CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`213801Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Cross-Discipline Team Leader (CDTL) Brief Memo
`
`Date
`From
`Subject
`NDA/BLA#
`/Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN)
`names
`Dosage forms /
`Strengths
`
`March 24, 2021
`Mark S. Hirsch, M.D.
`Cross-Discipline Team Leader (CDTL) Brief Memo
`NDA 202611 S-017
`NDA 213801
`Astellas Pharma US, Inc.
`September 28, 2020
`March 26, 2021
`Myrbetriq (mirabegron extended-release tablets)
`Myrbetriq Granules (mirabegeron extended-release granules for
`oral suspensión)
`Myrbetriq: Starting dose: 25 mg once daily. May increase to 50
`mg once daily after 4 to 8 weeks.
`
`Myrbetriq Granules: See table for once daily starting dose. May
`increase to lowest effective once daily dose after 4 to 8 weeks.
`Body Weight
`Starting Dose
`Maximum Dose
`11 kg to less than 22 kg
`3 mL (24 mg)
`6 mL (48 mg)
`22 kg to less than 35 kg
`4 mL (32 mg)
`8 mL (64 mg)
`Greater than or equal to 35 kg
`6 mL (48 mg)
`10 mL (80 mg)
`Myrbetriq: Treatment of neurogenic detrusor overactivity (NDO)
`in pediatric patients aged 3 years and older and weighing 35
`kilograms or more
`Myrbetriq Granules: Treatment of NDO in pediatric patients aged
`3 years and older
`Approval
`
`Indication(s)
`
`Recommended:
`
`The purpose of this CDTL Brief Memo Update is:
`
`1) To confirm my agreement with the review teams’ recommendations for Approval of
`these applications,
`
`2) To provide brief summaries of the discipline-specific and consultative reviews, and
`
`3) To confirm my agreement with the final labeling for these NDAs.
`
`1. Confirm CDTL Recommendation for Approval
`
`CDTL Note: For full CDTL conclusions on benefits and risks of Myrbetriq and Myrbetriq
`Granules for treatment of NDO in pediatric patients, the reader is referred to the final
`Clinical Review dated March 18, 2021, under the heading “Benefit-Risk Assessment”
`(Section 1.3). Here, I briefly summarize conclusions on the product’s benefits and risks
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`1
`
`

