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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`213801
`eCTD 0001
`28 September 2020
`28 September 2020
` Granules (mirabegron)
`MYRBETRIQ®
`Neurogenic detrusor overactivity (NDO) in
`pediatric patients aged 3 years and older
`Astellas Pharma Global Development Inc.
`Applicant:
`Division of Urology, Obstetrics and Gynecology
`Review Division:
`Laurie McLeod-Flynn, Ph.D., D.A.B.T.
`Reviewer:
`Kimberly Hatfield, Ph.D.
`Supervisor/Team Leader:
`Christine Nguyen, M.D.
`Division Director:
`Nenita Crisostomo,
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 213801 are owned by Astellas or are data for which
`Astellas has obtained a written right of reference. Any information or data necessary for
`approval of NDA 213801 that Astellas does not own or have a written right to reference
`constitutes one of the following: (1) published literature, or (2) a prior FDA finding of
`safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling.
`Any data or information described or referenced below from reviews or publicly
`available summaries of a previously approved application is for descriptive purposes
`only and is not relied upon for approval of NDA 213801.
`
`
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`Reference ID: 4753735Reference ID: 4772718
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY...........................................................................................3
`INTRODUCTION .....................................................................................................3
`1.1
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................3
`1.2
`RECOMMENDATIONS .............................................................................................3
`1.3
`2 DRUG INFORMATION..............................................................................................3
`DRUG ..................................................................................................................3
`2.1
`RELEVANT INDS, NDAS, BLAS AND DMFS............................................................4
`2.2
`DRUG FORMULATION ............................................................................................4
`2.3
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.......................................5
`2.6
`REGULATORY BACKGROUND .................................................................................5
`2.7
`STUDIES SUBMITTED.............................................................................................5
`STUDIES REVIEWED..............................................................................................5
`3.1
`PREVIOUS REVIEWS REFERENCED.........................................................................5
`3.3
`6 GENERAL TOXICOLOGY........................................................................................5
`REPEAT-DOSE TOXICITY .......................................................................................5
`6.2
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................11
`
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`Executive Summary
`1
`Introduction
`1.1
`MYRBETRIQ®
` Granules (mirabegron) is a beta-3 adrenergic agonist indicated for
`the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged
`3 years and older. MYRBETRIQ (mirabegron) 25 mg and 50 mg tablets were approved
`on 28 June 2012 under NDA 202611, for the treatment of overactive bladder (OAB) in
`adult patients.
`1.2 Brief Discussion of Nonclinical Findings
`In a juvenile rat study, mirabegron was administered at 0, 3, 10, and 30 mg/kg/day for
`13 weeks (beginning at 10 days of age), followed by a 4-week recovery period. At 10
`mg/kg/day and above (about twice the exposure in children at the MRHD of 50 mg/day),
`a reversible decrease in lipid droplets in white and brown adipose tissue (accompanied
`by decreases in body weight at 30 mg/kg/day, primarily in male rats), an expected effect
`of increased lipid metabolism in rats following beta-3-adrenergic agonism, was
`observed. The no effect level for this effect was 3 mg/kg/day. Similar results were
`observed in adult rats following 13 weeks of exposure. No adverse effects on
`development, behavior, sensory function, reproductive performance, or fertility were
`observed even at the high dose of 30 mg/kg/day (greater than 12 times). Liver was
`identified as a target organ at high doses in adult rats.
`
`No general toxicity specific to the juvenile period of development was identified under
`the conditions of this study.
`
`1.3 Recommendations
`1.3.1 Approvability
`Pharmacology/Toxicology recommends approval of this application.
`1.3.3
`Labeling
`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
`Drug Information
`2.1 Drug
`Generic Name: mirabegron
`
`Code Name: YM178
`
`Chemical Name: 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-
`phenylethyl]amino}ethyl)phenyl] acetamide
`
`
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`Molecular Formula/Molecular Weight: C21H24N4O2S / 396.5 g/mol
`Structure or Biochemical Description
`
`Pharmacologic Class: beta-3-adrenergic agonist
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`NDA 202611, IND 69416
`2.3 Drug Formulation
`MYRBETRIQ® Granules (Mirabegron granules for oral suspension): The granules in
`a
` bottle are mixed with 100 mL of water in the same
` bottle to prepare 8 mg/mL of oral suspension including the total volume of the
`granules.
