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

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of New Drugs
`Division of Pediatric and Maternal Health
`Silver Spring, MD 20993
`Telephone
`301-796-2200
`FAX
`301-796-9744
`
`From:
`
`M E M O R A N D U M
`ADDENDUM
`
`Shamir Tuchman, MD, MPH, Medical Officer
`Division of Pediatric and Maternal Health (DPMH)
`Office of Rare Diseases, Pediatrics, Urologic and
`Reproductive Medicine (ORPURM)
`Office of New Drugs (OND)
`
`Through:
`
`Mona Khurana, MD, Pediatric Team Leader
`DPMH, ORPURM, OND
`
`To:
`
`Subject:
`
`John J. Alexander, MD, MPH, Deputy Director
`DPMH, ORPURM, OND
`
`Division of Urology, Obstetrics, and Gynecology (DUOG)
`
`NDA and efficacy supplement review of cardiovascular
`data in pediatric patients with detrusor overactivity
`associated with a neurologic condition (NDO) treated with
`MYRBETRIQ1
`
`Applicant:
`
`Astellas Pharma Global Development, Inc.2
`
`Application number:
`
`NDA 213801, NDA 202611/S-17
`
`1 This review will refer to the drug product as “mirabegron”
`2 This review will refer to “Astellas Pharma Global Development, Inc.” as the “Applicant”
`
`
`
`Reference ID: 4767470Reference ID: 4772718
`
`

`

`Myrbetriq (mirabegron)
`NDA 213801, NDA 202611/S-17
`
`Division of Pediatric and Maternal Health
`
`March 2021
`
`Drug:
`
`Drug Class:
`
`Mirabegron
`
`Beta-3 Adrenergic Agonist
`
`Proposed Indication:
`
`Treatment of NDO in patients 3 to 17 years of age
`
`
`
`
`
`
`
`Approved Dosage Form:
`
`Tablet (25 mg and 50 mg)
`
`Route of administration:
`
`Oral
`
`Proposed Dosage Form(s): Granules for oral suspension (8 mg/mL)
`
`Proposed Dosing Regimen: Tablet: Patients weighing more than or equal to 35 kg:
`Initial 25 mg once daily up to 50 mg once daily
`Granules for oral suspension:
`11 kg to less than 22 kg: Initial 3 mL once daily
`up to 6 mL once daily
`22 kg to less than 35 kg: Initial 4 mL once daily
`up to 8 mL once daily
`35 kg or greater : Initial 6 mL once daily up to
`10 mL once daily
`
`Consult Request:
`DUOG requests DPMH to provide an assessment of the overall adequacy of the
`Applicant’s collection and analyses of the heart rate and blood pressure data in pediatric
`patients enrolled in studies that the Applicant has submitted as part of the NDA 213801
`and NDA 202611/S-17. The Applicant has submitted the final reports for both studies to
`fulfill post-marketing requirements (PMRs) under the Pediatric Research Equity Act
`(PREA) and to fulfill a Written Request (WR). With submission of these data, the
`Applicant is seeking approval of mirabegron for treatment of NDO in patients 3 to 17
`years of age.
`
`Referenced Materials:
`(cid:120) The following documents included in the mirabegron NDA and efficacy
`supplement #17 entered into DARRTS under NDA 202611/S-17, September 28,
`2020:
`
`2
`
`
`
`Reference ID: 4767470Reference ID: 4772718
`
`(b) (4)
`
`