`

`and confirm my agreement with the teams’ regulatory decisions to approve these
`applications.
`
`Background
`Mirabegron is a selective beta-3 adrenergic receptor agonist. Activation of beta-3 adrenergic
`receptors that reside on bladder smooth muscle causes relaxation of bladder smooth muscle
`inhibition of involuntary detrusor muscle contractions, and increased bladder capacity.
`Mirabegron is currently approved as Myrbetriq 25 mg and 50 mg mirabegron extended-release
`tablets for the treatment of overactive bladder (OAB) in adults. The Sponsor now provides
`data concerning the safety and efficacy of mirabegron for the treatment of neurogenic detrusor
`overactivity (NDO) in pediatric patients aged 3 years and older. NDO is defined as detrusor
`overactivity that occurs as a result of a known neurologic lesion, such as congenital
`myelomeningocele (spina bifida) or spinal cord injury. The goal of therapy in pediatric NDO is
`to preserve renal function and to minimize symptoms of detrusor overactivity by increasing
`bladder capacity. The clinical studies that support these applications investigated the approved
`Myrbetriq tablets (mirabegron extended-release tablets) and also a new mirabegron
`formulation, Myrbetriq Granules (mirabegron extended-release granules for oral suspension).
`Myrbetriq tablets are considered appropriate for children weighing 35 kg or more. Mybretriq
`Granules, the new oral suspension, facilitates swallowing for younger children and allows
`more accurate dose titration.
`
`Efficacy
`The efficacy of Myrbetriq and Myrbetriq Granules was demonstrated in the phase 3 study 178-
`CL-206A, an open-label, baseline-controlled, multicenter, dose-titration study in 86 pediatric
`patients aged 3 to < 18 years with NDO who had been practicing continuous intermittent
`catheterization (CIC). The study included a 24-week, dose-titration period followed by a 28-
`week, fixed-dose period. As previously mentioned, two dosage forms were studied: Myrbetriq
`(in patients ≥ 35 kg), and Myrbetriq Granules (in patients < 35 kg, and patients ≥35g who
`could not, or who preferred not, to take tablets). The study demonstrated clinically meaningful
`increases in maximum cystometric capacity, the primary efficacy endpoint, as well as
`improvements in the secondary efficacy endpoint, that included other urodynamic parameters
`and e-diary recorded bladder volume and urinary leakage measurements. The magnitude of
`treatment effect was similar across age groups.
`
`Safety
`The safety of Myrbetriq and Myrbetriq Granules was assessed in a total of 86 pediatric patients
`with NDO. Overall, the safety profile of mirabegron in pediatric patients with NDO was
`consistent with its safety profile in the treatment of adults with OAB. In the 52-week study
`178-CL-206A, there were no deaths and no drug-related SAEs. Discontinuations due to AEs
`were few (n=3) and none were determined to be study drug related. The most commonly
`reported adverse reactions were UTI (24.4%, which includes E.coli UTI, UTI bacterial, UTI,
`and UTI Pseudomonal), nasopharyngitis (5.8%), constipation (4.7%), and headache (3.5%).
`The high incidence of UTI events was thought to reflect, at least in part, the high incidence of
`UTI in pediatric NDO patients practicing CIC. AEs of special interest, also determined to be
`not drug related, included: bradycardia, QT prolongation, neoplasm, and seizure, each reported
`in a single patient; hypersensitivity reactions (n=5); and fetal disorder after exposure during
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`2
`
`

`

`pregnancy (n=1), which was erroneously coded. Vital signs assessment showed a mean
`increase from baseline in blood pressure (BP) of 4.3 mm Hg systolic and 1.7 mm Hg diastolic
`for patients less than 12 years of age. Larger BP increases were observed in patients less than 8
`years of age. The increases in BP did not appear to increase with mirabegron exposure.
`Finally, postmarketing AE cases were either confounded by comorbid conditions and
`concomitant medications or lacked key clinical information.
`
`Risk: Benefit
`From an overall risk: benefit perspective, mirabegron tablets and oral suspension are
`efficacious, have an acceptable safety profile consistent with the safety profile in adults, and
`provide an alternative treatment option for pediatric patients with NDO. Mirabegron tablets
`and oral suspension are a once-daily dosing regimen, and the data support safety and efficacy
`for patients as young as 3 years. The benefits compare favorably against the risks, which are
`similar to, and consistent with, the known risks in adults with OAB. The clinical studies of
`mirabegron tablets and oral suspension in pediatric patients with NDO identified no safety
`signals beyond those already known for mirabegron tablets in adults with OAB. Labelling is
`adequate to address the known risks.
`
`I confirm my agreement with the review team that the applications for Myrbetriq and
`Myrbetriq Granules for the treatment of NDO in patients 3 years of age and older should be
`Approved.
`
`2. Brief Summaries of the Discipline-Specific and
`Consultative FDA Reviews
`
`CDTL Note: For additional details on the discipline-specific and consultative reviews
`completed through May 18,2020, the reader is referred to the final Clinical Review dated
`March 18, 2021, under “Significant Issues from Other Review Disciplines Pertinent to
`Clinical Conclusions on Efficacy and Safety.” The reader is also referred to the final
`discipline-specific reviews themselves. Here, I summarize the recently completed
`discipline-specific and consultative reviews.
`
`2.1 Chemistry
`In the final Integrated Quality Assessment (IQA), dated March 24, 2021, the Chemistry (OPQ)
`team of Sam Bain, Donna Christner, Mark Seggel, Wendy Wilson-Lee, Yong Wu, Yubing
`Tang, Jason God, Julie Nemecek, Assadollah Noory, Vidula Kolhatkar, and Hong Cai had the
`following Recommendation and Conclusion:
`
`“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.
`
`3
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`

