`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`
`PRODUCT QUALITY REVIEW(S)
`
`
`

`

`QUALITY REVIEW
`
`Recommendation:
`
`APPROVAL
`
`{including the Overall Manufacturing Inspection Recommendation)
`
`NDA 209805
`
`ADDENDUM TO Review #1
`
`The recommendation from the Office of Pharmaceutical Quality (OPQ) is for Approval,
`including the Overall Manufacturing Inspection Recommendation dated 11/1/2017.
`
`This current recommendation for Approval replaces the 8/23/17 recommendation for a
`Complete Response.
`0 The 8/23/17 Complete Response recommendation resulted from the 8/17/17
`Facilities “Withhold” Recommendation for
`
`m“)
`
`manufacturer of sitagliptin phosphate monohydrate.
`o The 8/17/17 “Withhold” recommendation resulted from an inspection dated a”)
`which was followed by
`M0
`
`the proposed
`
`m“) and the firm’s response to
`The facility was re-inspected by FDA on
`deficiencies was found adequate by FDA.The GMP status of this facility was then
`changed to “Compliant”.
`
`Suong T. mmnmmma
`ou=FDAI ou=P¢op|e cn=5ucmg T.Tran -
`
`Tran -S Manama“
`
`Reference ID: 4180227
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SUONG T TRAN
`11/13/2017
`This addendum to the OPQ Integrated Quality Assessment, recommending "APPROVAL",
`replaces the OPQ recommendation dated 8/23/17.
`This addendum is finalized in DARRTS because Panorama closed the project and no additional
`document can be uploaded. A request was sent to CDER Informatics2 weeks ago to re-open the
`project so that this addendum can be uploaded; to date, our request has been ignored.
`
`Reference ID: 4180227
`
`

`

`QUALITY REVIEW
`
`Recommendation:
`
`(including the Facility Review/Overall Manufacturing Inspection Recommendation)
`
`— N
`
`DA 209805
`Review #1
`
`Review Date (see last page)
`
`Dru_ Name/Dosa_e Form ertugliflozin and sitagliptin tablet (fixed ratio combination)
`_
`W" 5/100. 15/100 mg/mg ertugliflozin/sitagliptin
`Route of Administration
`Rx/OTC Dis - ensed
`A1 nlicant
`
`Oral
`
`SUBMISSION S REVIEWED
`0000
`0002
`0003
`0008
`
`0012
`0014
`0015
`
`DOCUMENT DATE
`12/19/16
`1/13/17
`1/23/17
`3/21/17
`4/25/17
`5/8/17
`5/10/17
`6/7/17
`6/23/17
`7/25/17
`7/28/17
`
`0018 0021
`Environmental Assessment
`
`DISCIPLINE
`
`Regulatory Business
`Process Mana er
`1 111ication Technical Lead
`
`Dru Product
`
`Process/Microbiolo 3
`Facili
`Bio 1hannaceutics
`
`0 uali
`REVIEWER
`
`' Review Team
`
`Anika Lahnansingh
`
`Suon Su Tran
`Erika En- mid/Donna Christner
`Ravi Kasliwal/Danae Christodoulou
`
`Huai Chan Chen i'iu Hu
`Krishnakali Ghosh/Juandn'a Williams
`Pen- Duan/Haritha Mandula
`James Laurenson/Michael Fumess
`
`DIVISION/OFFICE
`
`Regulatory Business Process
`Mana - ement I/OPRO
`New Dru- Products II/ONDP
`New Dru- API/ONDP
`New Dru- Products II/ONDP
`Process Assessment lI/OPF
`Ins 1 -
`tional Assessment/OFF
`Bio 1 harmaceutics/ONDP
`
`Quality Review Data Sheet
`1. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs: Adequate (see Chapter II)
`B. Other Documents: NDA 21995 JANUVIA (sitagliptin) tablets, NDA 209805
`(eflugliflozin/sitagliptin), and NDA 209806 (ertugliflozin/metfonnin HCl) by
`the same applicant
`2. CONSULTS: n/a
`
`

