CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`022063Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`QUALITY ASSESSNIENT
`
`Recommendation: Approval
`
`NDA 022063
`
`Review# 2
`
`
`
`
`
`
`
`
`Drug Name/Dosage
`Form
`
`
`
`
`Mydayis (mixed salts of a single-entity amphetamine product)
`extended-release ca - sules
`
`
`12.5 m1, 25 m1, 37.5 m1, 50 m1
`
`Route of
`Administration
`
`RX/OTC Dis ensed
`
`Rx
`
`Shire Develoment LLC
`
`
`
`
`
`SUBMISSION(S)
`REVIEWED
`
`DOCUMENT
`DATE
`
`DISCIPLINE(S) AFFECTED
`
`DISCIPLINE
`
`PRIMARY REVIEWER SECONDARY REVIEWER
`
`0 uali Review Team
`
`Drug Master File/Drug
`Substance
`
`Haripada Sarker
`
`Ben Stevens
`
`m
`
`
`
`
`
`
`
`
`
`
`
`Process Mana er
`
`——
`
`OPQ-XOPQ—TEM-0001v04
`
`Page 1 of 1
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DNIFS:
`
`DMF
`
`#
`
`Type
`
`(hm Type 11
`
`Item
`
`Holder
`
`Referenced
`mm Dextroamphetami Adequate
`nesaccharate
`
`Date Review
`
`Com n leted
`12 MAY 2017
`
`Comments
`
`Type II
`
`Type II
`
`Type II
`
`Type In
`
`Type III
`
`Type IV
`Type IV
`
`Type”
`W
`
`Amphetamine
`aspartate
`
`Adequate
`
`4 Nov 2016
`
`Dextroamphetami Adequate
`ne sulfate
`
`12 MAY 2017
`
`Amphetamine
`sulfate
`
`Adequate
`
`9 Nov 2016
`
`(5) (4)
`
`* --
`
`*
`
`* --
`* ——
`
`*adequate infonnation in application.
`
`B. Other Documents: IND, RLD, or sister a
`
`lications
`
`DOCUMENT
`
`APPLICATION NUNIBER
`
`DESCRIPTION
`
`Adderall
`
`66329
`_1§E_
`—E_ 58037
`21303
`
`IND for this roduct
`AdderallXR
`AdderallXR
`
`11522
`
`2. CONSULTS
`
`None
`
`OPQ-XOPQ—TEM-0001v04
`
`Page 1 of 1
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSMENT
`
`Executive Summary
`
`1.
`
`Recommendations and Conclusion on Approvability
`
`Recommend approval from a product quality perspective. The applicant resolved
`the drug product dissolution deficiencies and demonstrated that they are still
`capable of manufacturing product of adequate quality.
`
`II.
`
`Summary of Quality Assessments
`
`A. Product Overview
`
`The proposed product, Mydayis extended release capsules, is similar to Adderall
`XR, but with a longer period of efficacy. Four strengths are proposed - 12.5 mg,
`25 mg, 37.5 mg, and 50 mg. It is indicated for the treatment of Attention Deficit
`Hyperactivity Disorder (ADI-1D). The applicant currently markets both Adderall
`and Adderall XR. These are immediate and extended release formulations of
`
`amphetamine mixed salts, with efficacy lasting ca. 4 and 8 hours, respectively.
`Patients sometimes take a dose of the immediate release product in the afternoon
`in order to extend the duration of efficacy of the extended release product through
`the evening hours. This NDA proposes the marketing of an extended release
`formulation of mixed amphetamine salts in a capsule dosage form with up to 16-
`hour duration of effect — this is intended to eliminate the need for the additional
`
`dosing of the of IR product. The pharmacokinetic profile of the formulation was
`targeted to be similar to a 20 mg dose of Adderall XR® followed by a 10 mg dose
`of ADDERALL® administered 8 hours later.
`
`In the first review cycle an approval recommendation was made from a CMC
`perspective, however an approvable action was taken in 2007, because of
`deficiencies related to the drug product dissolution method. In this resubmission
`these deficiencies were adequately addressed. Several manufacturing and control
`changes were made since the previous submission. Additional data were provided
`which supported the changes. A drug product expiry period of 24 months was
`found acceptable.
`
`Non-Proprietary Name Issue: Note that the non-proprietary name for this
`product will be (mixed salts of a single-entity amphetamine product) extended-
`release capsules. This is identical to Adderall XR’s non-proprietary name. It is
`also noted that each has a 25 mg dosage strength. OPQ recognizes the potential
`for confilsion and prescribing errors, however the non—proprietary name alone
`cannot be expected to describe the entire product, including its specific
`pharmacokinetics. Other labeling elements will be required to distinguish this
`product from Adderall XR, including proprietary name, ancillary carton
`statements, capsule colors and markings, NDC number, etc. This issue is outlined
`in more detail towards the end of this Executive Summary section.
`
`OPQ-XOPQ-TEM-0001v04
`
`Page 1 of 4
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`
`
`ADHD in patients 22} years and older
`
`Proposed Indication(s) including
`Intended Patient Population
`
`Duration of Treatment
`
`Chronic
`
`Maximum Daily Dose
`
`50 mgfor adults, 25 mg pediatrics
`
`Alternative Methods of
`Administration
`
`Sprinkle capsule contents an apple sauce.
`
`
`B. Quality Assessment Overview
`
`DRUG SUBSTANCE: The drug product contains equal amounts (by weight) of four
`amphetamine salts: dextroamphetamine sulfate and amphetamine sulfate,
`dextroamphetamine saccharate and amphetamine aspartate monohydrate. This results