`

`The prescribing information (PI) and patient package insert (PPI) as submitted March 23,
`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.”
`
`From the Chemistry review, the following is also notable:
`
`• The maximum use-period after Myrbetriq Granules are reconstituted with water is 28
`days at room temperature. This information was incorporated into labeling.
`
`• The dissolution rate of mirabegron from Myrbetriq Granules when alcohol is added
`(alcohol dose-dumping study) is increased. The addition of alcohol (5, 10, 20, and
`40%) increased the dissolution rate of mirabegron from Myrbetriq granules at pH 6.8.
`This information was incorporated into labeling.
`
`2.2 Division of Biometrics III (DB3)
`In their final Statistical review dated March 11, 2021, Jia Guo and Daphne Lin had the
`following Conclusion:
`
`“…Based on reviewer’s analyses, the submitted study demonstrated clinical benefit for this
`indication in pediatric patients…The study demonstrated that there is clinical benefit of
`mirabegron in treatment of NDO in pediatric subjects”.
`
`2.3 Clinical
`In our final Clinical review dated May 18, 2020, Elena Boley and I had the following
`Conclusion:
`
`“At this time, the Clinical review team recommends that this NDA and sNDA should be
`APPROVED”.
`
`In regard to efficacy, safety and risk: benefit analysis, the Clinical team concluded:
`
`•
`
`•
`
`“From the Clinical perspective, the evidence presented in this NDA and sNDA is
`adequate to support the effectiveness of this product in the treatment of pediatric
`patients with NDO.”
`
`“The safety profile of mirabegron tablets and oral suspension is consistent with the
`known risks of mirabegron tablets for the treatment of OAB in adults”.
`
`4
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`

`

`•
`
`“Mirabegron tablets and oral suspension provide an alternative treatment to the
`currently approved options, is efficacious, and has a different side effect profile.
`Additionally, mirabegron tablets and oral suspension offer a convenient once daily
`dosing regimen and data (was provided) to support safety and efficacy for pediatric
`patients as young as 3 years old. The benefits compare favorably against the safety
`profile which reflects the known risks apparent in the premarket and post-market
`experience with mirabegron tablets to date. The clinical trials of mirabegron tablets
`and oral suspension provided no safety signals beyond those known for mirabegron
`tablets in adults with OAB. Labelling is adequate to address the known risks of
`mirabegron….”
`
`2.4 Office of Clinical Pharmacology (OCP)
`In their final Clinical Pharmacology review dated March 5, 2021, Peng Zou, Yun Wang,
`Jingyu (Jerry) Yu, and Yanhui Lu had the following Conclusion:
`
`“The Office of Clinical Pharmacology, Division of Cardiometabolic and Endocrine
`Pharmacology and Division of Pharmacometrics, have reviewed the information contained
`in NDA 213801 and NDA 202611/S-017 and recommend approval of this NDA. The
`information also satisfies the PREA requirements 1898-1 and 1898-2 outlined in the
`approval letter for NDA 202611 dated Jun 28, 2012 and the written requests issued on
`Mar 18, 2016.”
`
`From the Clinical Pharmacology review, the following is also notable:
`
`•
`
`In pediatric patients, Myrbetriq and Myrbetriq Granules should be taken with food.
`This information was incorporated into labeling.
`
`• The weight-based doses of mirabegron in pediatric patients are:
`o Body weight ≥ 35 kg: tablets 25 to 50 mg once daily; granules 48 to 80 mg
`once daily
`o Body weight ≥ 22 kg and < 35 kg: granules 32 to 64 mg once daily
`o Body weight < 22 kg: granules 24 to 48 mg once daily
`This information was incorporated into labeling.
`
`• The dosing recommendations for specific pediatric populations are:
`o No dose adjustment is needed for pediatric patients with mild to moderate renal
`impairment or mild hepatic impairment.
`o The daily dose should not exceed the recommended starting dose in pediatric
`patients with severe renal impairment or moderate hepatic impairment.
`o Myrbetriq and Myrbetriq Granules are not recommended for use in pediatric
`patients with end-stage renal disease (ESRD) or severe hepatic impairment.
`This information was incorporated into labeling.
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`5
`
`