`

`Myrbetriq (mirabegron)
`Division of Pediatric and Maternal Health
`NDA 213801, NDA 202611/S-17
`
`March 2021
`o DPMH Pediatric Clinical Review Memo in DAARTS on February 16,
`2021
`
`Addendum:
`
`The following is a modification of the description of blood pressure (BP) category
`changes in children and adolescents from the DPMH Pediatric Clinical Review
`Memorandum entered into DARRTS on February 16, 2021 under NDA 213801. The
`information on changes in BP categories included in the memorandum cites proportions
`for children and adolescents calculated using the full patient population for which
`baseline BP measures were taken. However, a more appropriate population on which to
`base changes in BP category are those who had at least one BP measurement taken in a
`follow-up study visit. Therefore, the adjusted changes in BP categories referenced below
`are based on the cohort of patients in Study 178-CL-206A with at least one follow-up in-
`clinic BP measurement taken after the baseline study visit:
`
`Using criteria from the National Heart, Lung and Blood Institute (NHLBI) 4th Report on
`the Diagnosis, Evaluation, and Treatment of High Blood Pressure in children and
`Adolescents, 45 (82%), 3 (5%), and 7 (13%) of 55 patients 3 to less than 12 years of age
`(referred to as children for this analysis) were normotensive, pre-hypertensive, or had
`stage I hypertension (HTN), respectively, based on systolic blood pressure (SBP) criteria
`at the baseline in-clinic visit. The corresponding proportions for diastolic blood pressure
`(DBP) were similar in the same age group. For patients 12 to less than 18 years of age
`(referred to as adolescents for this analysis), the corresponding number of patients are 19
`(61%), 8 (26%), and 4 (13%) for SBP at the baseline in-clinic visit. There was a slightly
`higher proportion of adolescents who were normotensive (71%) at baseline using DBP
`criteria. The baseline proportion of study patients that had pre-existing HTN was largely
`similar between children and adolescents using either the SBP or DBP criteria. Compared
`to children, there was a lower proportion of normotensive adolescents at baseline due to a
`larger proportion with pre-hypertension as defined by the NHLBI 4th Report.
`
`Ten (24%) of the 41 children who were normotensive at baseline and had at least one
`follow-up BP measured at an in-clinic visit had a measured SBP at or above the 95th
`percentile based the NHLBI 4th Report while this occurred in only 1 of 19 (5%)
`adolescent patients who were normotensive at baseline. Six (15%) of the 41 children
`who were normotensive at baseline and had at least one follow-up BP measured at an in-
`clinic visit had a measured DBP at or above the 95th percentile based the NHLBI 4th
`Report during one of the clinic visits while this occurred in 2 (10%) of the 21 baseline
`normotensive adolescents. Overall 14% of children and 12% of adolescents changed
`
`3
`
`
`
`Reference ID: 4767470Reference ID: 4772718
`
`

`

`Myrbetriq (mirabegron)
`NDA 213801, NDA 202611/S-17
`
`Division of Pediatric and Maternal Health
`
`March 2021
`
`categories from either normotensive or pre-hypertensive at baseline to stage I HTN by
`either SBP or DBP criteria. One adolescent who had stage I systolic HTN at baseline
`developed stage II systolic HTN at the week 4 in-clinic visit and then subsequently
`returned to having stage I HTN at subsequent in-clinic visits without modification or
`discontinuation of mirabegron dosing. In children, 6 (60%) of the 10 patients who had a
`measured SBP at or above the 95th percentile continued to have sustained measurements
`above the 95th percentile at subsequent in-clinic visits (stage I HTN). For DBP, this
`proportion was 1 (17%) out of 6 children. Two of the 3 adolescents who developed stage
`I HTN were in the pre-hypertension category at baseline. No children developed stage II
`HTN by either SBP or DBP NHLBI 4th Report criteria at any point in the trial.
`
`In addition, the * at the bottom of Tables 3, 4, and 5 denoting “children” as “patients 1 to
`less than 12 years of age” is modified to “patients 3 to less than 12 years of age”. This is
`consistent with the lower age of enrollment in Study 178-CL-206A.
`
`
`
`Reference ID: 4767470Reference ID: 4772718
`
`4
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SHAMIR TUCHMAN
`03/24/2021 12:02:44 PM
`
`MONA K KHURANA
`03/24/2021 12:53:16 PM
`
`JOHN J ALEXANDER
`03/24/2021 07:25:22 PM
`
`
`
`Reference ID: 4767470Reference ID: 4772718
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`March 24, 2021
`Requesting Office or Division:
`Division of Urology, Obstetrics, and Gynecology (DUOG)
`Application Type and Number: NDA 213801
`Product Name and Strength:
`Myrbetriq granules (mirabegron for extended release oral
`suspension),
`8 mg/mL, 100 mL
`Astellas Pharma Global Development, Inc. (Astellas)
`2020-2062-3
`Denise V. Baugh, PharmD, BCPS
`Celeste Karpow, PharmD, MPH
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Acting Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised carton labeling received on March 24, 2021 for Myrbetriq. The
`Division of Urology, Obstetrics, and Gynecology (DUOG) requested that we review the revised
`carton labeling for Myrbetriq (Appendix A) to determine if it is acceptable from a medication
`error perspective. The revisions are in response to recommendations that we made during a
`previous label and labeling reviewa and two label and labeling memorandumsb,c.
`
`CONCLUSION
`2
`The Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Baugh D. Label and Labeling Review for Myrbetriq granules (NDA 213801). Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2021 MAR 22. RCM No.: 2020-2062-2.
`b Baugh, D. Label and Labeling Memorandum for mirabegron granules (NDA 213801) and Myrbetriq (NDA
`202611/S-017). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2021 MAR 17. RCM No.: 2020-2062-1 and 2020-
`2168-1.
`c Baugh, D. Label and Labeling Memorandum for mirabegron granules (NDA 213801). Silver Spring (MD): FDA,
`CDER, OSE, DMEPA (US); 2021 MAR 22. RCM No.: 2020-2062-2.
`1
`
`
`
`Reference ID: 4767848Reference ID: 4772718
`
`