`
`Composition of Mirabegron Granules for Oral Suspension
`
`USP: United States Pharmacopeia, NF: National Formulary, Ph. Eur.: European Pharmacopoeia
`
`Sponsor’s table
`
`MYRBETRIQ ER tablets (approved in 2012): Each MYRBETRIQ extended-release
`tablet for oral administration contains either 25 mg or 50 mg of mirabegron and the
`following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl
`cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric
`oxide, and red ferric oxide (25 mg tablet only).
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`Proposed Clinical Population and Dosing Regimen
`2.6
`Pediatric patients aged 3 years to < 18 years with neurogenic detrusor overactivity
`(NDO)
`2.7 Regulatory Background
`Myrbetriq (mirabegron) 25 mg and 50 mg tablets were approved on 28 Jun 2012 under
`NDA 202611 for the treatment of OAB in adult patients.
`3
`Studies Submitted
`3.1
`Studies Reviewed
`A 13-Week Oral Dose Toxicity Study of YM178 in Juvenile Rats with a 4-Week
`Recovery Period
`3.3
`Previous Reviews Referenced
`Application
`Reviewer
`IND 69416
`Eric Andreasen
`NDA 202611
`Eric Andreasen
`
`Date in DARRTS
`5/13/13
`4/11/12
`
`General Toxicology
`6
`6.2 Repeat-Dose Toxicity
`Study title: A 13-Week Oral Dose Toxicity Study of YM178 in Juvenile Rats
`with a 4-Week Recovery Period
`Study no.:
`Conducting laboratory and location:
`Date of study initiation:
`GLP compliance:
`QA statement:
`Drug, lot #, and % purity:
`
`6 February 2012
`yes
`yes
`YM178, Lot no. GLP-08020004, 100.7%
`pure
`
`178-TX-055
`
`Key Study Findings
`At 10 mg/kg/day and above, a decrease in lipid droplets in white and brown adipose
`tissue (accompanied by decreases in body weight at 30 mg/kg/day), an expected effect
`of increased lipid metabolism in rats following beta-3-adrenergic agonism, was
`observed. The no effect level for this effect was 3 mg/kg/day. However, no adverse
`effects on development, behavior, sensory function, reproductive performance, or
`fertility were observed even at the high dose of 30 mg/kg/day.
`
`No general toxicity specific to the juvenile period of development was identified under
`the conditions of this study.
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
`
`Methods
`
`Doses: 0, 3, 10, or 30 mg/kg/day (based on death at 100
`mg/kg/day in a dose range-finding study (IND
`69416, 178-TX-054, 13 November 2012).
`Frequency of dosing: daily
`Route of administration: Oral, gavage
`Dose volume: 10 mL/kg/day
`Formulation/Vehicle: 0.5% aqueous methylcellulose
`Species/Strain: Rats (SPF), Crl:CD(SD)
`Number/Sex/Group: 16 for general toxicity; 24 for development
`Age: 10 days
`Weight: Males 22.0-31.5 g, Females 22.9-32.1 g
`Satellite groups: 6/sex/group for toxicokinetics
`Study design: Juvenile rats were initially dosed at 10 days of
`age. One group was assessed for general
`toxicity; a second group was used to assess
`development, behavior, and reproductive
`function after 13 weeks of dosing and 4 weeks of
`recovery.
`
`Observations and Results
`
`Mortality
`No treatment related mortality was observed. One male each at 3 and 30
`mg/kg died from dosing errors, and one female at 30 mg/kg was euthanized 25 days
`after the last dose (irregular breathing first observed 16 to 18 days after the
`last dose), with foamy fluid observed in lungs and trachea.
`Clinical Signs
`Increased salivation was observed at 10 mg/kg/day (approximately 2-fold the MRHD in
`children, as it was in the 13-week adult rat toxicity study (NDA 202611, Study no. 178-
`TX-020).