`

`QUALITY REVIEW
`
`Executive Summary
`
`Recommendation and Conclusion on Approvability
`1.
`The current OPQ recommendation is for Com lete Res onse, includin the overall
`
`manufacm inspection recommendationfi
`_ M"
`
`Summary of Complete Response issues:
`
`(m4)
`
`is the proposed manufacturer of sitagliptin phosphate monohydrate.
`.
`.
`.
`.
`.
`.
`4
`Major defic1enc1es were observed during the recent inspection conducted from (m ’
`(ma)
`
`mm The applicant
`0 This facilifl will be re-inspected by FDA in
`stated that the facility would be removed from the NDA upon failure of the re-
`inspection (no plan to remove the facility from the NDA until then).
`
`0
`
`If this facility is removed from the NDA, the OPQ recommendation for the
`application would be changed because there is no other pending issue identified in
`our review. The NDA includes another manufacturer of sitagliptin phosphate
`monohydrate with an acceptable GMP profile.
`
`Action letter lan ua e:
`
`— «:on
`
`H.
`
`Summary of Quality Assessment
`
`A. Product Overview
`
`This is a 505(b)(l) NDA for ertugliflozin, a New Molecular Entity.
`Ertugliflozin is processed with the conformer L-pyroglutamic acid (LPGA) to yield
`the ertugliflozin-LPGA co-crystal. As per FDA’s guidance “Regulatory Classification
`of Pharmaceutical Co-Crystals”, the ertugliflozin—LPGA co-crystal
`(m4)
`Therefore, the active ingredient/drug
`substance of the product is “ertugliflozin”, to be reflected in the labeled established
`name and corresponding dosage strength.
`Reference is made to the approved NDA 21995 JANUVIA (sitagliptin) tablets, same
`applicant, for CMC information on the drug substance sitagliptin phosphate, a small
`synthetic molecule.
`
`The drug product is an immediate release oral tablet, in fixed ratio combinations with
`four strengths:
`(m4) 5/ 100, 15/ 100 mg/mg eflugliflozin/sitagliptin.
`
`

`

`QUALITY REVIEW
`
`Bioequivalence studies were conducted to compare all four combination strengths to
`the concomitant administration of ertugliflozin tablets and JANUVIA tablets. The
`biobatches had the commercial formulation with the exception of colors and
`debossing and were manufactured at the R&D site
`M“)
`The biowaiver request for the product manufactured at the commercial site
`mm is granted based on comparative dissolution
`
`profiles.
`
`Alternative Methods of Administration
`
`not finalized b GRMP -oal; see CDTL’s memo
`not finalized b GRMP oal: see CDTL’s memo
`not finalized b GRMP -oal; see CDTL’s memo
`
`Pro I osed Indication s
`
`Maximum Dail Dose
`
`A. Quality Assessment Overview
`
`Drug Substance: Ertugliflozin
`
`Enugliflozm: (15.25.354RS 33—5-(4-drloro-3—(441hoxybenzylphcnyly l-(hydroxymetlryl)-
`6.8-dioxabrcyclo[3 2.1]oaanc-2.3.+uiol
`
`Emgliflozm L-PGA: (15.25.38.411 SS—S-(4—chloro-3-(4—ethoxyberrzylphenyl)—l -
`(h)droxynrthyl)63-diombrcyclo[3 V2. 1]octane—2.3.4-urol compmnd mm (ZS-5-
`oxopyrrolrdrnc—l-carboxylrc and
`
`Figure 2.3.5.1—1.
`
`Enugliflozin and Ermgliflozin L—PGA Structures
`
`
`
`Enuallflozin
`
`Eflugllflozln L-PGA
`
`Molecular formula
`
`Enugliflozrrr C3H15C10«
`
`Enugliflozin L-PGA: CanClNOIo
`
`Molecular Weight
`
`megxmom 436.88 Drltons
`
`Enuglrflozr'n L-PGA. 566.00 Daltons
`
`Ertugliflozin is an unstable amorphous material that was developed as a 1:1 co-
`crystal with L—pyroglutamic acid (LPGA) in order to achieve better physical and
`chemical properties including stability. As per FDA’s guidance “Regulatory
`Classification of Pharmaceutical Co-Crystals”, the ertugliflozin—LPGA co-crystal
`(m4) and the active
`
`ingredient of the product is “ertugliflozin”. Adequate CMC information is
`provided in the NDA on ertugliflozin, LPGA, and the co-crystal.
`
`Ertugliflozin—LPGA is BCS l, non-hygroscopic, and crystalline
`
`M“)
`
`