`

`2.5 Pharmacology/Toxicology
`In their final Pharmacology/Toxicology review dated February 26, 2021, Laurie McLeod-
`Flynn and Kim Hatfield had the following Conclusion:
`
`“Pharmacology/Toxicology recommends approval of this application.”
`
`From the Pharmacology/Toxicology review, the following was also notable:
`
`• “In a juvenile rat study…no general toxicity specific to the juvenile period of
`development was identified under the conditions of this study”.
`
`• “No changes to Section 8 (Pregnancy) or Section 13 (Animal Toxicology) of the label
`are proposed, since adult and pediatric exposures to mirabegron (AUCs) are similar”.
`
`2.6 Division of Medical Policy Program (DMPP)
`In their final Patient Labeling review dated March 4, 2021, Nyedra Booker, Elvy Varghese
`and LaShawn Griffiths had the following Conclusion:
`
`“…The PPI is acceptable with our recommended changes.”
`
`All labeling changes recommended by DMPP were successfully instituted.
`
`2.7 Office of Prescription Drug Promotion (OPDP)
`In her final OPDP review dated March 3, 2021, Elvy Varghese stated:
`
`“OPDP’s comments on the proposed labeling are based on the draft labeling received by
`electronic mail from DUOG (Nenita Crisostomo) on February 24, 2021, and are provided
`below…OPDP has reviewed the attached proposed carton and container labeling for
`Myrbetriq Granules submitted by the Sponsor to the electronic document room on January
`4, 2021, and our comments are provided below…”
`
`All labeling comments made by OPDP were successfully addressed, either through internal
`discussion or by instituting specific labeling changes.
`
`2.8 Division of Medication Errors Prevention and Analysis (DMEPA)
`In their final DMEPA labeling reviews dated March 17, 2021 and February 22, 2021, Denise
`Baugh and Celeste Karpow had the following Conclusions:
`
`In regard to container and carton labeling:
`“Although the Applicant implemented or considered all of our Myrbetriq Granules
`container and carton labeling recommendations (Note: the recommendations from
`DMEPA’s February 22, 2021, review), we have additional recommendations…below…”.
`
`“The revised container and carton labeling submitted for Myrbetriq extended release
`tablets revised the established name from ‘Myrbetriq (mirabegron) extended release
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`6
`
`

