CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022063Orig1s000
`
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`
`

`

`NDA 22063
`
`
`
`
`Reviewer: Deepa Rao DVM, PhD
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`
`
`
`Application number:
`Supporting document/s:
`
`
` Applicant’s letter date:
`CDER stamp date:
` Product:
`
`Indication:
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`NDA 22063
`Supporting Document Number 44, Applicant
`Serial number 22
`December 20, 2016 (Resubmission/Class 2)
`December 20, 2016
`SPD 465; MydayisTM (Mixed salts of a single-
`entity Amphetamine)
`Attention Deficit Hyperactivity Disorder (ADHD)
`Shire Development LLC
`Division of Psychiatry Products
`Deepa B. Rao DVM, PhD
`Ikram Elayan, PhD
`Mitchell V. Mathis MD
`Latrice Wilson, Pharm D
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 22063 are owned by Shire Development LLC or are data
`for which Shire Development LLC has obtained a written right of reference.
`Any information or data necessary for approval of NDA 22063 that Shire Development
`LLC 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
`22063.
`
`
`
`
`Reference ID: 4103456
`
`1
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`

`

`NDA 22063
`
`
`
`
`Reviewer: Deepa Rao DVM, PhD
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION .................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS ............................................................................................ 5
`8 USE IN SPECIFIC POPULATIONS ......................................................................... 5
`8.1
`PREGNANCY ....................................................................................................... 5
`8.2
`LACTATION.......................................................................................................... 7
`8.4
`PEDIATRIC USE ................................................................................................... 7
`13
`NONCLINICAL TOXICOLOGY ............................................................................ 8
`13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY ................................. 8
`2 DRUG INFORMATION ............................................................................................ 9
`2.1 DRUG ................................................................................................................. 9
`2.2 RELEVANT INDS, NDAS, AND DMFS .................................................................. 11
`2.3 DRUG FORMULATION ......................................................................................... 11
`2.4 COMMENTS ON NOVEL EXCIPIENTS ..................................................................... 12
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 12
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 12
`2.7 REGULATORY BACKGROUND .............................................................................. 12
`3 STUDIES SUBMITTED .......................................................................................... 13
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 13
`4 PHARMACOLOGY ................................................................................................ 13
`4.1
`PRIMARY PHARMACOLOGY ................................................................................. 13
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION ................................. 13
`
`
`
`Reference ID: 4103456
`
`2
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`

`

`NDA 22063
`
`Abbreviations
`
`ADHD
`
`MAS
`
`MRHD
`
`
`
`
`
`
`
`
`
`Reviewer: Deepa Rao DVM, PhD
`
`Attention Deficit Hyperactivity Disorder
`
`Mixed Amphetamine Salts
`
`Maximum Recommended Human Dose
`
`
`Reference ID: 4103456
`
`3
`
`