`

`QUALITY REVIEW
`
`
`
`The drug substance specification includes standard quality attributes of a small
`synthetic molecule including chirality and LPGA content. Batch analysis data
`include batches fiom the commercial site “Pfizer Ireland Pharmaceuticals,
`Ringaskiddy, Irelan ” and the R&D site “Pfizer Sandwich, UK”.
`
`Particle size — This attribute is not critical to dissolution because the drug
`substance is BCS l
`i.e., hi
`soluble . Therefore, acc
`tance criteria are
`established
`
`tttttttt-W .. tt
`
`ts are considered qualified
`err
`;
`es 0
`1 cation
`exceed the ICH q
`by the Pharmacology Toxicology team. All specified impurities, including
`these three, were evaluated for mutagenicity and none was found positive
`(confirmed by the Pharmacology Toxicology team).
`
`P01
`
`0 hism — Ertu 'flozin-LPGA has the
`
`ertugliflozin has different h ico—chemical
`controlled b test methods
`
`r0 erties and can be readil
`
`Free
`
`g su stance specr cation is acceptable.
`
`Therefore, the lack of
`
`is acce table for Ertu iflozin—
`
`
`The retest period is based on stability data for
`batches, manufactured at “Pfizer Sandwich,
`UK” and the commercial site “Pfizer Ireland Pharmaceuticals, Ringaskiddy,
`Ireland”.
`
`

`

`QUALITY REVIEW
`
`Drug Substance: Sitagliptin
`Reference is made to the approved NDA 21995 JANUVIA (Sitagliptin) tablets,
`same applicant, for CMC information on the drug substance Sitagliptin phosphate,
`a small synthetic molecule.
`F
`F
`
`H‘ NH20
`
`' ”20
`
`g>fl ' H3P°4
`i.
`Sitagliptin phosphate monohydrate is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-
`trifluorophenyl)butyl]-5 ,6,7,8-tetrahydro-3-(trifluoromethyl)-1 ,2,4-t1iazolo[4,3-
`a]pyrazine phosphate (1:1) monohydrate.
`C16H15F5N50°H3P04'H20 molecular weight 523.32
`
`Drug Product
`The drug product is an immediate release oral tablet, in fixed ratio combinations
`with four strengths:
`“(4) 5/ 100, 15/100 mg/mg ertugliflozin/sitagliptin.
`The 5 mg or 15 mg ertugliflozin corresponds to 6.477 mg or 19.431 mg
`ertugliflozin—LPGA, respectively.
`
`Excipients: microcrystalline cellulose, dibasic calcium phosphate anhydrous,
`croscarmellose sodium, sodium stearyl fumarate, and magnesium stearate. The
`inert film coating contains hypromellose, hydroxypropyl cellulose, titanium
`dioxide, iron oxide red, ferrosoferric oxide/black iron oxide, and carnauba wax.
`
`There is no novel excipient, and there is no human/animal—derived excipient.
`
`(I!) (4)
`
`The regulatory drug product specification is adequate based on the supporting
`release and stability data and ICH guidelines for this type of dosage form,
`including information on elemental impurities.
`
`Degradants - No Sitagliptin degradant was observed
`The two specified ertugliflozin-related degradants
`
`a” (4)
`(5)“) have limits
`(ll) (4) Both
`
`were evaluated for mutagenicity and found negative (confirmed by the Phamlacology
`Toxicology team).
`M (4) are degradants resulting from the
`interaction between ertugliflozin and the
`m“) excipient in the
`formulation,
`m“) Both were
`found negative for mutagenicity (confirmed by the Pharmacology Toxicology team).
`
`Disintegration — The use of disintegration in lieu of dissolutionis acceptable based on
`ertugliflozin-LPGA and Sitagliptin phosphate monohydrate being both highly soluble, and
`disintegration was shown to be more discriminating than dissolution to changes in tablet
`hardness and tensile strength.
`
`Polymorphism is not part of the specification.
`
`M (4)
`
`

`

`l .A'n
`
`QUALITY REVIEW polymorph testing is not necessary.
`
`#
`
`Primary container closure system: The drug product is packaged i1-
`bottles/closures and aluminum blisters.
`
`Expiration Date & Storage Conditions: The shelf life of the drug product is 24
`months at room temperature.
`The long-term expiry is based on 12-month long-term (25 C/60% RH) and 6-month accelerated
`(40 C/75% RH) data are provided in the NDA for three primary stability batches of each of the
`5/100 and
`the 15/100
`strengths. Stability
`
`batches were manufactured at the R&D site
`, with ertugliflozin
`LPGA from the R&D site Pfizer Sandwich in
`Sita ptin phosphate
`
`e UK an W]
`
`monohydrate fiomE and were packaged in the commercial container closure
`
`es1gn to racket the 30-count and 90-cmmt bottles.
`
`systems, utilizing a
`
`Environmental assessment (EA): Eitugliflozin-LPGA is categorically excluded
`from an an EA. The NDA includes an BA for sitagliptin phosphate monohydrate.
`Based on all available information in the application and literature, a finding of no
`significant impact is granted and an environmental impact statement will not be
`required for this active ingredient.
`
`Special Product Quality Labeling Recommendation: not applicable
`Life Cycle Knowledge Information/ Final Risk Assessment:
`API
`none
`
`Drug product
`Process
`
`page 45 of Chapter 11
`none
`
`Facilities
`Biopharmaceutics
`
`page 6 of Chapter VI
`none
`
`
`
`