`
`Number of animals
`Unusual resting position
`Salivation
`Lacrimation
`
`Males (mg/kg/day)
`0
`3
`31
`26
`
`10
`26
`26
`2
`
`30
`31
`30
`24
`1
`
`Females (mg/kg/day)
`0
`3
`10
`31
`26
`26
`24
`
`30
`31
`31
`4
`
`Body Weights
`Body weights in males were decreased (7% to 12%) in the general toxicology group
`(and 6 to 16% in the development group) at 30 mg/kg/day (12-fold) from weeks 10 to
`13. Following the recovery period, body weights recovered by about half. Decreased
`
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`weight gain is expected pharmacology for beta-3 agonists in rats due to effects on fat
`metabolism.
`
`Female body weights were transiently reduced weeks 7 to 19 of dosing at 30 mg/kg/day
`in the general toxicology group but not in the development group. Body weights of dams
`were not affected during pregnancy.
`
`Decreases in body weight were also observed in the adult rat toxicity studies at 30 and
`100 mg/kg/day.
`
`Sponsor’s figure
`
`Sponsor’s figure
`Feed Consumption
`Food consumption was slightly increased during weeks 9 to 10 of dosing in males at 30
`mg/kg.
`Ophthalmoscopy
`No treatment related effects were observed.
`Hematology
`At 30 mg/kg/day, lymphocytes were slightly increased females, a finding that persisted
`following recovery. No effects were observed at 10 mg/kg/day. Similar findings were
`observed in adult rats.
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`Clinical Chemistry
`At 30 mg/kg/day, AST (20 %) and ALT (48%) were increased in both sexes, and
`triglycerides (58%) and calcium (3%) were decreased in males. All effects were
`reversed in males following recovery but were incompletely reversed in females.
`
`Similar findings were observed in adult rats at 30 and 100 mg/kg/day in the 26-week
`study, in the absence of any histopathology (Study no. 178-TX-025).
`Urinalysis
`At 30 mg/kg, urine output was increased and lighter in color in males (47%) at 6 weeks
`and in females at 6 (51%) and 13 (52%) weeks. No effect was observed following
`recovery.
`Gross Pathology
`No treatment related effects were observed.
`Organ Weights
`At 30 mg/kg/day, relative heart and lung weights were increased in both sexes (along
`with decreased body weight gain), relative kidney and submandibular gland weights
`were increased in males, relative liver weight was increased in females, absolute and
`relative ovarian weights were increased, and absolute (males and females) and relative
`thymus weights (males) were decreased, all in the absence of related histopathology.
`After 4 weeks of recovery, absolute and relative thymus weights, were still depressed
`(26 to 29%) in males, and absolute and relative ovary weights were increased (30 to
`33%). Relative heart and lung weights were also increased in adult males at 100
`mg/kg/day in the 13-week rat toxicology study (Study no. 178-TX-020), although
`increases in ovarian weight were not observed at this dose. At 3 and 10 mg/kg/day, no
`effects on organ weights were observed.
`
`Heart Absolute
`Relative
`Lung Absolute
`Relative
`Liver Absolute
`Relative
`Kidney Absolute
`Relative
`Ovaries Absolute
`Relative
`Submandibular Gland Absolute
`Relative
`Thymus Absolute
`Relative
`
` Statistically different from control
` * p < 0.05, ** p < 0.01
` Relative organ weights are normalized to body weight
`
`Males (mg/kg/day)
`3
`10
`30
`
`+18%*
`
`+9% *
`
`
`+12%*
`
`
`
`+15% *
`-36%**
`-25%*
`
`8
`
`Females (mg/kg/day)
`3
`10
`30
`
`
`+10%**
`
`+6%*
`
`+16%**
`
`
`+27%**
`+34%**
`
`
`-25%*
`-18%
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`Histopathology
`At 30 mg/kg/day, a slight to moderate decrease in lipid droplets was observed in the
`brown and white adipose tissue of male and female rats following treatment but was not
`observed following 4 weeks of recovery.
`
`At 10 mg/kg/day, a slight decrease in lipid droplets was observed in the brown and
`white adipose tissue of male and female rats following treatment but was not observed
`following 4 weeks of recovery.