`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`Executive Summary
`1
`Introduction
`1.1
`Shire Development LLC is seeking approval of SHP465 (under the trade name
`MydayisTM), for their once-daily new formulation, single-entity mixed amphetamine salt
`(MAS) drug product for oral administration in patients
` years old diagnosed with
`Attention Deficit Hyperactivity Disorder (ADHD). This new triple-bead formulation is
`based on the approved product Adderall® XR (NDA 21303), but allows relatively
`sustained-release delivery that extends up to 16 hours post-administration to provide
`ADHD patients with symptom control throughout the day following a convenient single
`morning dose.
`
`This NDA 22063 is currently a Class 2/Resubmission by Shire Development LLC (filed
`under a 505(b)(1) application on 12 December, 2016). The original application was filed
`on 21 July 2006. An Approvable Letter was issued by FDA 18 May, 2007 under the
`trade name
` This current Class2/Resubmission aims to address all the
`deficiencies identified in the Approvable Letter.
`1.2 Brief Discussion of Nonclinical Findings
`From a nonclinical perspective, the original application was considered approvable
`pending the incorporation of the findings from additional nonclinical studies [pre- and
`postnatal developmental reproductive toxicology study and the juvenile animal study]
`into the drug’s label.
`
`Review of the pre- and postnatal reproductive toxicology study and the juvenile animal
`study were completed under the original application for this NDA 22063 by Dr.Ikram
`Elayan (dated May 10, 2007). Changes in activity, body weight, and reproductive
`performance were observed in the reproductive toxicology study as a result of treatment
`with amphetamine during pregnancy and lactation on the dams and the pups (F1
`generation). Results from juvenile rat study indicated changes in activity, learning, and
`memory in pup rats treated with the MAS at a critical stage of their development
`(starting from post natal day 7 to maturation). Relevant changes from both studies are
`to be described in the labeling (see Section 1.3.3). Changes in the label (Sections 8 and
`13) have been incorporated to include findings from these studies and to reflect
`consistency with the dose multiples based on the most sensitive and appropriate
`population age group of patients.
`
`Information on nonclinical findings for carcinogenicity studies, genotoxicity studies, and
`fertility studies are minimally modified from the label for Adderall® XR to reflect dose
`multiples based on the most sensitive and appropriate population group of patients.
`
`Nonclinical studies for
`The new formulation includes an excipient
` (see Dr.Elayan’s review
`qualification of this excipient were reviewed under DMF
`dated May 10, 2007 under NDA 22063), and were considered adequate based on the
`results indicating that the excipient is not absorbed systemically in the rat and clinical
`data submitted by the sponsor (see Section 2.4).
`
`
`Reference ID: 4103456
`
`4
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`
`Other nonclinical studies were reviewed under NDA 22063 (pharmacodynamics – effect
`on cytochrome P450 activities), or under NDA 21303 (genotoxicity). NDA 21303 is also
`owned by Shire Development LLC. A list of supporting nonclinical studies with
`corresponding reviews is documented under Section 3.3. The original NDA for Adderall®
`IR (NDA 11522) was approved by FDA on 19 January 1960.
`
`1.3 Recommendations
`1.3.1 Approvability
`Based on the long history of clinical use of the active ingredients, supporting nonclinical
`studies that demonstrate the lack of systemic absorption of
`
`MydayisTM appears to be reasonably safe for approval.
`
`
`1.3.3 Labeling
`Sections 8 and 13 have been excerpted from the sponsor’s submission (Word file dated
`12/2016 under Module 1.14.1.2). Proposed changes are underlined and italicized in
`blue below. It should be noted that the following label changes documented in this
`review are work-in- progress changes to the most updated version of the label, and may
`not reflect the finalized label (pending at this time) accurately.
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Risk Summary
`
`The limited available data from published literature and postmarketing reports on use of
`amphetamine in pregnant women are not sufficient to inform a drug-associated risk for
`major birth defects and miscarriage. Adverse pregnancy outcomes, including premature
`delivery and low birth weight, have been seen in infants born to mothers dependent on
`amphetamines [see Clinical Considerations].
`
`In an embryofetal development study, amphetamine (d- to l- enantiomer ratio of 3:1, the
`same as in MYDAYIS) had no effects on embryofetal morphological development or
`survival when administered to pregnant rats and rabbits throughout the period of
`organogenesis up to doses 10 times the maximum recommended human dose
`(MRHD). However, in a pre- and post-natal development study, amphetamine (d- to l-
`ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a
`decrease in pup survival and a decrease in pup body weight that correlated with a delay
`in developmental landmarks at clinically relevant doses of amphetamine. In addition,
`adverse effects on reproductive performance were observed in pups whose mothers
`were treated with amphetamine. Long-term neurochemical and behavioral effects have
`also been reported in animal developmental studies using clinically relevant doses of
`amphetamine [see Data].
`
`
`
`Reference ID: 4103456
`
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`
`

