CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`210874Orig1s000
`PRODUCT QUALITY REVIEW(S)
`
`
`
`
`
`
`

`

`Labeling Addendum to NDA 210874
`
`The API saxagliptin
`
`
`
` the revised language
`pertaining to saxagliptin is in Section 11 ‘DESCRIPTION’ of the label has been revised as follows:
`
`Saxagliptin is an active inhibitor of the dipeptidyl-peptidase-4 (DPP-4) enzyme. It is isolated in the
`monohydrate form chemically known as (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo [3.3.1.1]
`dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
`monohydrate
`or
`(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboni
`trile hydrate. The empirical formula is C18H25N3O2•H2O and the molecular weight is 333.43. The structural
`formula is:
`
`
`Furthermore, as the above structural formula clearly indicates that the API
` Therefore, the description of the 4
`individual strengths of the drug product now contain a revised statement for saxagliptin: “exists in the
`form of HCl salt”
`. The description of the
`four strengths of the drug product is now as follows:
`
`QTERNMET XR is available as film-coated tablets of four strengths:
`(cid:120) 2.5 mg dapagliflozin/2.5 mg saxagliptin/1000 mg metformin HCl: Each tablet contains 2.5 mg
`dapagliflozin (equivalent to 3.08 mg dapagliflozin propanediol), 2.5 mg saxagliptin (exists in the
`form of HCl salt)), and 1000 mg metformin HCl (equivalent to 779.86 mg metformin.
`(cid:120) 5 mg dapagliflozin/2.5 mg saxagliptin/1000 mg metformin HCl: Each tablet contains 5 mg
`dapagliflozin (equivalent to 6.15 mg dapagliflozin propanediol), 2.5 mg saxagliptin (exists in the
`form of HCl salt) and 1000 mg metformin HCl (equivalent to 779.86 mg metformin).
`(cid:120) 5 mg dapagliflozin/5 mg saxagliptin/1000 mg metformin HCl: Each tablet contains 5 mg
`dapagliflozin (equivalent to 6.15 mg dapagliflozin propanediol), 5 mg saxagliptin (exists in the form
`of HCl salt) ) and 1000 mg metformin HCl (equivalent to 779.86 mg metformin).
`(cid:120) 10 mg dapagliflozin/5 mg saxagliptin/1000 mg metformin HCl: Each tablet contains 10 mg
`dapagliflozin (equivalent to 12.3 mg dapagliflozin propanediol), 5 mg saxagliptin (exists in the form
`of HCl salt) ) and 1000 mg metformin HCl (equivalent to 779.86 mg metformin).
`
`Digitally signed by Christopher Galliford -S
`DN: c=US, o=U.S. Government, ou=HHS,
`ou=FDA, ou=People,
`0.9.2342.19200300.100.1.1=2001708703,
`cn=Christopher Galliford -S
`Date: 2019.04.24 12:09:42 -04'00'
`
`Christopher
`Galliford -S
`
`Christopher Galliford ATL
`
`NDA 210874 QTERNMET
`
`Reference ID: 4423658
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`CHRISTOPHER GALLIFORD
`04/30/2019 03:04:58 PM
`
`Reference ID: 4423658
`
`

