
`
`Satisfactory
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`
`na
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`na
`
`yellowish white
`granules
`After reconstitution
`with 100 mL water,
`the oral
`suspension is pale
`brownish yellow to
`yellow with 8 mg/mL
`of mirabegron
`na
`
`na
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`Strength(s) in metric system
`
`If the active ingredient is a salt,
`apply the USP Salt Policy per FDA
`Guidance
`A description of the identifying
`characteristics of the dosage
`forms, including shape, color,
`coating, scoring, and imprinting
`
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`“functionally scored”
`For injectable drug products for
`parental administration, use
`appropriate labeling term (e.g.,
`single-dose, multiple-dose, single-
`patient-use). Other package type
`terms include pharmacy bulk
`package and imaging bulk
`package.
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`Reference ID: 4772718
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`1.2.3 Section 11 (DESCRIPTION)
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`OPQ-XOPQ-TEM-0001v06
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`Page 6
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`Effective Date: February 1, 2019
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`Reference ID: 4772718
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`Item
`DESCRIPTION section
`Proprietary and established
`name(s)
`
`Dosage form(s) and route(s)
`of administration
`If the active ingredient is a
`salt, apply the USP Salt
`Policy and include the
`equivalency statement per
`FDA Guidance.
`List names of all inactive
`ingredients. Use USP/NF
`names. Avoid Brand names.
`
`For parenteral injectable
`dosage forms, include the
`name and quantities of all
`inactive ingredients. For
`ingredients added to adjust
`the pH or make isotonic,
`include the name and
`statement of effect.
`If alcohol is present, must
`provide the amount of
`alcohol in terms of percent
`volume of absolute alcohol
`Statement of being sterile (if
`applicable)
`Pharmacological/
`therapeutic
`class
`
`Information Provided
`in the NDA
`
`MYRBETRIQ Granules
`(mirabegron for extended-
`release oral suspension)
`for extended-release oral
`suspension
`na
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`acesulfame potassium,
`diluted hydrochloric acid,
`ethylparaben, hypromellose,
`magnesium stearate,
`mannitol, methylparaben,
`silicon dioxide,
`simethicone, sodium
`polystyrene sulfonate, and
`xanthan gum
`
`
`na
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`na
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`Assessor’s Comments
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`Satisfactory
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`Satisfactory
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`na
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`Satisfactory
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`Satisfactory
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`na
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`na
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`beta-3 adrenergic agonist
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`Satisfactory
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`Chemical name, structural
`formula, molecular weight
`
`Satisfactory
`
`
`The chemical name of
`mirabegron is 2-(2-
`aminothiazol-4-yl)-N-[4-(2-
`{[(2R)-2-hydroxy-2-
`phenylethyl]amino}ethyl)phe
`nyl]acetamide having an
`empirical formula of
`C21H24N4O2S and a
`molecular weight of
`396.51. The structural
`formula of mirabegron is:
`
`If radioactive, statement of
`important nuclear
`characteristics.
`Other important chemical or
`physical properties (such as
`pKa or pH)
`
`na
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`
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`na
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`Satisfactory
`
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`Mirabegron is a white
`powder. It is practically
`insoluble in water (0.082
`mg/mL). It is soluble in
`methanol and dimethyl
`sulfoxide.
`
`na
`
`Section 11 (DESCRIPTION) Continued
`Information Provided
`Item
`in the NDA
`For oral prescription drug
`products, include gluten
`statement if applicable
`Remove statements that
`may be misleading or
`promotional (e.g.,
`“synthesized and developed
`by Drug Company X,”
`“structurally unique
`molecular entity”
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`na
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`Assessor’s Comments
`na
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`na
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`Reference ID: 4772718
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`1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)
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`Reference ID: 4772718
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`Information Provided in
`Item
`the NDA
`HOW SUPPLIED/STORAGE AND HANDLING section
`Satisfactory
`Available dosage form(s)
`for extended-release oral
`
`suspension
`Strength(s) in metric system 8 mg/mL of mirabegron Satisfactory
`
`Satisfactory
`
`
`Available units (e.g., bottles
`of 100 tablets)
`
`Assessor’s Comments
`
`Satisfactory
`
`
`na
`
`na
`
`Each bottle is filled with
`approximately 8.3 g of
`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.1 Carton
`Containing 1 Bottle
`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.
`
`Assess if the tablet is scored. na
`If product meets guidelines
`and criteria for a scored
`tablet, state “functionally
`scored”
`For injectable drug products
`for parental administration,
`use appropriate package
`type term (e.g., single-dose,
`multiple-dose, single-patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`package.
`
`
`Identification of dosage
`forms, e.g., shape, color,
`coating, scoring, imprinting,
`NDC number
`
`na
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`Reference ID: 4772718
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`Section 16 (HOW SUPPLIED/STORAGE AND HANDLING) (Continued)
`Information Provided in
`Item
`Assessor’s Comments
`the NDA
`na
`Special handling about the
`supplied product (e.g.,
`protect from light,
`refrigerate). If there is a
`statement to “Dispense in
`original container,” provide
`reason why (e.g. to protect
`from light or moisture, to
`maintain stability, etc.)
`If the product contains a
`desiccant, ensure the size
`and shape differ from the
`dosage form and desiccant
`has a warning such as “Do
`not eat.”
`Storage conditions. Where
`applicable, use USP
`storage range rather than
`storage at a single
`temperature.
`
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`
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`Latex: If product does not
`contain latex and
`manufacturing of product
`and container did not
`include use of natural
`rubber latex or synthetic
`derivatives of natural rubber
`latex, state: “Not made with
`natural rubber latex. Avoid
`statements such as “latex-
`free.”
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`Reference ID: 4772718
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`na
`
`
`na
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`Store MYRBETRIQ
`Granules at 20°C to 25°C
`(68°F to 77°F) with
`excursions permitted from
`15°C to 30°C (59°F to
`86°F) [see USP Controlled
`Room Temperature].
`Store the reconstituted
`suspension at 20°C to
`25°C (68°F to 77°F) for up
`to 28 days. Discard the
`unused portion after 28
`days.
`na
`
`na
`
`Satisfactory
`
`
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`na
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`Page 11
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`Include information about
`child-resistant packaging
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`1.2.5 Other Sections of Labeling
`There may be other sections of labeling that contain product-quality related
`information. For example, there are specific required/recommended warnings
`for certain inactive ingredients [e.g., aspartame, aluminum in large and small
`volume parenterals, sulfites, FD&C Yellow Number 5 (tartrazine), and benzyl
`alcohol]. Please notify the prescription drug division if the product contains any
`of th