`in a mmmixture of dextro- to levo- amphetamine base equivalent. All drug substance
`information is referenced to NDA 21303 and the related DMFs (DMF
`(om)
`(dextroamphetamine saccharate), DMF
`(m4) (amphetamine aspartate), DMF m“)
`(dextroamphetamine sulfate), DMF
`(m4) (amphetamine sulfate). Each was found
`adequate to support this application. This same salt mixture is used in several other
`amphetamine products.
`
`DRUG PRODUCT:
`
`The drug product will be marketed in capsule strengths of 12.5 mg, 25 mg, 37.5 mg,
`and 50 mg. All strengths are expressed in terms of the amount of mixed amphetamine
`salts. Each capsule contains immediate release beads and delayed release beads. The
`beads are composed of a sugar sphere core coated in a drug layer and further coated
`with
`M“) layer(s) — then filled into hard gelatin capsules. The three larger
`strengths are dose proportional — just difl'ering in capsule fill. The 25 mg, 37.5 mg and
`50 mg strength capsule contains three types of drug-releasing beads - an immediate
`release and two types of delayed release beads - which release amphetamine at either
`pH 5.5 or pH 7.0. The former releases drug after release from the stomach while the
`latter will not release the drug until it reaches further down the GI tract where the pH is
`more neutral. The 12.5 mg strength capsules also contain immediate release beads and
`two types of delayed release beads. However the immediate release and first (pH 5.5)
`delayed release bead differs from that of the other strengths
`(m4)
`
`Full CMC details are found in the 2007 Review #1 where an approval action was
`recommended from a CMC perspective — although changes to the dissolution test and
`acceptance criteria were requested. In this resubmission the applicant provided support
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 2 of 4
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`for the generally minor manufacturing and control changes. Three batches of each
`drug product strength were manufactured in 2014 to support the resubmission. They
`all met specification. Stability data through 12 months were provided for three
`commercial-scale batches of each strength. No significant changes were seen in these
`or during accelerated storage. 48 month long term stability data were provided for the
`pilot-scale batches fiom the original 2007 submission — again no significant changes
`were apparent. The totality of these data support the proposed 24 month drug product
`expiry period.
`
`a“)
`Dr. Yahong Wang, the OFF process reviewer, participated in the PAI at the
`drug product manufacturing site. Additional supporting data were requested which
`supported the proposed commercial manufacturing process. The manufacturing
`process utilizes
`mm
`to produce the beads for the 12.5
`M“) and for the
`mg strength capsules
`mar The
`higher three strengths
`manufacturing process for commercial scale retains the same unit operations and
`utilizes equipment of the same design and operating principles as those for the exhibit
`batches. A risk assessment was carried out on the drug product manufacturing process,
`with the process for each bead type undergoing a Design of Experiments (DoE) a mu)
`batch size to examine the effects of key processing parameters. This
`demonstrated that the process was adequately controlled and robust.
`
`The dissolution specifications for the release and stability were updated at Agency
`request (approvable letter (May 18, 2007) and the Agency’s response to the Sponsor’s
`Type C Meeting request (April 25, 2014). A :2} minute dissolution time point was
`added, and dissolution acceptance criteria were tightened to a (mu) range. The method
`was found to have some
`(m4) and was found adequate
`as a quality control. In vitro dose dumping was found at ethanol levels above 20%.
`The extended release claim was found to be acceptable.
`
`(m4) drug product manufacturing site found that
`The preapproval inspection of the
`the drug substance analytical methods were not transferred from the
`(b) (4) drug
`substance manufacturing sites. Method transfer and validation data were requested by
`the investigator and OPF. This was received on
`M“). Although the data did
`not completely meet Agency GMP expectations it was determined to be a low risk
`issue and the site was found to be acceptable to support this application.
`(m4) is
`expected to continue working this issue and ORA will ensure that this is followed-up in
`the next inspection of this site.
`
`Non-Proprietary Name Issue: Note that the non-proprietary name for this product
`will be (mixed salts of a single-entity amphetamine product) extended-release capsules.
`This is identical to Adderall )R’s non—proprietary name. It is also noted that each has a
`25 mg dosage strength. The applicant proposed using
`mm to
`aid in distinguishing these products. This was found unacceptable in-line with the
`Nomenclature Guidelines referenced by USP <1121>, which specifically states that
`
`OPQ-XOPQ-TEM—0001v04
`
`Page 3 of 4
`
`Effective Date: 14 February 2017
`
`