`

`QUALITY ASSESSMENT
`
`Recommendation:
`
`NDA: Approval
`
`NDA 210874
`O
`ReVIew 1
`
`
`
`I a-a/Saxa/Met XR
`
`release tablets
`
`Strength
`Dapa/Saxa/Met XR 2.5/2.5/1000 mg, 5/25/1000 mg, 5/5/1000 mg and
`
`10/5/1000 mg
`
`Route of Administration
`Oral
`
`Rx/OTC Dispensed
`Rx
`
`Agplicant
`AS TRAZENECA AB
`
`«—
`
`
`O uali Review Team
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`Quality Review Data Sheet
`
`1. RELATED/SUPPORTING DOCUMENTS:
`
`
`
`
`
`Adequate
`
`COMMENTS
`
`Based on
`information
`
`
`
`DATE
`
`
`ITEM
`
`
`REVIEW
`HOLDER
`STATUS1
`
`
`
`RE FEREN CED
`
`COMPLETED
`(b)
`
`
`provided in the
`NDA
`
`Adequate
`Based on
`information
`
`
`provided in the
`NDA
`
`Adequate
`
` information
`
`Based on
`information
`
`provided in the
`NDA
`Based on
`
`provided in the
`NDA
`
`1Adequate, Adequate with Information Request, Deficient, or N/A (There is enough data
`in the application, therefore the DMF did not need to be reviewed)
`
`B. Other Documents: IND, RLD, or sister applications
`
`DOCUMENT
`
`APPLICATION NUMBER
`
`DESCRIPTION
`
` 2
`
`NDA
`
`202293
`
`205 649
`
`22350
`
`2. CONSULTS:
`
`Dau._liflozin Farxi_a® Tablets
`
`Dapagliflozin/
`Metformin hydrochloride
`Xi _duoTM XR Tablets
`Saxa_u1itin Onl za® Tablets
`
`hydrochloride
`Kombil ze® XR Tablets
`
`0 em® Tablets
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`Recommendations
`
`Executive Summary
`
`. Recommendation and Conclusion on Approvability
`NDA 210874 is recommended for approval from a CMC perspective. There are
`no outstanding deficiencies and the manufacturing facilities have an approval
`recommendation. Labeling comments will be negotiated through the clinical
`project manager. A 24-month shelf-life will be granted through the approval letter
`based on stability data at intermediate storage conditions. The product should be
`stored below 30 °C (86 °F).
`
`. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Summary of Quality Assessments
`
`. Drug Substance [USAN N ame] Quality Summary
`The Qtemmet XR tablets are fixed combination drug product (FCDP) XR
`extended release tablets
`that contain three drug substances dapagliflozin,
`saxagliptin and metformin hydrochloride (Dapa/Saxa/Met). The three drug
`substances are described below:
`
`28,3R,4R,5S,6R)-2-[4-Chloro-3-(4-
`propanediol monohydrate,
`Dapagliflozin
`ethoxybenzyl) phenyl]-6—(hydroxymethyl) tetrahydro-Zprran-3,4,5-triol, (ZS)-
`propane-1,2-diol (1:1) monohydrate is a non-hygroscopic, white to off-white
`crystalline powder which exhibits no polymorphism. Dapagliflozin has a
`solubility of 1.6 mg/mL. Manufacturing, packaging, quality control testing and
`release of dapagliflozin drug substance are performed a
`W4)
`@(oThe
`
`dapafliglozin drug substance is considered satisfactory based on the approved
`status of NDA 202293.
`
`Saxagliptin, (1S,3S,5S)-2-[(ZS)-2-Amino-2-(3-hydroxytricyclo [3.3.1.13,7] dec-l-
`yl)acetyl]-2-azabicyclo [3.1.0]hexane-3—carbonitrile monohydrate,
`is a white to
`light yellow or light brown powder. Saxagliptin dehydrates before melting and its
`aqueous solubility at 24°C i 3°C is 17.6 mg/mL. Manufacturing, packaging,
`quality control testing and release of saxagliptin drug substance are performed at:
`(low
`
`The saxagliptin drug
`substance is considered satisfactory based on the approved status of NDA 22350.
`
`is a white
`Metformin hydrochloride, 1,1-Dimethylbiguanide hydrochloride,
`crystalline solid with an absence of polymorphism that is freely soluble in water
`and slightly soluble in alcohol. Manufacturing, packaging, quality control testing
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

`"mm"
`m
`
`QUALITY ASSESSMENT
`
`“""""""
`a..-.....-_..
`
`and release of saxagliptin drug substance are performed a—
`
`——
`
`. The metformin hydrochloride drug substance is
`considered satisfactory based on the approved status of NBA 202293.
`
`B. Drug Product [QTERNMET'M] Quality Summary
`Dapagliflozin, saxagliptin and metformin hydrochloride extended release tablets
`(Dapa/Saxa/Met XR) are rmnufactured in strengths of 25/25/1000 mg, 5/2.5/ 1000
`mg, 5/5/1000 mg and 10/5/1000 mg. Descriptions of the various tablet strengths are
`reproduced below:
`
`——_
`2505110110.;
`Althhnbhmbumwifihm‘dflflflm”
`Mane“.
`
`a.
`
`lib.
`
`Afimmmmmmwmuu-
`a;
`
`The applicant has drawn from their considerable experience in the manufacture of
`approved combinations of these drug substances—
`
`——
`
`Figure 2
`
`Schematic illustration‘ of the formulation design principle of the
`Dapa/Saxa/Met XR tablet.
`
`
`
`‘
`
`Schematic illustration, not according to scale
`
`The drug substances are the same dose and form as those found in currently approved
`drugs from the same applicant This includes combination tablets of two of the three
`APIs
`used
`in
`this
`application.
`These
`combinations
`are QTERNo
`(dapagliflozin/saxagliptin) KOMBIGLYZEo XR (saxagliptin/metformin HCl XR),
`
`4
`
`OPQ-XOPQ—TEM-0001v02 Effective Date: 13 Mar 2015
`
`

`

` ‘
`QUALITY ASSESSMENT
`
`and XIGDUO XR® (dapagliflozin and metformin hydrochloride XR). The drug
`product is a tablet dosage form for oral administration that combines Dapa/Saxa/Met
`XR. Long-term stability has been demonstrated when the product is packaged in
`high-density polyethylene (HDPE) bottles for commercial distribution.
`
`C. Summary of Drug Product Intended Use
`
`h drochloride Doaa/Saxa/Met
`
`h drochloride Ioaa/Saxa/Met
`
`Alternative Methods ofAdministration
`
`Patient Po . ulation
`
`Maximum Daily Dose
`
`p - 2 diabetes mellitus T2D
`As directedb .h sician
`
`Dapa/Saxa/Met XR 2.5/2.5/1000 mg, 5/25/1000
`In 5/5/1000 m and 10/5/1000 m-
`
`OVERALL ASSESSMENT AND SIGNATURES: EXECUTIVE
`
`SUMMARY
`
`
`
`5
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

`""""
`m
`
`QUALITY ASSESSMENT
`
`“""'""'"
`a..........-....
`
`Table of Contents
`
`Chapter 1: Drug Substance
`Chaper H: Drug Product
`Chapter 111: Environmental Assessment
`Chapter IV: Labeling
`Chapter V: Process
`Chapter VI: Facilities
`Chapter VII: Biopharmaceutics
`
` 6
`
`OPQ-XOPQ-TEM-OOOIVOZ Effective Date: 13 Mar 2015
`
`