`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`population is unknown. All pregnancies have a background risk of birth defect, loss or
`other adverse outcomes. In the U.S. general population, the estimated background risk
`of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and
`15- 20%, respectively.
`
`
`Clinical Considerations
`
`Fetal/Neonatal Adverse Reactions
`Amphetamines, such as MYDAYIS, cause vasoconstriction and thereby may decrease
`placental perfusion. In addition, amphetamines can stimulate uterine contractions
`increasing the risk of premature delivery. Infants born to amphetamine-dependent
`mothers have an increased risk of premature delivery and low birth weight.
`
`Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such
`as feeding difficulties, irritability, agitation, and excessive drowsiness.
`
`
`Data
`
`Animal Data
`Amphetamine (d- to l- enantiomer ratio of 3:1, the same as in MYDAYIS) had no
`apparent effects on embryofetal morphological development or survival when
`administered orally to pregnant rats and rabbits throughout the period of organogenesis
`at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately
`
`2 and 10 times, respectively, the maximum recommended human dose (MRHD) of
`25 mg/day given to adolescents, on a mg/m2 body surface area basis.
`Fetal malformations and death have been reported in mice following parenteral
`administration of d-amphetamine doses of 50 mg/kg/day (approximately 8 times the
`MRHD for adolescents on a mg/m2 basis) or greater to pregnant animals. Administration
`of these doses was also associated with severe maternal toxicity.
`
` pre- and postnatal development study was conducted with amphetamine (d- to l-
`enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and
`10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.6,
`2, and 3 times the MRHD of amphetamine (d- to l- ratio of 3:1) for adolescents of
`25 mg/day, on a mg/m2 basis. All doses caused hyperactivity and decreased weight
`gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup
`body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental
`landmarks, such as preputial separation and vaginal opening. Increased pup locomotor
`activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning.
`When pups were tested for reproductive performance at maturation, gestational weight
`gain, number of implantations, and number of delivered pups were decreased in the
`group whose mothers had been given 10 mg/kg.
`
`
` A
`
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`Reference ID: 4103456
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`(4)
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`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`A number of studies from the literature in rodents indicate that prenatal or early
`postnatal exposure to amphetamine (d- or d, l-) at doses similar to those used clinically
`can result in long-term neurochemical and behavioral alterations. Reported behavioral
`effects include learning and memory deficits, altered locomotor activity, and changes in
`sexual function.
`
`8.2 Lactation
`
`Risk Summary
`
`Based on limited case reports in published literature, amphetamine (d- or d, l-) is
`present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-
`adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no
`reports of adverse effects on the breastfed infant. Long-term neurodevelopmental
`effects on infants from amphetamine exposure are unknown. It is possible that large
`dosages of dextroamphetamine might interfere with milk production, especially in
`women whose lactation is not well established. Because of the potential for serious
`adverse reactions in nursing infants, including serious cardiovascular reactions, blood
`pressure and heart rate increase, suppression of growth, and peripheral vasculopathy,
`advise patients that breastfeeding is not recommended during treatment with MYDAYIS.
`
`8.4 Pediatric Use
`to 17 years has been
`Safety and effectiveness in pediatric patients with ADHD ages
`established in two placebo-controlled clinical studies [see Adverse Reactions (6.1),
`Clinical Pharmacology (12.3), Clinical Studies (14)].
`
`Safety and effectiveness in pediatric patients under
`established.
`
`Growth Suppression
`Growth should be monitored during treatment with stimulants, including MYDAYIS, and
`children who are not growing or gaining weight as expected may need to have their
`treatment interrupted [see Warnings and Precautions
`, Adverse Reactions (6.1)].
`
`Juvenile Animal Toxicity Data
`
`
` years of age has not been
`
`Juvenile rats treated with mixed amphetamine salts (same as in MYDAYIS) early in the
`postnatal period through sexual maturation demonstrated transient changes in motor
`activity. Learning and memory was impaired at approximately 8 times the maximum
`recommended human dose (MRHD) given to children on a mg/m2 basis. No recovery
`was seen following a drug free period. A delay in sexual maturation was observed at a
`dose approximately 8 times the MRHD in children on a mg/m2 basis, although there
`was no effect on fertility.
`
`
`Reference ID: 4103456
`
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`(4)
`
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`(4)
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`
`