`

`QUALITY ASSESSNIENT
`
`“
`
`M“) should not be used. DMEPA were made aware of this issue — as
`
`were the OPQ and OGD labeling groups. The Agency has requested that the applicant
`propose ways to educate consumers and HCPs on the difference between these
`products. Such educational materials were submitted for review in a 12 MAY 2017
`amendment. These materials used the term ‘
`mm to distinguish the
`products — DMEPA and OPDP were made aware that this term was unacceptable. The
`bottom-line is that OPQ recommends the nonproprietary name be (mixed salts of a
`single-entity amphetamine product) extended-release capsules. We recognize the
`potential for prescribing errors and confusion that this name may cause — especially as
`Mydayis and Adderall XR share a 25 mg dosage strength. However, the Agency has
`requested that the applicant to propose ways to distinguish these products since at least
`the 2007 action letter. The non-proprietary name alone cannot be expected to describe
`the entire product, including its specific pharmacokinetics. Other labeling elements
`will be required to distinguish this product from Adderall XR, including proprietary
`name, ancillary carton statements, capsule colors and markings, NDC number, etc.
`Recognizing that the proprietary name will likely be a prominent distinguishing feature
`for this product, OGD were alerted to this issue, as generic products generally do not
`have a nonproprietary name. They discussed this within their labeling teams and
`indicated that they acknowledge this issue, but did not have any recommendations on
`alternatives (email Sarah Kurtz 15 MAY 2017).
`
`C. Special Product Quality Labeling Recommendations
`
`0 Ensure that the product is used immediately after sprinkling on food as
`prolonged exposure may impact the beads’ enteric coating.
`0 Ensure that the product’s dosage form designation in the nonproprietary name
`is ‘extended release capsules’.
`0 Alcohol dose dumping language has been added by the biopharm review team.
`0 Labeling elements will be required to distinguish this product from Adderall
`XR, including proprietary name, ancillary carton statements, etc.
`
`OPQ—XOPQ-TEM—0001v04
`
`Page 4 of 4
`
`Effective Date: 14 February 2017
`
`

`

`David
`Claffey
`
`Digitally signed by David Claffey
`Date: 6/01/2017 03:45:28PM
`GUID: 508da71e00029e20b201195abff380c2
`
`50 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`LABELING
`
`NDA 22063
`
`R
`
`Regional Information
`
`1.14 Labeling
`
`
`
`

`

`
`
`QUALITY ASSESSMENT
`
`
`
`Mu~h—-_— ‘
`
`
`
`Reviewer’s Assessment:
`
`W i
`
`: ge form should be modified to state: extended-
`II .
`EE
`—-
`
`- stablished name,(font size
`». d prominence (21 CFR
`r 01.10(g)(2))
`
`, 01.10(d)(1); 21.CFR
`r 01.100(b)(4))
`
`I’ oute of administration
`, l.CFR 201.100(b)(3))
`
`I et contents"= (21 CFR
`
`‘Rx only” statement per 21
`’ 201.100(b)(l)
`
`notrequired)
`
`
`
`_I WWW
`
`—-
`—-
`—-
`
`Storage should be modified to: Store at room
`'Ima mre,20°Ct025°C(68"Fto77°F). Excursions
`I. a u 'ttcdbctween 15 °C to 30°C (59°F to 86°F)
`
`g.8
`
`