`

`QUALITY ASSESSMENT
`
`R.2
`
`Comparability Protocols
`
`No comparability protocols are proposed in this application.
`
`OVERALL ASSESSMENT AND SIGNATURES: DRUG PRODUCT
`
`ASSESSMENT OF ENVIRONMENTAL ANALYSIS
`
`The applicant states that this submission qualifies for a categorical exclusion in accordance
`with 21 CFR Part 25.31(a) and 25.15. To the applicant’s knowledge, no extraordinary
`circumstances exist that would warrant the preparation of an environmental assessment.
`
`Rm‘r’s Assgssmgnt:
`
`
`
`For two of the ingredients, dapagliflozin and saxagliptin, the applicant submitted
`claims for categorical exclusions from an environmental assessment (EA) in
`accordance with 21 CFR 25.31(b), which is for substances that increase in use but
`result in an expected introduction concentration (EIC) of < 1 ppb. The applicant
`
`included use amounts that were consistent with the claim and included the required
`statement of no extraordinary circumstances in accordance with 21 CFR 25.15 . The
`CDER EA Team reviewed the claims and agreed that there are no extraordinary
`circumstances. Therefore, the claims for an exclusion from an EA for these
`substances are acceptable.
`
`For metformin, the applicant provided an EA rather than a claim for an exclusion
`from an EA because, they stated, use is predicted to result in an EIC > 1 ppb. The EA
`Team, however, has determined that this substance already is > 1 ppb, and that
`
`27
`
`

`

`""‘""
`
`QUALITY ASSESSMENT
`
`approval would not result in an increased use because the indication for this NDA is
`for treating patients who are inadequately controlled on metformin using identical
`doses of this substance (CTD section 2.2, Introduction). Thus, this substance is
`subject to a categorical exclusion from an BA in accordance with 21 CFR 25.31(a),
`which is for actions that do not increase the use of the active moiety. FDA also notes
`
`that while approval would not result in extraordinary circumstances, the data
`submitted by the applicant and in the open literature indicate that cumulative effects
`fiom all uses of metformin indicate the need for additional monitoring by FDA of
`
`collections and environmental assessments.
`
`these risks outside of the subject action, such as through fiiture information
`
`OVERALL ASSESSMENT AND SIGNATURES: ENVIRONMENTAL
`
`
`
`
`
`
`
`Review of Common Technical Document-Quality (Ctd-Q) Module 1
`
`Labeling & Package Insert
`
`l-Lasmssn
`
`
`
`28
`
`

`

`QUALITY ASSESSMENT
`
`(a) “Highlights” Section (21CFR 201.57(a))
`
`Provided in NBA
`
`Product title, Drug_name _(201.57(a)(2))_
`Proprietary name and QTERNMET XR
`
`established name
`
`(dapagliflozin.
`saxagliptin. and
`metformin
`hydrochloride)
`extended release
`tablets for oral use.
`tablets for oral use
`
`Adequate accepted by DMEPA
`
`Conclusion: Adequate
`
`of administration
`
`substance symbol (if Not required
`a. ulicable
`DosaeForms and Stren hs 201.57 a 8
`A concise summary
`(Dapa/Saxa/Met XR)
`of dosage forms and
`in strengths of
`
`strengths
`
`2.5/2.5/1000 m2.
`5/25/1000 m2.
`5/5/1000 mg and
`10/5/1000 m
`
`30
`
`

`

`QUALITY ASSESSMENT
`
`(b) “Full Prescribing Information” SectiOn
`
`'D
`
`Frmn trnh21FR21
`
`4
`
`(Dapa/Saxa/Met XR) in strengths of 25/25/1000 mg, 5/2.5/1000 mg, 5/5/1000 mg and
`10/5/1000 m
`
`_ Information Provided in NBA
`
`Strengths: in metric system
`
`(Dapa/Saxa/Met XR) manufactured
`in strengths of 25/25/1000 mg,
`5/2.5/1000 mg, 5/5/1000 mg and
`10/5/1000 m-
`
`Conclusion: Adequate
`
`Ade . uate
`
`Adequate
`
`and
`saxagliptin
`A description of the identifying Dapagliflozin,
`characteristics of the dosage
`metformin hydrochloride extended
`forms, including shape, color,
`release tablets (Dapa/Saxa/Met XR)
`coating, scoring, and
`for
`oral
`administration
`in
`the
`imprinting, when applicable.
`strengths of:
`2.5/2.5/1000 mg as a light brown to
`brown biconvex, oval, film coated
`tablet, with “3001” debossed on one
`side.
`
`5/2.5/1000 mg A green biconvex,
`oval, film coated tablet, with “3002”
`debossed on one side.
`
`5/5/ 1000 mg as a pink biconvex,
`oval, film coated tablet, with “3003”
`debossed on one side.
`
`l0/5/1000 mg A grey biconvex,
`oval, film coated tablet, with “3004”
`debossed on one side.
`
`31
`
`