`
`In the 13-week adult rat toxicity study, similar decreases in lipid droplets were observed
`at similar doses, and hepatocyte swelling and focal necrosis were observed at 300
`mg/kg/day. Mirabegron has been shown to alter lipolysis and lipid metabolism in rats
`through beta-3 adrenergic receptor agonist activity, an effect that has not been reported
`in humans.
`
`Brown Adipose, decreased lipid droplets
`White Adipose, decreased lipid droplets
`
`Males (mg/kg/day)
`3
`10
`0/10
`8/10
`0/10
`6/10
`
`30
`10/10
`9/10
`
`0
`0/10
`0/10
`
`Females (mg/kg/day)
`0
`3
`10
`30
`2/10
`0/10
`4/10
`10/10
`0/10
`0/10
`4/10
`10/10
`
`Effects on Postnatal Development and Behavior
`
`Physical Development
`
`No treatment related effects on hair growth or eruption of incisors on Days 2
`and 5 of dosing (11 and 14 days of age) or eye opening on Days 5 and 9 of dosing (14
`and 18 days of age) were observed. Additionally, no treatment related effects on genital
`development (preputial separation on Days 33 and 40 of dosing [42 and 49 weeks of
`age] and vaginal opening on Days 26 and 33 of dosing [35 and 42 days of age] were
`observed.
`
`Early Behavior
`
`No treatment related effects on back righting and negative geotaxis on Days 2 and 5 of
`dosing (11 and 14 days of age) were observed.
`
`Sensory Functions
`
`On Days 19 to 25 of dosing (4 weeks of age), no treatment related effects on visual
`(visual placing response, pupillary reflex), auditory (Preyer’s reflex) or pain responses
`were observed.
`
`Open Field Test
`
`On Days 26 to 39 of dosing (5 to 6 weeks of age), no treatment related effects on
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`motility and emotionality (ambulation, grooming, rearing, defecation, and urination) in
`open field tests were observed.
`
`Conditioned Avoidance Response
`
`On Days 33 to 53 of dosing (6 to 8 weeks of age), no effects on conditioned avoidance
`response (2 60-minute shuttle box trials) were observed.
`
`Mating Ability
`
`During the 3-week mating period following the recovery period, no treatment related
`effects on mating, fertility index, embryofetal loss (mean number of corpora lutea,
`number of implantations, pre-implantation loss, post-implantation loss, or number of live
`fetuses) were observed. No embryo/fetal malformations were observed.
`
`Toxicokinetics (188 ng∙h/mL is the predicted AUC at the MRHD of 50 mg mirabegron)
`
`Cmax and AUC0-24 values varied throughout the dosing period. AUC0-24 values were 1.7
`to 8.9 times on Day 1, 0.3 to 0.5 times on Day 12, and 0.2 to 0.6 times on Day 36
`compared to those on Day 91. No apparent sex differences were observed. At 30
`mg/kg/day, a minimum of 12-times the AUC at the MRHD of 50 mg was observed on
`Day 12.
`
`Exposures in juvenile rats on days 12 and 36 of dosing were similar to those in adult
`rats administered a single dose (Study no.178-TX-020) or after 13 weeks of dosing
`(Study no.178-TX-042).