`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`In a juvenile developmental study rats received daily oral doses of amphetamine (d to l
`enantiomer ratio of 3:1, the same as in MYDAYIS) of 2, 6, or 20 mg/kg on days 7-13 of
`age; from day 14 to approximately day 60 of age these doses were given b.i.d. for total
`daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.8, 2
` and
`8
`times the maximum recommended daily dose of
`25 mg given to
` children on a
`mg/m2 basis. Post-dosing hyperactivity was seen at all doses; motor activity measured
`prior to the daily dose was decreased during the dosing period but the decreased motor
`activity was largely absent after an 18 day drug-free recovery period. Performance in
`the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose,
`and sporadically at the lower doses, when measured prior to the daily dose during the
`treatment period; no recovery was seen after a 19 day drug-free period. A delay in the
`developmental milestones of vaginal opening and preputial separation was seen at
`40 mg/kg but there was no effect on fertility.
`
`NONCLINICAL TOXICOLOGY
`13
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
`
`No evidence of carcinogenicity was found in studies in which d, l-amphetamine
`(enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at
`doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and
` and 1
`5 mg/kg/day in male and female rats. These doses are approximately
`times, respectively, the maximum recommended human dose of 50 mg/day on a mg/m2
`body surface area basis in adults.
`
`Mutagenesis
`
`Amphetamine, in the enantiomer ratio present, d- to l- ratio of 3:1, was not clastogenic
`in the mouse bone marrow micronucleus test in vivo and was negative when tested in
`the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio)
`has been reported to produce a positive response in the mouse bone marrow
`micronucleus test, an equivocal response in the Ames test, and negative responses in
`the in vitro sister chromatid exchange and chromosomal aberration assays.
`
`Impairment of Fertility
`Amphetamines, in the enantiomer ratio, d- to l- ratio of 3:1, did not adversely affect
`fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day
`(approximately 6 times the maximum recommended human
`dose of
`mg/day on a mg/m2 body surface area basis).
`
`
`25
`
`
`Reference ID: 4103456
`
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`(b) (4)
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`(b) (4)
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`(b)
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`(b)
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`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`2 Drug Information
`2.1 Drug
`The active ingredients in MydayisTM contain MAS. The MAS include equal amounts of
`the neutral sulfate salts of dextroamphetamine and amphetamine, the dextro isomer of
`amphetamine saccharate and d,l-amphetamine aspartate monohydrate, with the
`enantiomer ratio of d-amphetamine and l-amphetamine being in 3:1. The generic name,
`chemical name and corresponding CAS Number is tabulated below:
`
`
`The molecular formula/molecular weight and structure for each active ingredient is
`depicted below:
`
`
`
`
`
`
`
`Reference ID: 4103456
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`

`NDA 22063
`
`
`
`
`Reviewer: Deepa Rao DVM, PhD
`
`
`
`
`
`
`
`
`Generic Name
`MydayisTM (current resubmission)
` (original application)
`
`
`Code Name
`SHP465
`SPD465 (From Dr. Elayan’s review dated May 10, 2007 under NDA 22063)
`
`Reviewer Note:
`Nonclinical studies in Dr. Elayan’s review refer to the drug product as SPD465, whereas
`this Class 2/Resubmission refers to the drug product as SHP465. Meeting Package
`dated 11 May, 2015 states that “The product was previously referred to as SPD465;
`however, it is now being studied under the code of SHP465”.
`
`Pharmacologic Class
`Central Nervous System (CNS) Stimulant
`
`
`Reference ID: 4103456
`
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`

`NDA 22063
`
`Reviewer: Deepa Rao DVM, PhD
`
`2.2 Relevant INDs, NDAs, and DMFs
`
`IND 66329
`
`Product Name: Mixed Salts of Single-Entity Amphetamine (SHP 465)
`Sponsor: Shire Development Inc
`Indication: ADHD
`
`Status: Active since December 4, 2002
`
`(b) (4)
`
`NDA 21303
`Product Name: Adderall® XR
`
`Sponsor: Shire Development Inc
`Indication: ADHD
`
`Status: Approved on October 11, 2001
`
`IND 58037
`Product Name: Adderall® XR
`
`Sponsor: Shire Development Inc
`Indication: ADHD
`
`Status: Active since March 25, 1999
`
`NDA 1 1522
`Product Name: Adderall® IR
`
`Sponsor: Teva Womens Health Inc
`Indication: Obesity
`Status: Approved on January 19, 1960
`
`2.3 Drug Formulation
`
`MydayisTM is a once-daily, triple-bead, sustained-release drug product formulation of
`MAS to be marketed as 12.5, 25, 37.5, and 50 mg strength capsules. A summary of the
`capsule components in tabled below:
`
`Reference ID: 41 03456
`
`11
`
`