`

`QUALITY ASSESSMENT
`
`LABELING
`
`NDA 209805
`
`R
`
`1.14
`
`Regional Information
`
`Labeling
`
`

`

`QUALITY ASSESSMENT
`
`(b) (4)
`
`Reviewer’s Assessment:
`
`The labels contain all the necessary information and are accurate from a CMC perspective and
`
`are consistent with other fixed close combination drug product labels. However, since the
`
`product is moisture sensitive, I recommend that the following statement be placed on the 500
`
`tablet bottle immediate container labels (for all strengths) from which a pharmacy dispenses
`
`individual patient dose.
`
`”Dispense into a USP tightly closed, moisture-resistant container”.
`
`Also, the storage statement for the bottles should be revised from, ”Protect from moisture.
`
`Store in a dry place” to ”Store in tightly sealed container in a dry place” as a user may not be
`
`able to know what does protect from moisture means.
`
`In the final labeling the word TrademarkTM will be replace with the actual trademark of the drug
`
`product and the ”FPO” will be replaced by the image of actual tablet with embossed side up. An
`
`example is provided and reproduced below.
`
`(b) (4)
`
`CARTON LABELING
`
`52
`
`4 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCl/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
`
`
`
`

`

`QUALITY ASSESSM ENT
`
`except that the storage statement in the carton for 7 tablet HDPE sample bottles should
`
`be revised from, ”Protect from moisture. Store in a dry place" to ”Store in tightly sealed
`
`container in a dry place” as a user may not be able to know what does protect from moisture
`means.
`
`0 Package Insert:
`DOSAGE FORMS AND STRENGTHS
`
`(b) (4)
`
`o TRADEMARKTM 5 mg/100 mg tablets are beige, almond-shaped, film—coated tablets debossed
`with “554" on one side and plain on the other side.
`0 TRADEMARKTM 15 mg/100 mg tablets are brown, almond-shaped, film-coated tablets debossed
`with “555" on one side and plain on the other side.
`
`Reviewer's Assessment:
`
`The dosage form and strength description is acceptable from a CMC point of view.
`
`11
`
`DESCRIPTION
`
`TRADEMARK contains ertugliflozin L-pyroglutamic acid, a SGLT2 inhibitor, and sitagliptin
`phosphate, a DPP-4 inhibitor.
`
`Ertugliflozin
`The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2$,3S,4R,5S)—5-(4-chloro—3-(4—
`ethoxybenzy|)phenyl)—1-(hydroxymethyl)—6,8-dioxabicyclo[3.2.1]octane-2,3,4—triol, compound with (28)—5-
`oxopyrrolidine-Z—carboxylic acid. The molecular formula is C27H32CINO10 and the molecular weight is
`566.00.
`
`The chemical structure is:
`
` H
`
`H02
`
`Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and
`acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.
`
`Sitagliptin
`Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-
`trifluorophenyl)buty|]-5,6,7,8-tetrahydro-3-(trifluoromefl1yl)-1 ,2,4-triazolo[4,3-a]pyrazine phosphate (1 :1 )
`monohydrate.
`The empirical formula is C16H15F5N5O-H3PO4-H20 and the molecular weight
`structural formula is:
`
`is 523.32. The
`
`58
`
`

`

`""‘""
`m
`
`QUALITY ASSESSMENT
`
`"""n
`mam—hummin-
`
`V
`
`F
`
`F
`
`F
`
`H‘ NH2 0
`
`N
`K/
`
`/N\
`N
`N\<
`OF:
`
`' ”SP0.
`
`”:0
`
`Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is
`soluble in water and N, N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in
`ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
`
`TRADEMARK is available for oral use as film-coated tablets containing:
`
`0
`
`0
`
`6.48 mg ertugliflozin L-pyroglutamic acid equivalent to 5 mg of ertugliflozin and 128.5 mg sitagliptin
`phosphate monohydrate equivalent to 100 mg sitagliptin (TRADEMARK 5/100)
`
`19.43 mg ertugliflozin L-pyroglutamic acid equivalent to 15 mg of ertugliflozin and 128.5 mg sitagliptin
`phosphate monohydrate equivalent to 100 mg sitagliptin (TRADEMARK 15/100)
`
`ingredients are microcrystalline cellulose, dibasic calcium phosphate anhydrous,
`Inactive
`croscannellose sodium, sodium stearyl fumarate, and magnesium stearate.
`The film coating contains: hypromellose, hydroxypropyl cellulose, titanium dioxide, iron oxide red,
`ferrous or ferric oxide/black iron oxide and camauba wax.
`
`
`
`
`
`16
`
`HOW SUPPLIEDISTORAGE AND HANDLING
`
`TRADEMARK (ertugliflozin and sitagliptin) tablets are available in the strengths listed below:
`
`
`
`59
`
`