`
`Tmax (hr)
`
`Cmax (ng/mL)
`
`AUC0-24 (ng•hr/mL)
`
`Predicted multiple at
`the MRHD
`
`Males (mg/kg/day)
`3
`10
`30
`2
`4
`4
`4
`4
`4
`4
`2
`2
`4
`2
`2
`97
`577
`1,530
`6
`64
`336
`4
`88
`699
`17
`251
`1,167
`986
`4,967
`14,756
`61
`374
`2,461
`19
`504
`3,006
`110
`1,057
`8,574
`5 X
`26 X
`78 X
`0.3 X
`2 X
`13 X
`0.1 X
`2.7 X
`16 X
`0.6 X
`5.6 X
`46 X
`
`Females (mg/kg/day)
`3
`10
`30
`2
`2
`4
`4
`4
`4
`2
`2
`2
`2
`2
`2
`92
`662
`1,822
`6
`58
`412
`21
`178
`845
`31
`261
`1,530
`1,004
`4,602
`20,730
`70
`372
`2,284
`90
`705
`3,055
`148
`1,159
`8,139
`5 X
`24 X
`110 X
`0.4 X
`2 X
`12 X
`0.5 X
`3.8 X
`16 X
`0.8 X
`6.2 X
`43 X
`
`Day 1
`Day 12
`Day 36
`Day 91
`Day 1
`Day 12
`Day 36
`Day 91
`Day 1
`Day 12
`Day 36
`Day 91
`Day 1
`Day 12
`Day 36
`Day 91
`
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`Integrated Summary and Safety Evaluation
`11
`Mirabegron is a beta-3 adrenergic receptor agonist, as demonstrated using cloned
`human beta-3 adrenergic receptor (AR). Mirabegron relaxes the detrusor smooth
`muscle during the storage phase of the urinary bladder fill-void cycle by activation of
`beta-3 AR which increases bladder capacity. Although mirabegron showed very low
`intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicated
`that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg. (MYRBETRIQ
`label)
`
`In a juvenile rat study, mirabegron was administered at 0, 3, 10, and 30 mg/kg/day for
`13 weeks (beginning at 10 days of age), followed by a 4-week recovery period. At 10
`mg/kg/day and above (about twice the exposure in children at the MRHD of 50 mg/day),
`a reversible decrease in lipid droplets in white and brown adipose tissue (accompanied
`by decreases in body weight at 30 mg/kg/day, primarily in male rats), an expected effect
`of increased lipid metabolism in rats following beta-3-adrenergic agonism, was
`observed. The no effect level for this effect was 3 mg/kg/day. However, no adverse
`effects on development, behavior, sensory function, reproductive performance, or
`fertility were observed even at the high dose of 30 mg/kg/day (greater than 12 times the
`MRHD).
`
`No general toxicity specific to the juvenile period of development was identified under
`the conditions of this study, although variations in exposure over developmental periods
`in juvenile animals complicate direct comparison with exposures and effects in the 13-
`week study in adult rats.
`
`In a 13-week study in adult rats, mirabegron was administered at 0, 10, 30, 100, or 300
`mg/kg/day, followed by four weeks of recovery. Lethality was observed at 100
`mg/kg/day and above, and dose dependent reductions in body weight and body weight
`gain were observed in males at 30 mg/kg/day and greater. Decreased lipid droplets in
`brown and/or white adipose were observed at 10 mg/kg/day and greater. Liver toxicity
`(hepatocyte swelling) was observed at 300 mg/kg/day. (NDA 202611 Review,
`Andreasen, 11 April 2012)
`
`Mirabegron was also previously reviewed in studies up to 26 weeks in rats and 52
`weeks in dogs under NDA 202611.
`
`In a 26-week study in rats, no mortality was observed up to 100 mg/kg/day (56-59x
`MRHD in adults) Reduced body weight was observed at 30 mg/kg in males. Relative
`liver weights increased at ≥ 30 mg/kg/day in both sexes. Effects on fat accumulation
`were observed at 10 and 30 mg/kg/day, in males and females, respectively.
`(Andreasen, 2012)
`
`In a 52-week study in monkeys, no drug related deaths occurred at doses up to 30
`mg/kg/day (8x MRHD). Increased PR interval was observed at ≥ 30 mg/kg within 2
`hours of dosing. A NOAEL was 10 mg/kg/day (2x MRHD in females and 2.5x MRHD in
`males). (Andreasen, 2012)
`
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`Elevated liver enzymes (< 2 fold) compared to non-treated animals, were noted in rats
`and dogs at high doses which fully or partially returned to pre-exposure levels after drug
`withdrawal. Adverse hepatic histology observed in rats included eosinophilic pigment
`deposition at exposures 12-17 times the MRHD, along with hepatocyte swelling and
`fibrosis at lethal exposures 130 times the MRHD. Hepatocyte hypertrophy, vacuolation
`and lipid accumulation were noted in dogs at 25 times the MRHD. Since hepatotoxicity
`was only observed in rodents and dogs but not monkeys, was reversible, and did not
`cause adverse histopathology except at or near the lethal dose with large multiples of
`the clinical exposure, the potential for hepatotoxicity at the dose proposed for marketing
`was judged as low (Andreasen, 2012).