`

`tablets’ to ‘Myrbetriq (mirabegron extended release tablets)’…We have no concerns with
`the revisions to the established name based on the recommendations from OPQ”.
`
`In regard to the Prescribing Information (PI):
`“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)”
`
`On March 24, 2021, the Sponsor returned a final carton label that was found acceptable by
`DMEPA (via email from Celeste Karpow, March 24, 2021). That final item served to
`conclude the successful labeling discussions with Sponsor that resolved all carton and
`container labeling issues. All labeling changes recommended by DMEPA were successfully
`instituted or resolved.
`
`In their final DMEPA tradename review dated February 5, 2021, 2020, Beverly Weitzman and
`Celeste Karpow had the following Conclusion:
`
`“The proposed proprietary name, Myrbetriq Granules, is acceptable.”.
`
`2.9 Office of Scientific Investigations (OSI)
`In their final OSI consult dated January 28, 2021, Ling Yang, Min Lu and Kassa Ayalew had
`following Conclusion:
`
`“The ongoing COVID-19 global pandemic has significantly limited ORA’s ability to
`conduct onsite GCP inspections. Following discussions between OSI and DUOG, a
`decision was made that assessment of the application could proceed without GCP
`inspections if they were not possible before the action due date. At this time, following
`guidelines to protect the health, safety, and welfare of FDA employees and study staff,
`and with repeated evaluations of the current situation and mission-critical priorities,
`the planned inspections in support of NDA 213801 have been cancelled”.
`
`We conducted a thorough review of the results from study 178-CL-206A and identified no
`data discrepancies, significant differences between subgroups, nor reasons to request a for-
`cause inspection. For these reasons, we dispensed with routine clinical site inspections.
`
`2.10 Interdisciplinary Review Team for Cardiac Safety Studies (IRT-CSC)
`In their final IRT-CSC consult dated January 27, 2021, in response to DUOG questions
`concerning AEs reported as QT prolongation, Lars Johannesen and Christine Garnett had
`following Conclusions:
`
`“We recommend Fridericia’s correction for HR unless there are significant increases in
`HR, which is generally defined as a mean increase of > 10 bpm. We do not recommend the
`use of Bazett’s correction for QT because it has been shown to be inferior for adults (ICH
`E14 Q&A (R3) section 1.5) and has been shown to be associated with false positive
`increases in QTc particularly if the heart rate is elevated. In the thorough QT study for
`mirabegron, the observed mean HR increase at 50 mg was less than 10 bpm and it
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`7
`
`(b) (4)
`
`

`

`therefore seems reasonable to use Fridericia’s correction method for doses not associated
`with significantly higher exposure than 50 mg.”
`
`“The 9 individual cases reported in the consult request do not elevate the risk of QT
`prolongation by mirabegron because there were no cases of QTcF prolongation as defined
`by QTcF > 450 ms. The fluctuations in QTcF are due to normal variability in the QTcF”.
`
`2.11 Division of Pediatric and Maternal health (DPMH)
`In their final DPMH consult dated February 16, 2021, in response to a DUOG request for
`consultative advice on vital signs data, Shamir Tuchman, Mona Khurana and John Alexander
`had the following findings and Conclusions:
`
`• “In children, the (mean) SBP increased by 4.3 mm Hg and the (mean) DBP by 1.7 mm
`Hg from baseline after the week 4 in-clinic visit. Within this group, the (mean) SBP
`increased by 5.9 mm Hg and the (mean) DBP increased by 2.3 mm Hg from baseline
`after the week 4 in-clinic visit in patients less than 8 years of age.
`• The magnitude of the observed SBP and DBP increases seen in adolescents from Study
`178-CL-206A were similar to those already reported in the approved adult
`population….
`• Mirabegron appears to have increased BP disproportionately in children compared
`with adolescents…. The reasons for this occurrence are unclear based on review of the
`vital sign data.
`• Approximately 22% of the children who were normotensive at baseline developed at
`least one measured BP at or above the 95th percentile (Note: for normal BP) in Study
`178-CL-206A, and HTN (Note: BP at or above the 95th percentile for normal BP) was
`sustained in approximately 60% of these children.
`• None of the observed BPs in children led to stage II HTN, and one adolescent
`developed stage II HTN which was not sustained. No patients required discontinuation
`from the trial because of changes in BP or HR.
`• Mirabegron appeared to impact SBP more than DBP… A potential explanation in the
`preferential increase in SBP relative to DBP with mirabegron use may include off-
`target beta-1adrenergic effects that caused increased cardiac inotropic and
`chronotropic effects without changes in peripheral vascular resistance.
`• The increases in BP, which caused sustained shifts in BP categories in more than half
`of the children, do not represent a barrier to approvability of mirabegron but should be
`described in mirabegron labeling…monitoring for an adverse reaction of HTN
`is readily possible with mirabegron use and approved anti-hypertensive drug products
`can be used to lower BP in children where chronic use is needed… Symptoms, such as
`headaches, which may be attributable to BP increases were uncommon in Study 178-
`CL-206A and did not lead to discontinuation of mirabegron…. If DUOG plans to
`approve the dosages administered in Study 178-CL-206A for use in patients 3 to less
`than 12 years of age, labeling should reflect changes in BP associated with use at the
`approved dosages, particularly in younger children (e.g. 3 to 7 years of
`age)…Mirabegron did not cause clinically meaningful changes from baseline in HR in
`children and adolescent patients in Study 178-CL-206A…Describe (the) BP and HR
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`8
`
`