`

`QUALITY ASSESSM ENT
`
`(D) (4)
`
`TRADEMARK tablets, 5 mg/100 mg, are beige, almond-shaped, film-coated tablets debossed with
`“554” on one side and plain on the other side. They are supplied as follows:
`(m4)
`
`NDC 0006—5367—03 unit-of-use bottles of 30
`NBC 0006—5367—06 unit-of—use bottles of 90
`NBC 0006-5367-07 bulk bottles of 500
`
`TRADEMARK tablets, 15 mg/100 mg, are brown, almond-shaped, film-coated tablets debossed
`with “555” on one side and plain on the other side. They are supplied as follows:
`(m4)
`
`NDC 0006-5368-03 unit-of-use bottles of 30
`NBC 0006—5368—06 unit-of-use bottles of 90
`NBC 0006—5368—07 bulk bottles of 500
`
`Storage of Bottles
`Store at 20—25°C (BB-77°F), excursions permitted between 15-30°C (between 59—86°F). Protect from
`moisture. Store in a dry place.
`
`(hm)
`
`Reviewer’5 Assessment:
`
`The ”How Supplied” and ”Storage” statements are accurate from a CMC perspective and are
`
`acceptable. However, as indicated previously the storage statement for the bottles should be
`
`revised from, ”Protect from moisture. Store in a dry place” to ”Store in tightly sealed container
`
`in a dry place” as a user may not be able to know what does protect from moisture means.
`
`List of Deficiencies:
`
`1. Place statement ”Dispense into a USP tightly closed moisture—resistant container”, on the
`
`500 tablet bottles immediate container labels (for all strengths).
`
`2. Revise the storage statement for the bottles (immediate container labels, sample carton
`
`labels and package insert) from, ”Protect from moisture. Store in a dry place" to "Store in
`
`tightly sealed container in a dry place" as a user may not be able to know what does
`
`protect from moisture means.
`
`60
`
`

`

`QUALITY ASSESSMENT
`
`Primary Labeling Reviewer Name and Date:
`
`Ravindra K. Kasliwal, Ph.D.
`CMC Reviewer
`
`Branch VI, DNDP—ll
`
`ONDP / OPQ
`
`August 21, 2017
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed):
`
`I concur with primary reviewer’s recommendations.
`
`Suong T. Tran, Ph.D.
`Team Lead
`
`Branch VI, DNDP-ll
`
`ONDP/ OPQ
`
`61
`
`

`

`Su (Suong)
`Tran
`
`Ravindra
`Kasliwal
`
`Digitally signed by Su (Suong) Tran
`Date: 8/23/2017 11:13:27AM
`GUID: 508da71f00029ec8b75e233f12b15339
`
`Digitally signed by Ravindra Kasliwal
`Date: 8/23/2017 12:41:58PM
`GUID: 508da7220002a0e4e2c176d5eddcbe42
`
`