`

`APPENDIX A. IMAGE OF LABELING RECEIVED ON MARCH 24, 2021
`
`Carton labeling
`
`
`
`Reference ID: 4767848Reference ID: 4772718
`
`2
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DENISE V BAUGH
`03/24/2021 08:01:52 PM
`
`CELESTE A KARPOW
`03/24/2021 11:07:09 PM
`
`
`
`Reference ID: 4767848Reference ID: 4772718
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`Requesting Office or Division:
`Application Type and Number:
`Product Name and Strength:
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Acting Team Leader:
`
`March 22, 2021
`Division of Urology, Obstetrics, and Gynecology (DUOG)
`NDA 213801
`Myrbetriq granules (mirabegron for extended release oral
`suspension),
`8 mg/mL, 100 mL
`Single Ingredient Product
`Prescription (Rx)
`Astellas Pharma Global Development, Inc. (Astellas)
`March 17, 2021 and March 19, 2021
`2020-2062-2
`Denise V. Baugh, PharmD, BCPS
`Celeste Karpow, PharmD, MPH
`
`1
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`

`

`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised container labels, carton labeling, and prescribing information
`(PI) received on March 19, 2021 and revised pouch labels received on March 17, 2021 for
`Myrbetriq Granules (extended release for oral suspension). The Division of Urology, Obstetrics,
`and Gynecology (DUOG) requested that we review the revised PI, container labels, pouch
`labels, and carton labeling (Appendices A) to determine if they are acceptable from a
`medication error perspective. The revisions are in response to recommendations that we made
`during a previous label and labeling reviewa and memorandumb.
`2
`FINDINGS AND RECOMMENDATIONS
`Our evaluation of the proposed Myrbetriq Granules PI and carton labeling identified areas of
`vulnerability that may lead to medication errors. Below, Table 2 includes our recommendations
`for the proposed Myrbetriq Granules PI for DUOG and Table 3 includes our recommendation
`for the carton labeling for Astellas. We ask that the Division convey Table 2 in its entirety to
`Astellas so that the recommendation is implemented prior to approval of this NDA.
`Our recommendations to the container labels and pouch labels were implemented and we have
`no additional recommendations at this time.
`
`The following table (Table 2) outlines issues and recommendations for the Division:
`
`Table 1. Identified Issues and Recommendations for Division of Urology, Obstetrics, and
`Gynecology (DUOG)
`RECOMMENDATION
`RATIONALE FOR CONCERN
`IDENTIFIED ISSUE
`Full Prescribing Information – Section 2 Dosage and Administration
`1.
`Astellas proposed further
`Astellas proposed these
`The third bullet in Section 2.6
`revisions to Section 2.6
`revisions to further
`was revised from “Measure
`(Preparation
`emphasize the importance
`100 mL of water, add the total
`Instructions). We agreed
`of shaking the suspension
`amount to the bottle, and
`to these additional
`to achieve complete
`immediately shake vigorously
`statements during
`dispersion.
`for 1 minute, then let it stand
`labeling discussions.
`for 10 to 30 minutes.” to read
`“Measure 100 mL of water,
`add the total amount to the
`
`a Baugh, D. Label, Labeling, and Packaging Review for mirabegron granules (NDA 213801) and Myrbetriq (NDA
`202611/S-017). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2021 MAR 17. RCM No.: 2020-2062-1 and 2020-
`2168-1.
`b Baugh, D. Label and Labeling Memorandum for mirabegron granules (NDA 213801) and Myrbetriq (NDA
`202611/S-017). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2021 MAR 17. RCM No.: 2020-2062-1 and 2020-
`2168-1.
`
`2
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`