`

`QUALITY ASSESSMENT
`
`ll'D ritin21 FR21
`
`12
`
`QTERNMET XR tablets for oral use is an extended-release formulation and
`contains dapagliflozin, saxagliptin, and metformin hydrochloride. There are four
`strengths:
`
`
`
`(Ii) (4)
`
`(I!) (4)
`
`E Each film-coated tablet contains dapagliflozin 10 mg (equivalent to 12.3 mg
`dapagliflozin propanedio
`moi, saxagliptin 5 m
`(mo, and metformin hydrochloride 1000 mg.
`E Each film-coated tablet contains dapagliflozin 5 mg (equivalent to 6.15 mg
`dapagliflozin
`propanedio
`
`m4)», saxagliptin 5 mg
`(5x9 and metformin hydrochloride 1000 mg.
`E Each film-coated tablet contains dagagliflozin 2.5 mg (equivalent to 3.08 mg
`dapagliflozin propanedio
`x4), saxagliptin 2.5 mg
`(”"9
`tformin hydrochloride] 000 mg.
`"'""
`“mtablet contains gagagliflozin 5 mg (equivalent to 6.15 mg
`E Eac
`danagliflozin nmnanedio (m4)
`, saxagliptin 2.5 mg
`(ml)
`, and metformin hydrochloride 1000 mg.
`
`
`
`Inactive ingredients: The product contains carboxymethyl cellulose sodium,
`crospovidone, hypromellose 2208,
`iron oxides, lactose anhydrous, magnesium
`stearate, microcrystalline cellulose, polyvinyl alcohol, macrogol/polyethylene
`
`glycol, silicon dioxide, talc, and titanium dioxide.
`
`Dapagliflozin
`Dapagliflozin is an active inhibitor of sodium-glucose cotransporter 2 (SGLT-2).
`
`Dapagliflozin propanedio] is described chemically as D-glucitol, 1,5-anhydro-1-
`C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-,(1S)-, compounded with (2S)-
`
`l,2-propanediol, hydrate (1:1:1). Empirical formula: C21H25C106'C3H802'H20.
`Molecular weight: 502.98.
`
`Ho“ \1/
`
`’on
`
`.
`
`I
`
`\
`
`. 3,0
`
`Saxagliptin
`
`Saxagliptin is an active inhibitor of the dipeptidyl-peptidase—4 (DPP-4) enzyme.
`Saxagliptin
`is
`described
`chemically
`as
`(1S,3S,5S)-2-[(ZS)-2-amino-2-(3-
`hydroxytricyclo
`[3.3 .1 .1]
`dec-l -yl)acetyl]-2-azabicyclo[3 .1 .Olhexane-3-
`
`(1 S,3S,5S)-2-[(ZS)-2-amino-2-(3-hydroxy-1-
`or
`carbonitrile, monohydrate
`adamantan- 1 -yl)acetyl]-2-azabicyclo[3 .1 .Olhexane-3-carbonitrile hydrate.
`
`Empirical formula: C18H25N302°H20. Molecular weight: 333.43.
`
`32
`
`

`

` QUALITY ASSESSMENT
`
`(m4)
`
`Ht)
`
`”:5
`
`\$ Ollzi)
`
`(N
`
`0
`
`Mezformin hydrochloride
`
`hydrochloride
`
`Metformin
`diamide
`(N,N-dimethylimidodicarbonimidic
`hydrochloride
`0')“, molecular
`formula of C4H11N5-HC1 and a molecular weight of 165.63
`23::
`
`structural formula is:
`
`(um) The
`
`CH3
`I
`/N
`
`NH
`”
`Y Y 2
`NH
`NH
`
`Information Provided in NBA— ’
`
`A -nuate
`
`d d
`
`solub 111 Conclusion: Adequate
`
`name
`
`administration
`Active moiety expression of
`
`strength with equivalence statement
`for salt if a nlicable
`Inactive ingredient information
`
`(quantitative, if iniectables
`21CFR201.100(b)(5)(iii)), listed by
`USP/NF names.
`
`————
`
`A -nuate
`
`Provided
`
`Provided
`
`Adequate
`
`Adequate
`
`A
`
`dnuate
`
`d-
`
`d-
`A -nuate
`
`_———
`————A uuate
`-————
`
`an nlicable
`
`molecularwei_ht
`
`If radioactive. statement of
`important nuclear characteristics.
`Other important chemical or
`physical properties (such as pKa,
`
`Not required
`
`Provided
`
`Adequate
`
`Adequate
`
`33
`
`

`

`QUALITY ASSESSMENT
`
`l-Hw li
`
`tra aanlin 21FR21
`
`1
`
`Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C
`
`(59°F to 86°F).
`
`_ Information Provided in NBA
`Strength of dosage form
`(Dapa/Saxa/Met XR) in strengths of
`2.5/2.5/1000 mg. 5/2.5/ 1000 mg.
`5/5/1000 m_ and 10/5/1000 m-
`
`Adequate
`
`Available units (e.g.. bottles of
`
`100 tablets
`
`Bottles of5, 10, 30 or 60 tablets —
`
`Ade . uate Identification of dosage forms.
`
`e.2.. shape. color. coating.
`scoring, imprinting, NDC
`number
`
`Provided
`
`Adequate
`
`_——from 1i_ht do not freeze
`
`Ade . uate
`
`Ade . uate
`
`Manft
`
`r'tri trnam lit
`
`atth n
`
`fPIfllwin
`
`tinl
`
`_ Information Provided in NDA Manufacturer/distributor name (21
`
`AstraZeneca Pharmaceuticals
`LP Wilmin 0 DE 19850
`
`CFR 201.1
`
`Conclusion: Adequate
`
`2. Container and Carton Labeling
`
`1)
`
`Immediate Container Label
`
`Container labels are reproduced from the application below:
`
`4 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`34
`
`