`

` QUALITY REVIEW
`
`CHAPTER III: Environmental Analysis
`
`

`

`QUALITY ASSESSMENT
`
`ENVIRONNIENTAL ANALYSIS
`
`R
`
`Regional Information
`
`Summary: The applicant provided an environmental assessment (EA) for SIT and a claim for a
`
`categorical exclusion for ERT. For the BA for SIT, FDA concludes that (l) the EA contains
`
`sufficient information to enable FDA to determine whether the proposed action may significantly
`
`affect the quality of the human environment and (2) the proposed action does not appear to
`
`significantly affect the environment. A finding of no significant impact (FONSI) is
`
`recommended for SIT. For the categorical exclusion claim for ERT, the applicant cited the
`
`appropriate exclusion and provided the required statement of no extraordinary circumstances.
`
`FDA requested additional infonnation to confirm the lack of extraordinary circmnstances. The
`
`claim and supporting information were reviewed and the claim found to be acceptable.
`
`Environmental Analysis
`
`The applicant filed an NDA for the use of ertugliflozin CERT) administered as a fixed-dose
`
`combination with sitagliptin (SIT) for the treatment of type 2 diabetes mellitus (T2DM).
`ERT/SIT is formulated as an immediate-release tablet for oral administration in four dose
`
`strengths (i.e., 5 mg or 15 mg ERT, each in combination with
`
`(m4) 100 mg SIT).
`
`SIT EA
`
`The applicant submitted an EA, dated March 16, 2016, for SIT, pursuant to 21 CFR 25, noting
`
`that the EA was compiled in accordance with Guidance for Industry: Environmental
`
`Assessments of Human Drug and Biologics Application (USFDA, 1998). Briefly, this EA noted
`
`the following:
`
`1. Fate/Depletion. The physical/chemical characteristics of SIT suggest that sitagliptin has a
`
`low probability for bioaccumulation in the environment. In the human absorption-
`
`distribution—metabolism-excretion (ADME) study, SIT was confnmed to be primarily
`
`renally eliminated, indicating significant uptake. Approximately 85% was accounted for
`
`by the parent drug substance. SIT is not susceptible to hydrolysis, does not photolyze,
`
`and shows very little primary degradation in the aerobic and anaerobic sediment-water
`
`systems. Therefore, when calculating the expected introductory concentration (BIC),
`removal due to wastewater treatment was not taken into account.
`
`iii rig/L.
`2. Exposure. The EIC of SIT, assuming no degradation or adsorption, is
`Metabolism in the body results in an EIC value of (”mug/L. In the aquatic environment,
`
`assuming no dilution or degradation, SIT has a maximum expected environmental
`concentrations (MEEC) of ((2; ug/L. The PEC for sediment was not provided. No air
`
`exposure is expected.
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 1 of 3
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`3. Toxicity Chronic toxicity data in the aquatic environment were provided for three
`
`species. The most sensitive aquatic organism was P. subcapitata (green algae) with a 72-
`
`hour lowest no—observed—effect concentration (NOEC) of 840 ug/L. For sediment, two
`
`species were assessed, and Lumbriculus variegatus (blackwonn) resulted in the lowest
`NOEC,
`{'3 mg/kg, based on survival.
`
`(we) of magnitude greater
`4. E. This aquatic toxicity NOEC of 840 ug/L more than
`than the EIC of {'3 ug/L, thus indicating negligible risk, especially given the conservative
`
`assmnptions regarding the EIC. The sediment risk could not be calculated because only
`
`toxicity data were available.
`
`The applicant concluded that no environmental issues were anticipated related to patient use of
`
`this product.
`
`ERT Categorical Exclusion
`
`The applicant submitted a claim for a categorical exclusion from an EA for ERT in accordance
`with 21 CFR Part 25.3 1(b), noting that the EIC will be below 1 ppb, and in particular
`(m4) ppb.
`
`The applicant stated that to the best of their knowledge, no extraordinary circumstances exist.
`
`Reviewer’s Assessment:
`
`SIT EA
`
`The main goals of this review of the SIT EA, per 21 CFR 25.15(a) and (b), are to determine (1)
`whether the EA contains suflicient information to enable the Agency to determine whether the
`proposed action may significantly affect the quality of the human environment and (2) if so,
`whether the proposed action will significantly affect the environment.
`
`The EA was found to be missing expected sediment concentration data with which to compare
`with the toxicity data and thus characterize the risk for sediments. Therefore, FDA requested that
`the applicant provide maximum and/or expected SIT concentrations in sediments to allow fl1is
`comparison. In response, the applicant used the EIC value of m“) ug/L to model a corresponding
`PEC sediment value of mmmg/kg. This value is
`m4) lower than the designated
`NOEC of {'4'} mg/kg, thus indicating negligible risk from SIT in sediments from this application.
`FDA examined the supporting calculations and agreed with the conclusion.
`
`The remainder of the BA for SIT contains sufficient information to enable a determination of
`
`whether the proposed action may significantly affect the quality of the human environment. The
`data appeared to be accurate and objective. This assessment should be considered worst-case.
`Specifically, the calculation of the EIC does not take into consideration of (l) degradation during
`wastewater treatment or (2) dilution, degradation, or removal in surface water. FDA expects that
`a PEC would be more than an order of magnitude below the EIC. Therefore, FDA agrees that
`SIT poses no significant environmental risk via this application.
`
`OPQ—XOPQ—TEM-0001v03
`
`Page 2 of 3
`
`Effective Date: 18 Feb 2016
`
`