`

`Table 1. Identified Issues and Recommendations for Division of Urology, Obstetrics, and
`Gynecology (DUOG)
`IDENTIFIED ISSUE
`
`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`bottle, and immediately shake
`vigorously for 1 minute, then
`let it stand for 10 to 30
`minutes. Shake vigorously
`again for 1 minute.”
`The fourth bullet was revised
`from “If granules have not
`dispersed, shake vigorously for
`1 minute.” to read “If granules
`have not dispersed, shake
`vigorously for another 1
`minute.”
`
`Full Prescribing Information – Section 17 Patient Counseling
`1. During discussions
`These statements were
`between DMEPA and the
`added to align the FPI with
`Division of Medical Policy
`the Patient Package Insert
`Programs (DMPP), we
`(PPI).
`agreed to add
`statements regarding
`proper administration of
`Myrbetriq Granules to
`Section 17 (Patient
`Counseling) of the Full
`Prescribing Information
`(FPI).
`
`The statements added to
`Section 17 of the FPI were:
`“MYRBETRIQ Granules
`Advise pediatric patients
`and/or their caregivers to use
`an appropriate measuring
`device and instructions for
`measuring the correct dose of
`MYRBETRIQ Granules for
`extended-release oral
`suspension. Instruct patients
`or their caregivers that
`patients should take
`MYRBETRIQ Granules for
`extended-release oral
`suspension orally within 1
`hour after preparation with
`food once daily and not save
`the dose for later.
`
`The bottle should be shaken
`for 1 minute each day if the
`suspension will not be used for
`2 or more days. When ready
`
`3
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`

`

`Table 1. Identified Issues and Recommendations for Division of Urology, Obstetrics, and
`Gynecology (DUOG)
`IDENTIFIED ISSUE
`
`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`to use, shake the bottle
`vigorously for 1 minute then
`let it stand until the foam on
`top of the suspension is gone
`(approximately 1 to 2
`minutes).”
`
`The following table (Table 3) outlines issues and recommendations to convey to the
`Applicant:
`
`Table 2. Identified Issues and Recommendations for Astellas Pharma Global Development,
`Inc. (entire table to be conveyed to Applicant)
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN
`Carton Labeling
`1. We note the statement,
`‘Pharmacist: reconstitute
`product prior to dispensing
`and dispense with dosing
`device’ on the principal
`display panel lacks
`prominence.
`
`RECOMMENDATION
`
`Improve the prominence of the
`statement ‘Pharmacist:
`reconstitute product prior to
`dispensing and dispense with
`dosing device’ on the principal
`display panel by increasing its
`font size, changing the font color
`from black to red, boxing the
`statement, or by other means.
`
`As currently presented, we are
`concerned this statement may
`be overlooked. As a result, the
`product might be dispensed to
`the patient as granules
`without reconstitution by the
`pharmacist.
`
`4
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`