`

`QUALITY ASSESSMENT
`
`Comments on the Information Provided'1n
`NDA
`
`Conclusions
`
`ize and prominence (21
`
`QTERNNIET XR (dapagliflozin, saxagliptin, and
`
`metformin hydrochloride) extended release tablets
`for oral use.
`
`trength (21CFR
`'01.10(d)(1); 21.CFR
`'01.10°<b>(4))
`
`(Dapa/Saxa/Met XR) manufactured in strengths 0'
`.5/25/1000 mg, 5/25/1000 mg, 5/5/1000 mg an
`10/5/1000 m
`
`Adequate
`
`Adequate
`
`30 or 60 tablets
`
`Not required for an oral dosage form
`
`Provided
`
`Adequate
`
`l' oute of administration
`r 1.CFR 201.100 b 3
`
`I et contents* (21 CFR
`' 015 l a
`
`I ame of all inactive
`' gredients (; Quantitative
`1' gredient information is
`equired for injectables)
`r 1CFR 201.100 b 5 **
`
`9 01.18
`
`FR 201.17
`
`1CFR201.100 -
`
`1
`
`not re- uired
`
`I
`
`I C number
`per 21 CFR 201.2)
`
`requested, but not
`equired for all labels or
`
`labeling), also see 21 CFR
`
`' 07.35(b)(3)
`
`|=ar Code per 21 CFR
`
`
`
`01.2w” —_
`
`Provided
`
`Adequate
`
`I ame of
`I nufacturer/distributor
`
`21 CFR 201.1
`
`amings
`
`Provided
`
`Adequate
`
`Store at 20°C to 25°C (68°F to 77°F);
`excursions permitted between 15°C to
`30°C 59°Fto 86°F .
`
`Adequate
`
`*21 CFR 20151(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.
`
`39
`
`

`

`QUALITY ASSESSNIENT
`
`**For solid oral dosage forms, CDER policy provides for exclusion of “oral” from 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.
`
`Conclusion: Adequate
`
`2) Carton Labeling
`The drug product is supplied only in bottles, there is no secondary packaging.
`
`40
`
`

`

`QUALITY ASSESSMENT
`
`metformin hydrochloride) extended release tablets
`for oral use.
`
`strength (221CFR201.10(d)(1);
`
`(Dapa/Saxa/Met XR) manufactured in strengths 0
`
`Adequate
`
`10/5/ 1000 m;
`
`
`
`——. anufacturer/disuibutor
`
`I ot number per 21 CFR
`' 01.18
`
`I xpiration date per 21 CFR
`' 01.17
`
`I arne of all inactive
`Ingredients (except for oral
`gs); Quantitative ingredient
`
`information is required for
`I‘niectables)[ 201.10(a),
`
`' 1CFR201.lOO(d)(2)]
`
`4 o .licable
`
`FR 201.100(d)(2), FD&C
`‘ ct 503(b)(4)
`
`per 21 CFR 201.2)
`
`requested, but not required
`
`Ior all labels or labeling), also
`ee 21 CFR 207.35(b)(3)
`
`'01.25 c 2 **
`
`Information” (21 CFR 201.55)
`
`‘Keep out of reach of
`
`e-uired for OTC
`
`Space is provided
`
`Adequate
`
`Space is provided
`
`Not required for an oral dosage form
`
`Adequate
`
`Provided
`
`Adequate
`
`Provided
`
`Not included
`
`Adequate
`
`

`

`QUALITY ASSESSMENT
`
`I' oute of Administration (not
`equired for oral, 21 CFR
`01.100 d 1 and d 2
`
`Not required
`
`Adequate
`
`above. As there is no need for secondary packaging, this is adequate.
`ADEQUATE
`
`Conclusion: There is no carton for the drug product, it is provided only in the bottles described
`
`OVERALL ASSESSNIENT AND SIGNATURES: LABELING
`
`R '
`
`r’ A
`
`57 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`42
`
`