`

`NDA 22063
`
`Reviewer: Deepa Rao DVM, PhD
`
`(0) (4)
`
`The SL1381 IR and DR in the 12.5 mg capsules are from the approved Adderall XR®
`product. The composition of the beads
`"M"
`are detailed in the Quality review. Individual inactive ingredients in
`"’"" were considered to be within
`
`the beads
`
`acceptable limits compared to the FDA inactive ingredients list.
`
`2.4 Comments on Novel Excipients
`
`The following is excerpted from Dr. Elayan’s review dated May 10, 2007:
`The nonclinical stggies submitted for the qualification of the
`“M" excipient
`are considered adequate for the purpose of the qualification and
`the results indicated that the excipient is not absorbed systemically in the rat, which is
`also believed to be true in humans based on the data submitted by the sponsor. All the
`studies demonstrated that the excipient at the doses used in these studies, did not
`result in any systemic toxicity. Therefore, it is considered that the levels of this excipient
`that humans will be exposed to will be safe and should not pose any systemic
`toxicity in response to oral administration. Moreover, the daily levels of the acrylate
`W" are considered to be acceptable as specified by the manufacturer of the
`excipient, and as expected from treatment with the high recommended dose. This is
`based on the fact that the levels of these
`“m" in this drug product are much lower
`than levels found in other approved products containing similar
`"m".
`
`2.5 Comments on Impurities/Degradants of Concern
`
`No nonclinical studies on impurities were conducted.
`For a complete review, refer to the Quality review for this NDA.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`Patients diagnosed with ADHD aged m“) years.
`
`2.7 Regulatory Background
`
`NDA 22063 was originally submitted on 21 July 2006 (under the trade name
`and an Approvable Letter was issued to Shire on 18 May 2007.
`
`"m
`
`Reference ID: 41 03456
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`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`Studies Submitted
`3
`No nonclinical studies have been submitted with this current Class 2/Resubmission.
`3.3 Previous Reviews Referenced
`Genotoxicity Studies:
`The mouse micronucleus assay and the E.coli component of the Ames assay were
`reviewed under NDA 21303 by Dr. Edward Fisher (review dated August 7, 2001 in
`DARRTS)
`
`Reproductive Toxicology Studies:
`The fertility studies (Segment 1), and the embryo-fetal toxicity studies (Segment 2) were
`reviewed under NDA 21303 by Dr. Edward Fisher (review dated August 7, 2001 in
`DARRTS). The prenatal and postnatal toxicity studies (Segment 3), and the juvenile
`animal studies were submitted to NDA 21303 (DARRTS SDN 96, June 7, 2004), and
`reviewed under the current NDA 22063 by Dr. Ikram Elayan (review dated May 10,
`2007).
`
`Nonclinical studies to support the use of the excipient
`were submitted to DMF
` and have been reviewed under the current NDA 22063
`by Dr. Ikram Elayan (review dated May 10, 2007).
`
`Other reviews of literature and limited data are included under NDA 11522 (approved 19
`January 1960).
`4
`Pharmacology
`4.1 Primary Pharmacology
`Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant
`activity. The exact mode of therapeutic action in ADHD is not known.
`
`Integrated Summary and Safety Evaluation
`11
`Based on Shire Development LLC’s original drug product Adderall® XR under NDA
`21303 for ADHD (approved on October 11, 2001), the sponsor has pursued a new
`formulation that is longer acting extending up to 16 hours post-administration. This new
`formulation was originally filed on 21 July, 2006 under this NDA 22063. An Approvable
`Letter (18 May 2007) was issued by the FDA on 18 May 2007 for NDA 22063 (under the
` Currently, this NDA 22063 is a Class 2 resubmission by Shire
`trade name
`Development LLC filed on December 12, 2016 under a 505(b)(1) application that aims
`to address all the deficiencies identified in the Approvable Letter.
`
`From a nonclinical perspective, the original application filed in 2006 was considered
`approvable pending the incorporation of the findings from additional nonclinical studies
`[pre- and postnatal reproductive toxicology study and the juvenile animal study] into the
`drug’s label.
`
`
`Reference ID: 4103456
`
`13
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`(b) (4)
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`(b) (4)
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`