`

`QUALITY ASSESSMENT
`
`Adequate
`
`er 21 CFR 201.2)
`requested. but not required
`I or all labels or labeling),
`
`
`
`
`Adequate
`
`
`Adequate
`
`,5 u
`*21 CFR 201.51(h) A drug shall be exempt from compliance with the net quantity declaration required by
`this section if it is an ointment labeled “sample , physician’s sample”, or a substantially similar
`statement and the contents of the package do not exceed 8 grams.
`“For solid oral dosage forms, CDER policy provides for exclusion of “oral” fiom the container label.
`**Not required for Physician’s samples. The bar code requirement does not apply to prescription drugs
`sold by a manufacturer. repacker, relabeler, or private label distributor directly to patients, but versions of
`the same drug product that are sold to or used in hospitals are subject to the bar code requirements.
`
`Information Request, 18 May, 2017: Revise the description ‘
`
`Capsule” to
`
`(0) (4)
`
`”Extended-Release Capsule” to meet USP guidelines.
`
`Sponsor's Response Summary (19 May, 2017):
`
`Shire has requested reconsideration of the change to the description of the extended-release
`
`capsules. The Applicant’s request is based on the Applicant’s efforts to differentiate the drug
`
`product from Adderal XR (extended-release) in proposed educational materials, and the
`
`Applicant further contends that the description more accurately reflects the drug product
`
`formulation.
`
`FDA Response (24 May, 2017):
`
`We acknowledge your 19 MAY 2017 email response to the 18 MAY 2017 request to change the
`
`dosage form designation from
`
`mm to 'extended release’ and recognize the need
`
`to distinguish this product from products for shorter duration. However it is not possible to do
`
`so based on the nonproprietary name. The Nomenclature Guidelines referenced by USP <1121>
`
`states that ”Expressions such as "prolonged-release", ”repeat-action", ”controlled-release”,
`
`”sustained-release", and their corresponding acronyms should not be used to describe such
`
`dosage forms." Therefore we request that you revise all labeling to reflect lextended release’
`
`dosage form designation.
`
`

`

`QUALITY ASSESSM ENT
`
`Information Request, 18 May, 2017: Revise the storage condition to be consistent with USP
`
`controlled room temperature: ”Store at room temperature, 20 ”C to 25°C (68 ”F to 77 "F).
`
`Excursions permitted between 15 ”C to 30 ”C (59"F to 86 ”F). ”
`
`Sponsor's Response Summary (19 May, 2017):
`
`Shire has accepted the request to revise the storage condition text, and the changes will be
`
`incorporated in labels which will be submitted to NBA 022063.
`
`Reviewer’s Assessment: Inadequate
`
`The Applicant has been advised that the container labels must be revised to describe the
`
`dosage form as extended release capsules, and that the storage condition description must be
`
`modified to be consistent with USP guidelines. In response to the request to modify the
`
`description of the dosage form, the Applicant requested reconsideration in order to
`
`differentiate from extended release Adderall. However, as USP <1121> stipulates that
`
`”extended-release” must be used for this dosage form, the Agency has reiterated the necessity
`
`to make this change to conform to USP nomenclature guidelines. The Applicant is expected
`
`comply with this revision to be USP compliant. As the Applicant has agreed to revise the storage
`
`condition text and to submit the changes, the container labels are othenivise acceptable.
`
`Carton Labeling
`
`Not provided
`
`Reviewer’s Assessment:
`
`NA
`
`List of Deficiencies:
`
`1. Revise the description ‘
`
`(m4) Capsule” to ”Extended-Release Capsule” to
`
`meet USP guidelines.
`
`2. Revise the storage condition to be consistent with USP controlled room temperature:
`
`”Store at room temperature, 20°C to 25°C (68°F to 77'F). Excursions permitted between
`
`15°C to 30°C (59°F to 86 ”F). ”
`
`Primary Labeling Reviewer Name and Date:
`
`Dan Berger
`
`5/25/2017
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`Wendy Wilson-Lee
`
`5/25/2017
`
`