`

`APPENDIX A. LABELS AND LABELING
`F.1
`List of Labels and Labeling Reviewed
`Using the principles of human factors and Failure Mode and Effects Analysis,c along with
`postmarket medication error data, we reviewed the following Myrbetriq Granules labels and
`labeling submitted by Astellas Pharma Global Development, Inc.
`
`Pouch Label received March 17, 2021 (one for Ireland and one for Japan)
`•
`• Container Label(s) received on March 17, 2021 and March 19, 2021
`• Carton labeling received on March 17, 2021 and March 19, 2021
`Prescribing Information (Image not shown) received on March 17, 2021 at the
`•
`following link: \\CDSESUB1\evsprod\nda213801\0036\m1\us\114-labeling\draft-
`labeling\draft-labeling-text\myrbetriq-uspi-clean-17mar21.docx
`
`c Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`5
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`5 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DENISE V BAUGH
`03/22/2021 06:19:35 PM
`
`CELESTE A KARPOW
`03/22/2021 10:34:34 PM
`
`
`
`Reference ID: 4766435Reference ID: 4772718
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Product Name and Strength:
`
`Date of This Memorandum:
`March 17, 2021
`Requesting Office or Division:
`Division of Urology, Obstetrics, and Gynecology (DUOG)
`Application Type and Number: NDA 213801 (mirabegron granules), NDA 202611/S-017
`(Myrbetriq)
`Myrbetriq granules (mirabegron for extended release oral
`suspension),
`8 mg/mL, 100 mL
`Myrbetriq (mirabegron extended release tablets),
`25 mg and 50 mg
`Astellas Pharma Global Development, Inc. (Astellas)
`2020-2062-1 (Myrbetriq Granules) and
`2020-2168-1 (Myrbetriq)
`Denise V. Baugh, PharmD, BCPS
`Celeste Karpow, PharmD, MPH
`
`Applicant/Sponsor Name:
`OSE RCM #:
`
`DMEPA Safety Evaluator:
`DMEPA Acting Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised container label, pouch and carton labeling received on March
`4, 2021 for Myrbetriq Granules (extended release for oral suspension) and revised container
`labels and carton labeling on March 11, 2021 and March 15, 2021 for Myrbetriq (extended
`release tablets). The Division of Urology, Obstetrics, and Gynecology (DUOG) requested that we
`review the revised container label, pouch label, and carton labeling (Appendices C and D) to
`determine if it is acceptable from a medication error perspective. The revisions are in response
`to recommendations that we made during a previous label and labeling reviewa and in response
`to an information request sent on March 5, 2021b.
`
`a Baugh, D. Label, Labeling, and Packaging Review for mirabegron granules (NDA 213801) and Myrbetriq (NDA
`202611/S-017). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2021 FEB 22. RCM No.: 2020-2062 and 2020-
`2168.
`b Roule, J. FDA Communication: Carton and Container for NDA 202611 for Myrbetriq. Silver Spring (MD): FDA,
`CDER, Division of Urology, Obstetrics, and Gynecology (US); 2021 MAR 04. NDA 202611 Supplement-17.
`1
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`

`

`Additionally, during the course of our review of the label and labeling for Myrbetriq
`granules (NDA 213801) and Myrbetriq (NDA 202611/S-017)c, the Office of Pharmaceutical
`Quality (OPQ) identified a discrepancy in the presentation of the established name for
`Myrbetriq (NDA 202611). Specifically, the presentation of the name on the approved
`Myrbetriq container label and carton labeling was determined to be inconsistent with the
`Prescribing Information (PI) for Myrbetriq Granules (mirabegron for extended-release oral
`suspension). As such, the Agency requested Astellas submit revised container and carton
`labeling for Myrbetriq (mirabegron) extended release tabletsd (Appendix D) and the
`Division of Urology, Obstetrics, and Gynecology (DUOG) requested that we review the
`revisions to the Myrbetriq container label and carton labeling.
`
`c Baugh D. Label, Labeling, and Packaging Review for Myrbetriq (NDA 213801) and mirabegron granules (NDA
`202611/S-017). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2021 FEB 22. RCM No.: 2020-2062 and 2020-
`2168.
`d Roule, J. FDA Communication: Carton and Container for NDA 202611 for Myrbetriq. Silver Spring (MD): FDA,
`CDER, Division of Urology, Obstetrics, and Gynecology (US); 2021 MAR 04. NDA 202611 Supplement-17.
`2
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`