`NDA 22063
`
`Reviewer: Deepa Rao DVM, PhD
`
`The new formulation (under the tradename MydayisTM ) is a single-entity MAS product
`for oral administration in patients “""years old diagnosed with ADHD. MAS have been
`approved since 19 January, 1960 (under NDA 11522 as Adderall® IR).
`
`It should be noted that nonclinical studies in Dr. Elayan’s review refer to the drug
`product as SPD465, whereas this Class 2/Resubmission refers to the drug product as
`SHP465. Meeting Package dated 11 May, 2015 states that “The product was previously
`referred to as SPD465; however, it is now being studied under the code of SHP465".
`
`The active ingredients in MydayisTM is MAS (similar to Adderall® XR) include equal
`amounts of the neutral sulfate salts of dextroamphetamine and amphetamine, the
`dextro isomer of amphetamine saccharate and d,l-amphetamine aspartate
`monohydrate, with the enantiomer ratio of d-amphetamine and l-amphetamine being in
`3:1. The new formulation includes an excipient
`“m", namely,
`"m
`Moreover, the daily levels of the acrylate
`are considered to be acceptable as
`specified by the manufacturer of the excipient, and as expected from treatment with the
`high recommended dose. This is based on the fact that the levels of these
`W" in
`this drug product are much lower than levels found in other approved products
`containing similar
`9"".
`
`(b) (4)
`
`No additional nonclinical studies were submitted or reviewed under this Class 2/
`
`Resubmission.
`
`(bmwere reviewed
`Nonclinical toxicology studies for qualification of
`under DMF
`"’"" (see Dr. Elayan’s review dated May 10, 2007 under NDA 22063),
`and were considered adequate based on the results indicating that the excipient is not
`absorbed systemically in the rat and clinical data submitted by the sponsor (see Section
`2.4).
`
`Review of the pre- and postnatal reproductive toxicology study and the juvenile animal
`study were completed under the original application for this NDA 22063 by Dr. lkram
`Elayan (dated May 10, 2007). Changes in activity, body weight, and reproductive
`performance were observed in the reproductive toxicology studies as a result of
`treatment with amphetamine during pregnancy and lactation on the dams and the pups
`(F1 generation). Results from juvenile rat study indicated changes in activity, Ieaming,
`and memory in pup rats treated with the Adderall mixture at a critical stage of their
`development (starting from post natal day 7 to maturation). Relevant changes from both
`studies are to be described in the labeling (see Section 1.3.3). Changes in the label
`(Sections 8 and 13) have been incorporated to include findings from these studies and
`changes to reflect consistency with the dose multiples based on the most sensitive and
`appropriate population age group of patients.
`
`lnforrnation on nonclinical findings for carcinogenicity studies, genotoxicity studies, and
`fertility studies (reproductive toxicology studies segment 1) are minimally modified from
`
`Reference ID: 41 03456
`
`14
`
`

`

`
`
`Reviewer: Deepa Rao DVM, PhD
`
`NDA 22063
`
`the label for Adderall® XR to reflect dose multiples based on the most sensitive and
`appropriate population age group of patients.
`
`
`Other nonclinical studies were reviewed under NDA 22063 (pharmacodynamics – effect
`on cytochrome P450 activities), or under NDA 21303 (genotoxicity). NDA 21303 is also
`owned by Shire Development LLC. A list of supporting nonclinical studies with
`corresponding reviews is documented under Section 3.3. The original NDA for Adderall
`(NDA 11522) was approved by FDA on 19 January 1960.
`
`Based on the long history of clinical use of the active ingredients, supporting nonclinical
`toxicology studies that demonstrate the lack of systemic absorption of the copolymer
`excipient
`and acceptable level of acrylate
` based on the
`high recommended dose when compared to other approved products, MydayisTM
`appears to be reasonably safe for approval.
`
`
`Reference ID: 4103456
`
`15
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DEEPA B RAO
`05/25/2017
`
`IKRAM M ELAYAN
`05/25/2017
`
`Reference ID: 4103456
`
`