`

`Dan
`Berger
`
`Wendy
`Wilson- Lee
`
`Digitally signed by Dan Berger
`Date: 5/25/2017 01:46:39PM
`GUID: 56e6e1b5001a2fedae663c62a5ce7513
`
`Digitally signed by Wendy Wilson- Lee
`Date: 5/25/2017 02:41:41PM
`GUID: 50816dbc000085595ca3284bbca465a8
`
`39 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`BIOPHARMACEUTICS
`
`Product Background:
`
`NDA: 022-063
`
`Drug Product Name / Strength: Mydayis (mixed salts of a single—entity amphetamine product)
`"’"" Capsules (or SHP465) / 12.5, 25, 37.5, and 50 mg
`
`Route of Administration: Oral
`
`Applicant Name: Shire
`
`Review Summary:
`
`(hm) Capsules (also
`Mydayis (mixed salts of a single-entity amphetamine product)
`known as SHP465) is a once-daily, tn'ple-bead,
`(m4) single-entity mixed
`amphetamine salt (MAS) product for oral administration, and is comprised of sulfate salts of
`dextro and levo-amphetamine, with dextroamphetamine saccharate and amphetamine aspartate
`monohydrate. The current formulation of SHP465 capsules is based conceptually on a frequently
`used combination in clinical practice, i.e., ADDERALL XRQ in the morning, followed by a dose
`of MAS later in the day.
`
`The proposed dissolution method was developed based on the approved method for
`ADDERALL XR® (extended-release) Capsules which has a similar formulation design as the
`proposed drug product. The proposed dissolution method is discriminating with respect to
`alterations in the encapsulation process. Overall, the proposed dissolution method is adequate for
`quality control of SHP465 capsules. The proposed dissolution acceptance criteria,based on the
`Agency’s previous recommendations, are acceptable.
`
`From a Biopharmaceutics perspective, NDA 022—063 for Mydayis (mixed salts of a single-entity
`amphetamine product)
`(m4) Capsules (or SI-IP465)/ 12.5, 25, 37.5, and 50 mg is
`recommended for APPROVAL.
`
`The FDA recommended dissolution method and acceptance criteria for Mydayis (mixed salts of
`a single-entity amphetamine product)
`(m4) Capsules (or SHP465) are as follows:
`
`
`
`
`Media 1: pH 1.1i0.1, Dilute HCl
`Media 2: pH 6.0:t0. 1, Phosphate Buffer
`Media 3: H 7.5i0.l, Phoshate Buffer
`
`Temperature
`37.0i0.5 °C
`
`

`

`QUALITY ASSESSMENT
`
`
`
`Dissolution Volume
`
`750mL Dilute HCl for the first 2 hours
`
`950mL pH 6.0 Phosphate Buffer for the 3“1 hour
`
`1000mL pH 7.5 Phosphate Buffer for the remainder
`
`
`
`
`Acceptance criteria
`
`% Dissolved
`
`List of Submissions being reviewed:
`
`
`eCTD sequence #
`Received Date
`Document
`0022
`12/20/2016
`Class 2 Resubmission
`
`Highlight Key Outstanding Issues from Last Cycle:
`
`0 Lack of in Vitro alcohol dose dumping study, noted in the Approvable Letter dated 18
`
`May 2007
`
`( hflpJ/dantsfda.gov:9602/darrts/ViewDocument?documentId=090140af80142349 )
`
`0 Pending acceptance of the final dissolution method and acceptance criteria for all
`
`strengths, noted in the Approvable Letter dated 18 May 2007
`
`( l_1t_tp://darrts.fda.gov:9602/dants/ViewDocument?documentId=090l40af‘80142349 )
`
`0 Lack of dissolution method development report, noted in the FDA written comments
`
`dated 25 Apr 2014 (\\CDSESUB1\evsprod\NDA022063\0022\m1\us\correspondence-
`
`regarding-meetings-ZSaprZO14.9df )
`0 Pending addition of the 33-min sampling time to monitor the dissolution of the
`immediate release component, noted in the FDA written comments dated 25 Apr 2014
`
`(\\CDSESUB 1\evsprod\NDA022063\0022\m l \us\correspondence-regarding—meetings-
`
`25apr2014.pd£)
`
`Concise Description Outstanding Issues Remaining: None
`
`BCS Designation
`
`No BCS designation request was submitted. The drug product was not evaluated by the FDA
`BC S committee.
`
`Reviewer’s Assessment:
`
`Solubility: All APIs are freely soluble in water independent of pH (see Table 1).
`2
`
`