`
`Cardiac effects
`
`Increases in heart rate were observed in rats (i.v., about 2 times the exposure at the
`MRHD), dogs (oral, about at 0.1 times), and rabbits (i.v., 9 times), and monkeys (oral,
`12 times). Ventricular tachycardia was observed in dogs and monkeys at exposures 29
`to 37 times the MRHD. The beta-1-adrenergic agonist metoprolol partially reversed the
`increases in heart rate in these species indicating that increased heart rate in animals
`may be mediated at least partly through beta-1-adrenergic receptor activity overlap.
`Risk assessment for cardiovascular effects was conducted in clinical trials in adults and
`children (Andreasen, 2012).
`
`Reproductive toxicity
`
`Fertility studies in rats showed that mirabegron had no effect on either male or female
`fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at
`100 mg/kg in female rats was estimated to be 22-fold the MRHD in women and 93-fold
`the MRHD in men (MYRBETRIQ label).
`
`No embryo-fetal lethality or morphological fetal developmental abnormalities were
`produced in pregnant rats following daily oral administration of mirabegron during the
`period of organogenesis (Days 7 to 17 of gestation) at 0, 10, 30, 100, or 300 mg/kg,
`doses which were associated with systemic exposures (AUC) 0, 1, 6, 22, and 96-fold
`the MRHD. Skeletal variations (wavy ribs, delayed ossification) were observed in
`fetuses at doses 22-fold the systemic exposure at the MRHD and were reversible during
`development. Exposures 96-fold the MRHD were maternally-toxic (mortality, decreased
`body weight gain) and associated with fetal growth reduction (MYRBETRIQ label).
`
`Mirabegron-related material was present in rat milk and in the stomach of nursing pups
`following administrations of a single 10 mg/kg oral dose of 14C-labeled mirabegron to
`lactating rats (MYRBETRIQ label).
`
`Pregnant rabbits were treated with daily oral doses of mirabegron at 0, 3, 10, or
`30 mg/kg/day during the period of organogenesis (Days 6 to 20 of gestation), which
`resulted in plasma exposures that were 0, 1, 14, or 36-fold the MRHD based on AUC.
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`Reference ID: 4753735Reference ID: 4772718
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`NDA # 213801 Reviewer: Laurie McLeod-Flynn
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`At 10 mg/kg/day (14-fold the MRHD) and higher, fetal body weights were reduced. At
`30 mg/kg/day, maternal toxicity (increased heart rate, mortality, reduced body weight
`gain, reduced food consumption) occurred, and fetal deaths, fetal cardiomegaly and
`fetal dilated aortae were observed at systemic exposure levels (AUC) 36-fold the MRHD
`(MYRBETRIQ label).
`
`In a pre- and postnatal developmental study, rats were treated with daily oral doses of
`mirabegron at 0, 10, 30, or 100 mg/kg/day (0, 1, 6, or 22-fold the MRHD) from day 7 of
`gestation until day 20 after birth. Decreased maternal body weight was observed along
`with decreased pup survival in the first few days after birth (92.7% survival) compared to
`the control group (98.8% survival), at 100 mg/kg/day (22-fold the MRHD). Pup body
`weight gain was reduced until postnatal day 7 but not further affected throughout the
`remainder of the lactation period. In utero and lactational exposure did not affect
`developmental milestones, behavior, or fertility of offspring. No effects were observed at
`30 mg/kg/day.
`
`Genotoxicity/Carcinogenicity
`
`Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not
`induce chromosomal aberrations in human peripheral blood lymphocytes at
`concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus
`assay (MYRBETRIQ label).
`
`Long-term carcinogenicity studies were conducted in rats and mice dosed orally with
`mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and
`female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day.
`Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-
`fold higher than the MRHD in rats and 21 to 38-fold higher than the MRHD in mice than
`the human systemic exposure at the 50 mg dose (MYRBETRIQ label).
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`Reference ID: 4753735Reference ID: 4772718
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`Signature Page 1 of 1
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`LAURIE L MCLEOD FLYNN
`02/26/2021 01:35:28 PM
`
`KIMBERLY P HATFIELD
`02/26/2021 01:40:01 PM
`I concur with the review and recommendations of Dr. McLeod-Flynn.
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`Reference ID: 4753735Reference ID: 4772718
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