`

`QUALITY ASSESSMENT
`
`BI PHARMA E TI
`
`Product Background: The Applicant is seeking approval of QTERNMET XR
`dapagliflozin/saxagliptin/metformin hydrochloride extended-release fixed combination drug
`product indicated for Type 2 Diabetes Mellitus. QTERNMET XR (dapagliflozin, saxagliptin and
`metformin hydrochloride) extended release tablets is indicated as an adjunct to diet and exercise
`to improve glycemic control in adults with type 2 diabetes mellitus (T2DM
`
`W0
`
`Planned Tablet Strengths, Dosage and Daily Dose of Dapa/Saxa/Met XR
`(dapagliflozin/saxagliptin/metformin‘l XR)
`
`Planned Tablet Strengths - dapagliflozin/saxagliptin
`Imetformin XR (mg)
`
`Dosage
`
`Daily Dose
`dapagliflozin/saxagliptin
`Imetformin XR (mg)
`
`5/5/1000
`
`10/5/1000
`
`1 tablet once a day
`
`5/5/ 1000
`
`1 tablet once a day
`
`10/5/1000
`
`25/25/1000
`
`2 tablets once a day
`
`5/5/2000
`
`5/2.5/1000
`
`2 tablets once a day
`
`10/5/2000
`
`a Strengths and doses of metformin are given as amount of metformin hydrochloride. XR
`Extended Release
`
`NDA: 210874
`
`Drug Product Name / Strength: QTERNMET XR dapagliflozin/saxagliptin/metfonnin
`hydrochloride extended-release fixed combination drug product, 2.5/2.5/1000 mg, 5/2.5/1000
`mg, 5/5/1000 mg and 10/5/1000 mg.
`
`Route of Administration: Oral
`
`Applicant Name: AstraZeneca Pharmaceuticals LP
`
`Review Summary:
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 1 of 18
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`AstraZeneca (Sponsor) has developed a triple fixed combination drug product (FCDP)
`containing dapagliflozin, saxagliptin and metformin hydrochloride extended release (XR) as
`an adjunct to diet and exercise to improve glycemic control in adults with T2DM 00“)
`«no
`
`The formulation design principl
`
`(I!) (4)
`(mo
`
`(5) (4)
`
`Dapagliflozin, saxagliptin and metformin hydrochloride extended release tablets (Dapa/Saxa/Met
`
`XR) were developed based on the commercial products XIGDUO XR (dapagliflozin and
`metformin HCl XR, approved in the US 2014) and ONGLYZA (saxagliptin, approved in the US
`
`2009). Knowledge from the development of the commercial combination products, QTERN
`(dapagliflozin and saxagliptin, approved in the US 2017) and KOMBIGLYZE XR (saxagliptin
`and metformin HCl XR, approved in the US 2010), was also considered since they build on the
`same drug substances and formulation design principles.
`
`The drug release profile expecte
`
`(5) (4)
`(m4)
`
`The Applicant proposes to use the same dissolution method that was previously approved for the
`
`ONGLYZA and XIGDUO XR. The Applicant adequatelyjustified the dissolution method
`parameters for the proposed extended-release tablet product. The acceptance criteria for
`dissolution of dapagliflozin and metformin HCl in Dapa/Saxa/Met XR is consistent with the
`requirements for dissolution of dapagliflozin and metformin HCl in XIGDUO XR. The
`Dapa/Met XR core used for manufacture of Dapa/Saxa/Met XR is the same as used in XIGDUO
`XR (strengths of 2. 5/1000 mg, 5/1000 mg and 10/1000 mg) and the dissolution method used for
`Dana/Saxa/Met XR15 identical to the method used for XIGDUO XR (USP Apparatus 1
`(W)
`wbaskets) at 100 rpm in 1000 mL of pH 6. 8 potassium phosphate buffer (50 mM)), refer to
`NDA 205,649 for XIGDUO XR. The acceptance criterion for dissolution of saxagliptin1n
`
`OPQ-XOPQ—TEM—0001v03
`
`Page 2 of 18
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Dapa/Saxa/MetXR is consistent with the requirements for dissolution of saxagliptin in
`ONGLYZA®, refer to NDA 22350 for ONGLYZA. The dissolution methods used for the two
`
`products are different, USP Apparatus 1 (baskets) is used for Dapa/Saxa/Met XR and USP
`Apparatus 2 (paddles) is used for ONGLYZA. In vitro dissolution for saxagliptin and
`dapagliflozin from Dapa/Saxa/Met XR 2.5/2.5/1000 mg, 5/2.5/1000 mg, 5/5/ 1000 mg and
`10/5/1000 mg tablets was rapid in all test dissolution media, Wit
`3% dissolved in 30 minutes.
`
`Dissolution data submitted support the proposed dissolution acceptance criteria. The Applicant’s
`proposed dissolution acceptance criteria are acceptable.
`
`In vitro alcohol interaction studies was conducted for this particular finished drug product as per
`agency’s request, and the data indicate a decrease in metforrnin release with increase in alcohol