`

`QUALITY ASSESSMENT
`
`API
`Amphetamine Aspartate Monohydrate
`
`Amphetamine Sulfate, USP
`
`Table 1. Agueous Solubility of the APIs
`Agueous solubility
`
`Freely soluble in water
`Solubility(mg/mL)
`
`l .049
`
`1.0 l 3
`
`1.018
`
`1.0 l 2
`
`soluble in water
`
`Freel
`
`
`
`
`
`Dextroamphetamine Saccharate
`
`Dextroamphetamine Sulfate, USP
`
`
`[.046
`
`
`Freel
`
`soluble in water
`
`[.040
`[.009
`
`l.0l2
`
`
`Freely soluble in water
`
`Solubility(mg/mL)
`1.039
`
`”143
`L044
`
`[,0 l 2
`
`
`
`
`
`Permeability: Not provided.
`
`Dissolution: Refer to section “Dissolution Method and Acceptance Criteria” below.
`
`Dissolution Method and Acceptance Criteria
`
`The dissolution method shown in Table 2 was recommended by FDA in the Approvable letter
`dated 18 May 2007. The dissolution acceptance criteria were proposed based on the FDA
`recommendation dated 18 May 2007 (for 2, 3, and 10 hour time points) and 25 Apr 2014
`(addition of 0.5 hour time point).
`
`
`Table 2. The Dissolution Method and Acceptance Criteria
`USP A aratus II
`.addles
`
`A aratus
`
`
`
`Media 1: pH 1.1i0.l, Dilute HCl
`Media 2: pH 6.0i0.1, Phosphate Buffer
`Media 3: H 7.5i0.l, Phos hate Buffer
`
`Temperature
`37.0i0.5 °C
`
`

`

`QUALITY ASSESSMENT
`
`Dissolution Volume
`
`750mL Dilute HCl for the first 2 hours
`
`Proposed Acceptance criteria
`
`950mL pH 6.0 Phosphate Buffer for the 3“1 hour
`lOOOmL .H 7.5 Phos hate Bufi'er for the remainder
`
`—| —
`_I —
`
`Dissolution Method Development: (p_\CDSESUBl\evsrod\NDA022063\0022\m3\32-bod-
`data\32 —dru - rod\s
`465—ca sule—all-stren
`s\32 2- harm-dev\ harmaceutical-develo ment-
`
`—I
`—| =
`
`drugpp—roduct.df )
`
`

`

`QUALITY ASSESSMENT
`
`dissolution acceptance criteria, and (2) the acceptance criteria are basically what FDA
`previously recommended based on the complete dissolution profiles. The proposed dissolution
`acceptance criteria are acceptable.
`
`MODIFIED RELEASE ORAL DRUG PRODUCTS — In- Vitro Alcohol Dose
`
`Dumping
`
`Two in-vitro alcohol dose dmnping studies were conducted in dissolution media with 0, 10, 20,
`
`and 40% (v/v) ethanol (\\CDSESUB1\evsprod\NDA022063\0022\m3\32-body—data\32p-d1ug-
`
`prod\spd465-capsule-all-streng1hs\3292-pharm—dev\phannaceutical-development—drug—
`
`product.pd_f ).
`
`Study 1 l l: Full dissolution profiles (up to 14 hours) were obtained at n=12 units for all strengths
`of SHP465 capsules (12.5, 25, 37.5, and 50 mg) using the dissolution conditions described in the
`original NDA submission (dated 21 Jul 2006). The mean dissolution overlay graphs for each
`dosage strength, comparing the drug release from SHP465 capsules as a fimction of ethanol
`content, are shown in Figure 2. Increased drug releases were observed at initial timepoints across
`dosage strengths in the presence of 20% and 40% ethanol.
`‘23
`1.11
`
`‘03
`
`33
`
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`
`53
`
`
`
`
`1m- (um-p
`
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`
`12.5 mg
`
`25 mg
`
`
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`
`