`

` CONCLUSION
`2
`We provide additional recommendations for the Division to consider in the Myrbetriq Granules
`Prescribing Information (Table 2).
`Although the Applicant implemented or considered all of our Myrbetriq Granules container
`label and carton labeling recommendations (Appendix A), we have additional recommendations
`in Table 3 below.
`In addition, the sponsor submitted revised container labels and carton labeling for
`Myrbetriq extended-release tablets in response to the Agency’s March 5, 2021 request.
`The revised container labels and carton labeling submitted for the Myrbetriq extended-
`release tablets revised the established name from ‘Myrbetriq (mirbegron) extended
`release tablets’ to ‘Myrbetriq (mirabegron extended release tablets)’ which was
`recommended to the sponsor by OPQ. We have no concerns with the revisions to the
`established name based on the recommendations from OPQ.
`3
`RECOMMENDATIONS FOR ASTELLAS PHARMA GLOBAL DEVELOPMENT, INC.
`We recommend the following recommendations in Table 3 be implemented prior to approval
`of this NDA:
`
`Table 1. Identified Issues and Recommendations for Division of Urology, Obstetrics, and
`Gynecology (DUOG)
`RECOMMENDATION
`RATIONALE FOR CONCERN
`IDENTIFIED ISSUE
`Full Prescribing Information – Section 16 How Supplied/Storage and Handling
`1. We note the statement
`Revise the storage statement,
`Use of the word
`in section 16.2 of the PI,,
`‘Store the
`
`‘
`’ is not
`‘Store the
`
`suspension at 20˚C to 25˚C
`commonly used when
`suspension at 20˚C to
`(68˚F to 77˚F) . . . ‘to read
`referring to compounding
`25˚C (68˚F to 77˚F) . . .’
`‘Store the reconstituted
`activities and it may cause
`suspension at 20˚C to 25˚C
`confusion.
`(68˚F to 77˚F) . . . ‘
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`RECOMMENDATION
`
`Table 2. Identified Issues and Recommendations for Astellas Pharma Global Development,
`Inc. (entire table to be conveyed to Applicant)
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN
`Myrbetriq Granules Container Label(s) and Carton Labeling
`1. We note the statement
`Use of the word
`on the container label
`‘
`’ is not
`and carton labeling
`commonly used when
`(italics added for
`referring to compounding
`emphasis), ‘Store the
`activities and it may cause
` suspension
`confusion.
`at 20˚C to 25˚C (68˚F to
`77˚F) . . . ‘
`Myrbetriq Granules Carton Labeling
`
`Revise the storage statement,
`‘Store the
`
`suspension at 20˚C to 25˚C
`(68˚F to 77˚F) to read ‘Store
`the reconstituted suspension
`at 20˚C to 25˚C (68˚F to 77˚F) .
`. . ‘
`
`1.
`
`2.
`
`For pharmacist
`compounding
`instructions, we note
`that the pharmacist is
`instructed to measure
`100 mL of
`
`water.
`
`The statement
`‘Pharmacist: reconstitute
`product prior to
`dispensing and dispense
`with dosing device” lacks
`prominence and is
`located at the bottom of
`the principal display
`panel in small black font.
`
`Reference to
`
`
`
`.
`
`
`
`
`
`
`
`
`We are concerned that this
`statement may be
`overlooked and the
`pharmacist will dispense
`the product without adding
`water and mixing the
`contents.
`
`3.
`
`The statement
`
` is
`presented in red, bold
`
`
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`The statement
`
`
`
`
`
`competes in prominence
`4
`
`Consider revising the
`statement ‘
`
`
`
`’ to read
`‘Measure 100 mL of water . . .’
`so that the pharmacist can
`decide which water source is
`appropriate for compounding
`purposes.
`Move the statement,
`‘Pharmacist: Reconstitute
`product prior to dispensing
`and dispense with dosing
`device’ to appear before the
`‘Rx only’ and net quantity
`statements. Additionally,
`increase the prominence of
`this statement taking into
`account all pertinent factors,
`including typography, layout,
`contrast, and other printing
`features. See also
`recommendation # 4.
`Delete the statement ‘
`
`
`
` from the
`principal display panel.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`RECOMMENDATION
`
`Table 2. Identified Issues and Recommendations for Astellas Pharma Global Development,
`Inc. (entire table to be conveyed to Applicant)
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN
`font on the principal
`with more important
`display panel.
`information on the principal
`display panel. In addition,
`this statement appears
`under pharmacist
`preparation instructions as
`well as in the
`patient/caregiver
`instructions and is
`redundant.
`We are concerned that this
`statement may be
`overlooked.
`
`4. On the principal display
`panel, the statement
`‘shake vigorously for 1
`minute before each use’
`is located below the ‘Rx
`only’ statement and the
`net quantity ‘100 mL’.
`
`We recommend relocating the
`statement ‘shake vigorously
`for 1 minute before each use’
`to appear after the statement,
`‘Pharmacist: Reconstitute
`product prior to dispensing
`and dispense with dosing
`device’ and to appear before
`the ‘Rx only’ and ‘net quantity
`statement’.
`Therefore, we recommend the
`following sequence of
`information appear below the
`drug identifying information
`on the principal display panel:
`‘Pharmacist: Reconstitute
`product prior to dispensing
`and dispense with dosing
`device’
`Discard after __/__/___
`‘Shake vigorously for 1 minute
`before each use’
`We recommend the Rx Only
`and net quantity statements
`appear below the
`aforementioned statements
`on the principal display panel.
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`5
`
`