`

`QUALITY ASSESSM ENT
`
`ERT Categorical Exclusion
`
`Given the status of ERT as a new molecular entity, FDA conducted a literature search and also
`used a fish plasma model (FPM) based on Huggett et a1. (2003) to screen for aquatic
`environmental risk. No additional literature was found, but the FPM showed that based on an
`EIC of M“) ug/L, a therapeutic concentration of
`(”’mug/mL (Cmax from p. 9 of module 2.6.6,
`Toxicology Written Summary), and a log D of m“) (pH 3;; from www.chemspider.com), the
`effect ratio (ER)
`(m4), thus indicating the need for additional information. Therefore, to assist
`us in confirming that extraordinary circumstances do not exist for ERT, FDA ask the applicant to
`provide any readily available literature, data, and/or analysis for estimating or providing (1) a
`more realistic expected environmental concentration, (2) more relevant toxicity data (including
`from similar molecules), and/or (3) any other indicators ofpossible environmental risk.
`
`The applicant responded by providing a Phase II, Tier A environmental fate and effects
`assessment of ERT, conducted as per the EMEA/CHMP/SWP/4447/00 entitled “Guideline on
`the Environmental Risk Assessment of Medicinal Products for Human Use” (June 1, 2006). This
`Environmental Risk Assessment (ERA) is based on a calculated PEC for surface water of M“)
`rig/L, which is higher than the US EIC of
`(mu) ug/L, and still higher if dilution in surface water
`was accounted for as in the ERA PEC derivation. The PEC/PNEC risk quotients derived for
`surface water, ground water, micro—organisms, and sediment are all below the respective action
`criteria and, therefore, the applicant concludes that ERT will not present an environmental risk
`following patient use. FDA reviewed this ERA and agrees that ERT in this application does not
`present extraordinary circumstances.
`
`References:
`
`Huggett, D. B., J. C. Cook, J. F. Ericson and R. T. Williams (2003). A theoretical model for
`utilizing mammalian pharmacology and safety data to prioritize potential impacts of human
`pharmaceuticals to fish. Human and Ecological Risk Assessment: An International Journal,
`9(7):]789-1799.
`
`Decision:
`
`The BA for SIT is adequate for approval of the NDA. The EA contains sufficient information to
`enable FDA to determine whether the proposed action may significantly affect the quality of the
`human environment. Based on an evaluation of the information provided in the EA and
`additional reports, and on the scientific validity of the conclusions of the EA, no significant
`adverse environmental impacts are expected from the approval of this NDA for SIT. Therefore,
`based on the information available to date, a FONSI is recommended for this portion of the
`application. For the categorical exclusion claim for ERT, the applicant cited the appropriate
`exclusion and provided the required statement of no extraordinary circumstances. FDA requested
`additional information to confirm the lack of extraordinary circumstances. The claim and
`supporting information were reviewed and the claim found to be acceptable.
`
`Primary EA Reviewer Name and Date: James P. Laurenson, June 14, 2017
`
`Secondary Reviewer Name and Date (and Secondary Summary, as needed): M. Scott Furness,
`
`June 16, 2017
`
`0PQ-XOPQ—TEM-0001v03
`
`Page 3 of 3
`
`Effective Date: 18 Feb 2016
`
`

`

`James
`Laurenson
`
`Michael
`Furness
`
`Digitally signed by James Laurenson
`Date: 6/14/2017 04:06:56PM
`GUID: 51dc6bdb0000c62de59b85452e59746f
`
`Digitally signed by Michael Furness
`Date: 6/14/2017 04:27:08PM
`GUID: 502e8c7600003dd8331cf6eebf43697a
`
`

`

`Finding of No Significant Impact
`
`NDA 209805 Ertugliflozin/Sitagliptin (ERT/SIT)
`Tablet,
` 5/100 mg, and 15/100 mg
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`The National Environmental Policy Act of 1969 (NEPA) requires Federal agencies to assess the
`environmental impact of their actions. The Food and Drug Administration (FDA) is required
`under NEPA to consider the environmental impact of approving certain drug product
`applications as an integral part of its regulatory process.
`
`Merck & Co., Inc. (Merck) requests approval of NDA 209805 for the treatment of type 2
`diabetes mellitus. The product is a tablet with ertugliflozin/sitagliptin in the following
`combinations doses:
` 5/100 mg, and 15/100 mg. Ertugliflozin is an oral,
`selective inhibitor of sodium glucose cotransporter-2 (SGLT2) and has been categorically
`excluded from an environmental assessment (EA). Sitagliptin is an orally-active inhibitor of the
`dipeptidyl peptidase-4 (DPP-4) enzyme and is the subject of this finding.
`
`In support of its application, Merck prepared an EA, including an amendment, for sitagliptin
`(attached). This EA evaluates the potential environmental impact from the use and disposal of
`this product. The FDA Center for Drug Evaluation and Research (CDER) has reviewed the EA
`and has carefully considered the potential environmental impact due to approval of this
`application. CDER conducted a literature search that did not result in any conflicting
`information. Based on the CDER review of the entirety of this information, FDA has determined
`that approval of the present application for sitagliptin is not expected to have a significant impact
`on the human environment. Therefore, FDA is issuing a finding of no significant impact
`(FONSI), and thus an environmental impact statement will not be prepared.
`
`Attachments: March 24, 2016, Environmental Assessment; and June 5, 2017, Amendment
`
`(b) (4)
`
`(b) (4)
`
`