`

`rnen
`mm!
`
`QUALITY ASSESSMENT
`
`“"9“
`a-Ir-hh—nh— ‘
`
`Figure 2. Overlay Graph of Mean Dissolution Results (Full Profiles) Using Ethanol Media for
`SHP465 Capsules
`
`Stufl (2 1: Full dissolution profiles were obtained at n=12 units for the highest 50-mg strength of
`SHP465 capsule with sampling times at every 15 minutes for up to 3 hours. The graphic
`illustration of the mean dissolution profiles obtained in the various amounts of ethanol is
`presented in Figure 3.1.o
`-o- mean-meant)
`so -
`+ 5965')!!!
`
`
`
`
`
`
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`D
`a)
`40
`W
`U “n. gum) 120
`140
`16“
`1'0
`2110
`Figure 3. Mean dissolution profiles for SHP465 50 mg capsules using ethanol media
`(early time points)
`
`The results showed that,with the increasing amounts of ethanol (at 20% and most noticeably at
`40%), the dissolution rate for SHP465 capsules is significantly increased beyond the 20-minute
`test point. The results may be attributed to the alcohol solubility of the functional coatings used
`for the pulsatile delayed and delayed— beads in the SHP465 capsule formulation.
`
`Reviewer’s Assessment:
`
`The presence ofincreasing amount ofethanol at 20% and higher appear to proportionally
`
`increase the dissolution rate ofthe proposed drug product in early time points (less than 3
`
`hours). It is noted that thefollowing language regarding alcohol intake was included in the
`
`proposed labeling ofthe drug product:
`
`************
`
`Page 16, section 12.3:
`Alcohol Eflect
`
`
`
`

`

`QUALITY ASSESSMENT
`
`Page 23, Medication Guide:
`Tell your doctor ifyou or your child has ever abused or been dependent on alcohol, prescription
`
`medicines or street drugs.
`
`************
`
`It appears that there is no clear labeling instruction regarding the potential risk or clinica
`
`consequence as a result ofconcomitant use ofMYDA YIS and alcohol consumption. The results
`
`ofin-vitro alcohol-induced dosing dumping will be communicated to the Clinical and the
`
`Clinical Pharmacologv review teamsfor the proper labeling recommendation.
`
`EXTENDED RELEASE DOSAGE FORMS — Extended Release Claim
`
`According to the OCP review for the original submission of NBA 022-063,2 a single dose of
`
`37.5 mg of the proposed drug product is bioequivalent to an ADDERALL‘D XR 25 mg + mixed
`
`amphetamine salts [R 12.5 mg administered 8 hours later. The pharmacokinetic comparison, as
`
`illustrated in Figure 4, suggested that SPD465 capsule exhibits characteristics of extended—
`
`release that appear to further extended the release (noticable the prolonged time to peak
`
`concentration or Tmax) in comparison with ADDERALL XR®. The results support the
`
`extended—release claim of the proposed drug product.
`
`
`50
`
`40
`
`e'
`:
`
`'
`9
`
`‘
`
`+ spmes 375 mg
`—<9— ADDERALL XR8 25 mg
`+ Mxed Amphetamine salts 12 5 mg
`
`X T
`
`ime (hr)
`
`10
`
`
`
`d-AmphetammeMeanPlasma
`
`
`
`Concentration(ng/mL)
`
`Figure 4. Mean PK profile compalison between a single dose of SPD465 37.5 mg, and an
`ADDERALL XR® 25 mg + mixed amphetamine salts IR 12.5 mg administered 8 hours later
`
`List ofDeficiencies:
`
`None.
`
`10
`
`

`

`QUALITY ASSESSMENT
`
`Primary Biopharmaceutics Reviewer Name and Date: Jing Li Ph.D., 3&1/201 7
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`Ta-Chen Wu, Ph.D., 3/28/20] 7.
`
`11
`
`

`

`Jing
`Li
`
`Ta-Chen
`Wu
`
`Digitally signed by Jing Li
`Date: 3/29/2017 10:01:34AM
`GUID: 508da7420002bb05ac913303b23c39bb
`
`Digitally signed by Ta-Chen Wu
`Date: 3/29/2017 10:07:28AM
`GUID: 508da6df000269e151ff37cd8f4e13a1
`
`

`

`David
`Claffey
`
`Digitally signed by David Claffey
`Date: 6/05/2017 10:39:54AM
`GUID: 508da71e00029e20b201195abff380c2
`
`