`concentration particularly above 40% ethanol.
`
`Requests for biowaivers for the remaining two Dapa/Saxa/Met XR tablet strengths, 2.5/2.5/1000
`
`mg and 5/5/1000 mg are adequate pending acceptable outcome of BB studies and dose
`proportionality with therapeutic dose range per clinical pharmacology review (please refer to
`clinical pharmacology review for additional details).
`
`From the Biopharmaceutics perspective, NDA 210874 for QTERNMET XR
`Dapagliflozin/saxagliptin/metformin hydrochloride extended-release fixed combination drug
`product, 2.5/2.5/1000 mg, 5/2.5/1000 mg, 5/5/1000 mg and 10/5/1000 mg is recommended for
`approval pending acceptable outcome of BB studies and dose proportionality with therapeutic
`
`dose range per clinical pharmacology review (please refer to clinical pharmacology review for
`additional details).
`
`List Submissions bein- reviewed table :
`Date of Submission
`-
`Jul 2,2018
`$0015
`Janua
`11,2019
`
`February 1 l, 2019
`$0017
`
`
`
`Pur - use of Submission
`
`Highlight Key Outstanding Issues from Last Cycle: N/A
`
`Concise Description Outstanding Issues Remaining: N/A
`
`BCS Designation
`
`Reviewer’s Assessment: N/A for modified release products
`
`Dapagliflozin and Saxagliptin components are immediate release in the proposed finished drug
`
`product. Dapagliflozin is a non-ionizable compound; thus, its aqueous solubility and partition
`
`coefficient are not affected by changes in pH. The aqueous solubility of dapagliflozin is 2.1
`
`mg/mL across the pH range of 1.2 to 6.8 at 37°C.Dapagliflozin is highly permeable in in vitro
`
`intestinal permeability models. The absolute oral bioavailability of dapagliflozin is high (78%)
`
`and it has dose proportional pharmacokinetics (PK) ranging from 0.1 mg to 500 mg following
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 3 of 18
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`oral administration. Based on these data, dapagliflozin is a BCS Class 3 compound (with high
`
`solubility/<90% absolute oral bioavailability as per the BC S).
`
`The aqueous solubility of saxagliptin is variable with pH, ranging between 17.6 mg/mL and 149
`
`mg/mL in the physiological pH interval. At the highest dose strength of 5 mg, the dose/solubility
`
`is less than 1 mL, making saxagliptin a high solubility compound (as per the BCS). As a result,
`
`absorption of saxagliptin is not expected to be limited by its aqueous solubility or dissolution at
`
`physiological pH values. Based upon its aqueous solubility and its permeability in the Caco-2
`
`system, saxagliptin would be designated a BCS Class 3 compound.
`
`The firm provided their rational for Dapagliflozin having characteristics as high solubility/high
`
`in vitro permeability and at least 78% absorbed from the gastrointestinal tract with linear
`
`pharmacokinetics, which makes it BCS Class l-like rather than BCS Class 3.
`
`Dissolution Method andAcceptance Criteria
`
`Reviewer’s Assessment: ADEQUATE
`
`Dissolution Method;
`
`The proposed dissolution method is described in the following table:
`
`Dissolution parameters
`
`Parameter
`
`Dissolution Apparatus
`
`Dissolution Medium
`
`Dissolution Medium Volume
`
`Temperature in Vessel
`
`Rotation Speed
`
`Sampling Time for dapagliflozin
`
`Sampling Time for saxagliptin
`
`Setting
`
`USP Apparatus 1 (baskets, ZO-Mesh)
`
`50 mM potassium phosphate buffer, pH 6.8
`
`1000 mL
`
`37°C
`
`100 rpm
`
`30 minutes
`
`30 minutes
`
`Sampling Time for metformin hydrochloride
`
`60, 180 and 600 minutes
`
`filo—x4)
`
`2 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 4 of 18
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`o The dissolution method is adequate.
`
`o Dissolution profiles for all commercial tablet strengths using the final dissolution method are
`shown below. These tablet lots were used in the registration stability study.
`
`Results
`
`Results
`
`Results
`
`101 (9"-103)
`
`101 (95-106)
`
`101 (95-106)
`
`
`
`
`Batch results for D a/Saxa/Met XR film coated tablets 2.5/2.5/1000 m
`
`
`Batch number
`H0156
`Eliot“
`flNOlss
`
`Acceptance criteria
`Test
`
`
`Dissolution
`
`
`anagliflozin.
`melywiththerequirements in USP Ph Eu:
`Mean (Mm-Max)
`nt 50 mmutes
`97 (95-100)
`99 (97-100)
`94 (93-96)
`Saxagliplill.
`Shall comply “ilh tllc qululemcms ill USP Ph Ell:
`Mean (Min-Max)