`

`ERTUGLIFLOZIN/SITAGLIPTIN FDC
`MODULE 1.12.14 ENVIRONMENTAL ASSESSMENT
`
`PAGE 1
`
`1. Date:
` 
`
`24 March 2016
`
`2. Name of Applicant/Petitioner:
`
`Merck & Co., Inc.
`
`3. Address:
`
`Sumneytown Pike
`West Point, PA 19486
`
`4. Description of Proposed Action:
`a. Requested Approval
`Merck & Co., Inc., is filing a New Drug Application pursuant to section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for ertugliflozin/sitagliptin (MK 8835A)
` 5/100mg and 15/100mg) packaged in high density polyethylene
`(HDPE) bottles with desiccant and closures with heat induction seal liner, and in
`aluminum foil blister and lidding. An EA has been submitted pursuant to 21 CFR
`part 25.
`
`b. Need for Action
`Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme
`developed by Merck & Co., Inc. for the treatment of type 2 diabetes mellitus.
`Sitagliptin is present in MK-0431 tablets in the form of sitagliptin phosphate
`monohydrate (sitagliptin phosphate, MK-0431).
`
`c. Locations of Use
`The product will be used in hospitals, clinics, and/or in homes throughout the United
`States.
`
`d. Disposal Sites
`At U.S. hospitals, pharmacies, or clinics, empty or partially empty packages will be
`disposed of according to hospital, pharmacy, or clinic procedures. In the home,
`empty or partially empty containers will typically be disposed of by a community's
`solid waste management system, which may include landfills, incineration, drug take-
`
`04FCK3
`
` 
`
`(b) (4)
`
`

`

`ERTUGLIFLOZIN/SITAGLIPTIN FDC
`MODULE 1.12.14 ENVIRONMENTAL ASSESSMENT
`
`PAGE 2
`
` 
`
`back programs and recycling, although minimal quantities of unused drug could be
`disposed of in the sewer system.
`
`5. Identification of Substances that are Subject of the Proposed Action:
`a. Nomenclature
`i. Established Name (U.S. Adopted Name – USAN): Sitagliptin (as sitagliptin
`phosphate)
`ii. Brand/Proprietary Name/Trade Name: JANUVIA
`iii. Chemical Names:
` Chemical Abstracts (CA) Index Name (inverted form): 7-[(3R)-3-amino-
`1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-
`1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate
`b. Chemical Abstracts Service (CAS) Registration Number: 65467-77-9
`c. Molecular Weight: 523.32
`d. Molecular Formula: C16H15F6N5O . H3 PO4 . H2O
`e. Structural (graphic) Formula:
`
`6. Environmental Issues:
`Summary. The pharmacologic agent, sitagliptin, is used to treat Type 2 diabetes mellitus.
`Sitagliptin is also marketed singly or with metformin under the trademarks JANUVIA
`and JANUMET. The Expected Introduction Concentration (EIC) for sitagliptin
`phosphate for all products, based on the latest production estimates for 2020
`(Confidential/Appendix B)
`
`
` an Environmental Assessment (EA) was
`conducted as described by the Guidance for Industry. Based on the predicted EIC and the
`
`04FCK3
`
` 
`
`(b) (4)
`
`

`

`ERTUGLIFLOZIN/SITAGLIPTIN FDC
`MODULE 1.12.14 ENVIRONMENTAL ASSESSMENT
`
`PAGE 3
`
` 
`
`low aquatic toxicity of sitagliptin, no environmental issues are anticipated related to
`patient use of this product.
`
`Physical/Chemical Characteristics. A summary of physical/chemical data is given in
`Appendix A. The aqueous solubility of sitagliptin is 69.5 mg/