`

`5.
`
`RECOMMENDATION
`Ensure the side panel of the
`carton labeling, titled,
`‘PHARMACIST:’ aligns with
`Section 2.6 of the ‘to-be-
`marketed’ PI.
`
`Table 2. Identified Issues and Recommendations for Astellas Pharma Global Development,
`Inc. (entire table to be conveyed to Applicant)
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN
`Since the Prescribing
`We are concerned that
`Information (PI) has
`differences between the
`been revised, the
`pharmacist preparation
`Preparation instructions
`instructions on the carton
`for the pharmacist on
`labeling and Section 2.6
`the carton labeling
`(Preparation and Storage
`submitted March 4, 2021
`Instructions for Myrbetriq
`are not the same as
`Granules) of the Prescribing
`Section 2.6 (Preparation
`Information may cause
`and Storage Instructions
`confusion and may cause
`for Myrbetriq Granules)
`important steps to be
`PI.
`overlooked.
`DMEPA preliminarily agreed with the proposed pharmacist preparation instructions below for
`Section 2.6 of the PI submitted by email to the Agency on March 12, 2021,:
`• Discard the pouch and desiccant prior to reconstitution. Do not dispense.
`Tap the closed bottle several times to loosen the granules.
`•
`• 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.
` 1 minute.
`If granules have not dispersed, shake vigorously for
`•
`• Record the 28 day expiration date on the container and carton based on the
`reconstitution date.
`• 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.
`•
`• Discard the unused portion after 28 days.
`After reconstitution with 100 mL water, the suspension contains 8 mg/mL of mirabegron.
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`6
`
`(b) (4)
`
`

`

`APPENDIX A. ASTELLAS’ RESPONSE TO FEBRUARY 23, 2021 INFORMATION REQUEST
`(RECEIVED FROM SPONSOR MARCH 5, 2021)
`\\CDSESUB1\evsprod\nda213801\0031\m1\us\111-information-amendment\multiple-module-
`information-amendments\1-11-4-information-amendment.pdf
`
`APPENDIX B. ASTELLAS’ RESPONSE TO MARCH 5, 2021 INFORMATION REQUEST (RECEIVED
`FROM SPONSOR MARCH 15, 2021)
`\\CDSESUB1\evsprod\nda202611\0186\m1\us\12-cover-letters\cover-letter.pdf
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`7
`
`15 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DENISE V BAUGH
`03/17/2021 02:56:12 PM
`
`CELESTE A KARPOW
`03/17/2021 03:08:03 PM
`
`
`
`Reference ID: 4763969Reference ID: 4772718
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy
`
`PATIENT LABELING REVIEW
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`March 4, 2021
`
`Nenita Crisostomo, RN
`Regulatory Health Project Manager
`Division of Urology, Obstetrics, and Gynecology
`(DUOG)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Nyedra W. Booker, PharmD, MPH
`Senior Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`Elvy Varghese, PharmD.
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`Drug Name (established
`name), Dosage Form
`and Route and
`Application
`Type/Number :
`
`MYRBETRIQ GRANULES (mirabegron for extended-
`release oral suspension), NDA 213801
`MYRBETRIQ (mirabegron extended-release tablets) for
`oral use, NDA 202611/S-017
`
`Applicant:
`
`Astellas Pharma Global Development, Inc.
`
`
`
`Reference ID: 4756838Reference ID: 4772718
`
`

`

`1
`
`INTRODUCTION
`On September 23, 2020, Astellas Pharma Global Development, Inc. submitted for
`the Agency’s review an Original New Drug Application (NDA 213801): Request for
`Priority Review Designation, for MYRBETRIQ GRANULES (mirabegron for
`extended-release oral suspension). The proposed indication for MYRBETRIQ
`GRANULES (mirabegron for extended-release oral suspension) is for the treatment
`of neurogenic detrusor overactivity (NDO) in pediatric patients.
`On September 28, 2020, Astellas Pharma Global Development, Inc. submitted for
`the Agency’s review a Prior Approval Supplement (PAS): Labeling Exclusivity
`Determination Requested/Request for Priority Review Designation, to the Original
`New Drug Application (NDA 202611/S-017) for MYRBETRIQ (mirabegron
`extended-release tablets) for oral use. The purpose of this submission is to