`0-1 an 30 minutes
`
`Metfonnin hydrochloride.
`Shall comply “ilh lllc qulllreulcurs ill USP Pll Ell:
`26 (26-27)
`26 (26-27)
`27 (26-28l
`MeanlMiu-Max)
`“moi label claim after I 1:
`
`of label claim after 3 h
`55 (55-56!
`5’! (53-56}
`54 (54-55)
`
`
`(ll-laltl claim After 10 ll
`03 (02-04.
`03 (OI-04)
`04 (02.05)
`
`
`Butch nulnbfl'
`JF0259
`Jf0260
`JF0261
`
`Results
`Results
`Results
`
`
`
`
`Accept-nee criteria
`
`ansgliflozin.
`Mean (Min-Max)
`
`Snxngliplin.
`Mean (Min-Max)
`
`Mclformm hydrochlondc.
`Mean (Min-Max)
`
`Slimmmply with the reqtnrements in USP l’h Eur.
`Q-
`at 50 minutes
`
`95 (ii-97'
`
`99 (96-100l
`
`98 {95-1'JOI
`
`Slit-J'siamply With the requirements in USP Ph Eur.
`Q-
`nt 30 minutes
`
`100 (96-102)
`
`97 (94-98)
`
`100 (95-105)
`
`Shall comply m'th the requirements in USP P11 Eur.
`”mama claim after I h
`aflnbel claim afiel’ 5 h
`oflnbel claim after 10 11
`
`26 (n-7,.
`55 (5-1-56)
`9| (90-921
`
`:7 {26-27)
`55 {55-55)
`9| (90-9!)
`
`26 {26-27)
`55 -_ 55-56)
`92 -92-93)
`
`Batch results for Daga/Saxa/Met XR film coated tablets 5/2.5/ 1000 mg
`Batch number
`HKOIS'I
`
`RICO 158
`
`HKOISQ
`
`Test
`Dissolution
`
`Dopnglitlozin.
`Mean (Mill-Max)
`Suxngliptin.
`Mean (Min-Max)
`Metformin hydrochloride.
`Mean (Min-MM)
`
`Acceptance criteria
`
`Results
`
`Results
`
`Resulls
`
`Sho&léfimply “ith the requirements in USP Ph Eur.
`Q=
`at 30 minutes
`Slmll mply with the requirements in USP Ph Eur.
`Q= mat 30 minutes
`Shall comply with the requirements in USP Ph Eur.
`moor label claim after 1 h
`ot‘lnbel claim after 3 h
`oflabel claim after 10 h
`
`95 (92-98)
`
`94 190-96)
`
`96 (93-98)
`
`10] (97-106)
`
`102 (98-108)
`
`10] (96-106)
`
`:7 17-18)
`56 (55-57)
`94 (93-95)
`
`2.7 (26-28)
`56 (55-56)
`94 192-95)
`
`:7 (17-28)
`56 (55-57)
`94 (93-95)
`
`
`Batch number
`JNOHJ
`”0145
`
`Test
`
`Acceptance criteria
`
`Results
`
`Resuks
`
`OPQ-XOPQ-TEM-0001v03
`
`Page 7 of 18
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSMENT
`
`Dissolution
`
`annghflozm.
`Mean (Min-Max)
`
`Samgliptm.
`Mean (Min-MM)
`Metformin liydmclllmidc.
`Mean (Min-Mm
`
`Slit-brainy)” “1111 the requirements in USP Ph Eur.
`Q—
`;41 30 millulcs
`
`95 ( 93-971
`
`95 091-101)
`
`5111-“ Mmply “1111 the requmements in USP P11 Eur.
`Q— (Q at 301nillule~
`Shall comply “1111 the requirements in USP P11 Eur.
`”maflnbcl claim 1.11“ l l)
`at‘labcl claim lifter 3 h
`oflabcl claim after 10 h
`
`101 (98-1091
`
`105 190-113)
`
`26 (25-271
`54 (54-551
`92 (91-931
`
`27 (27-25)
`56155-56)
`94193-95)
`
`
`Batch results for Dapa/Saxa/Met XR film coated tablets 5/5/1000 mg
`Batch number
`BRINGS
`11370159
`“NO-‘88
`
`'l‘cst
`Dissolution
`
`DapaglifloziiL
`Mean (Mm-Max)
`Samgliptui.
`Mean (Mm-Max)
`
`Acceptance critcrln
`
`Results
`
`Results
`
`Results
`
`Shall comply with the requirements in USP P11 Eur.
`0-0991]: 50 minutes
`Shall comply with the i'equlicments 1n USP P11 Eur.
`0.110(4).“ 30 minutes
`
`96 (95-98!
`
`95 [89-98)
`
`93 186-98)
`
`99 (97-1011
`
`100 (911-104)
`
`10.1 (95-1041
`
`Melfm min llyilmchloriilc.
`Mean Min-Max)
`
`Shall con ly with the i'equucmcnts 1n USP P11 Eur.
`27 (26.27)
`16 (26-27
`:7 (27.27;
`a”
`-flabel claim after 1 h
`56 (55-57)
`54 (54-55)
`56 (55-561
`-flabcl claim alter 3 h
`.f label claim after 10 11
`94 (93-94 1
`93 (92—94)
`95 (94-96)
`
`
`
`Batch results for Dapa/Saxa/Met XR film coated tablets 10/5/1000 mg
`Batch number
`HROlé-l
`M0165
`HK0166
`
`
`Dissolution
`
`Shall comply with the requirements in USP Ph Em.
`Q= @051: 30 minutes
`Shall comply with the requirements in USP Ph Em.
`talflfim 30 minutes
`Shall co
`1); u ith the requirements in USP Ph Eu.
`27 (17—25)
`27 1:27.27}
`:7 (27-231
`°’
`)flabcl clam] after 1 11
`56 (55-56)
`56 {55-56}
`56 (55-56)
`71th clam] after 3 h
`of label claim after 10 h
`95 (91-91)
`94 195-94;
`9-1 (95-95)
`
`Batch number
`“0262
`JF0263
`JF0164
`
`
`9: (89-95)
`
`93 (90-971
`
`95 (91-100)
`
`Dapagliflozin
`Mean (Min-Max)
`Snxagliptin.
`Mean (Min-Max)
`Melfumiiil hydrochloride.
`Mean (Min-Max)
`
`102 (99.105)
`
`103 (101-107)
`
`102 (9"-105)
`
`Test
`Dissolution
`
`Acceptance criteria
`
`Results
`
`Results
`
`Results
`
`anaghflozin.
`Mean (Min-Max)
`
`Shogiwnply with the requirements in USP Ph Eur.
`Q
`at 30 minutes
`
`08 (OJ-IOO)
`
`06 (03-98)
`
`94 (GO-l0!)
`
`Saxagliptin.
`Mean (Min-Max}
`Mctformin hydrochloride.
`M