`

`findings from Study 178-CL-206A in Sections 5, 6, and 8.4 of product labeling with
`pediatric approval for NDO”.
`All labeling changes recommended by DPMH were instituted in labeling.
`
`2.12 Pediatric Review Committee (PeRC)
`In the final March 11, 2021, meeting minutes from the February 23, 2021, PeRC meeting,
`PeRC had the following Conclusion:
`
`“The PeRC agrees that the PREA PMR has been fulfilled and that this product has been
`fully assessed for pediatric patients 3 years and older and the labeling will be updated
`accordingly”.
`
`2.13 Pediatric Exclusivity Meeting (PedEx)
`In the final March 1, 2021, meeting minutes from the February 10, 2021, PedEx meeting,
`Niquiche Guity and Mary Thanh Hai of PedEx stated:
`
`“Pediatric Exclusivity Granted”
`3. Confirm CDTL Agreement with Final Labeling
`Labeling discussions were held with the entire FDA review team on February 4, 5, 10, 11, 16
`and 18, 2021. The Division’s edits to the Myrbetriq/Myrbetriq Granules (combined) PI were
`conveyed to Sponsor on February 24, 2020.
`
`The Sponsor accepted most of the Division’s edits and returned the PI with revisions on March
`5, 2021.
`
`The FDA review team met again on March 10, 2021 to discuss the Sponsor’s edits to the
`FDA-edited PI and to complete FDA edits to the Sponsor’s Myrbetriq and Myrbetriq Granules
`combined PPI. The Division’s current edits to the PI and PPI were conveyed to Sponsor on
`March 11, 2021 and March 16, 2021, respectively.
`
`The Sponsor accepted almost all of the Division’s edits to the PI and returned that document
`on March 17, 29021 with a few minor additional Sponsor revisions. The Division accepted the
`Sponsor’s edits to the PI, made one final edit, and conveyed the PI back to Sponsor on March
`18, 2021. The Sponsor returned the PI on March 19, 2021 with full agreement.
`
`The Sponsor also returned the PPI on March 19, 2021, accepting all the FDA edits, and adding
`a few Sponsor edits. FDA had two final edits to the PPI which were conveyed to the Sponsor
`on March 22, 2021, and the Sponsor agreed to these last two PPI changes and returned the
`final PPI (along with a final PI) on March 23, 2021.
`
`I confirm that I agree with the final agreed-upon Myrbetriq/Myrbetriq Granules PI and PPI.
`
`In parallel with labelling discussion on the PI and PPI, there have been discussions with
`Sponsor concerning the container and carton labeling. On March 19, 2021, the Sponsor
`
`9
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`

`

`submitted revised container/carton labeling meant to comply with all prior DMEPA requests
`for revision. The final container/carton labels, containing minor Sponsor edits only, were
`reviewed by DMEPA and found acceptable, except for one minor additional DMEPA
`recommendation for the carton label, which was conveyed to Sponsor on March 23, 2021 and
`agreed by Sponsor on March 24, 2021. All issues for carton and container labeling have been
`resolved.
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`10
`
`

`

`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/
`------------------------------------------------------------
`
`MARK S HIRSCH
`03/24/2021 05:40:00 PM
`
`CHRISTINE P NGUYEN
`03/24/2021 05:48:49 PM
`
`
`
`Reference ID: 4767808Reference ID: 4772718
`
`