CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202343Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`A'
`
`Man:
`
`Org. .ode:
`
`Priority:
`
`Stamp Date:
`
`PDUFA Date:
`
`Action Goal:
`
`NDA 202343/000
`
`510
`
`4
`
`07-DEC-2010
`
`O7-OCT-2011
`
`District Goal:
`
`08-AUG-2011
`
`FDA CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Sponsor:
`
`MERCK SHARP DOHME
`
`UGZCD 48
`
`NORTH WALES. PA 194541099
`(5) (4)
`
`(silagliptin/simvastatin) Tablet
`
`Brand Name:
`
`Estab. Name:
`
`Generic Name:
`
`Product Number; Dosage Form; Ingredient; Strengths
`001; TABLET; SITAGLIPTIN PHOSPHATE; 100MG
`001; TABLET: SIMVASTATIN; 10MG
`002; TABLET; SITAGLIPTIN PHOSPHATE; 100MG
`002; TABLET: SIMVASTATIN; 20MG
`003; TABLET: SITAGLIPTIN PHOSPHATE; 100MG
`003; TABLET; SIMVASTATIN; 4OMG
`
`FDA Contacts:
`
`K. SHARMA
`
`Project Manager
`
`8. TRAN
`Team Leader
`301 -796-1 764
`
`
`Overall Recommendation:
`ACCEPTABLE
`'
`on 04~OCT-2011
`by D. SMITH
`‘
`()
`
`
`EstabIIshment:
`
`CFN:
`
`(b) (4)
`
`FEI:
`
`may
`(5)“)
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE PACKAGER
`
`DRUG SUBSTANCE RELEASE TESTER
`
`DRUG SUBSTANCE STABILITY TESTER
`
`Profile:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`OAI Status:
`
`NONE
`
`Last Muestone;
`
`Mllestone Date:
`
`Decision:
`
`0C RECOMMENDATION
`
`27-DEG2010
`
`ACCEPTABLE
`
`Reason:
`BASED ON PROFILE
`
`
`October 4, 2011 3:02 PM
`
`FDA Confidential - Internal Distribution Only
`
`Page 1 of 3
`
`Reference ID: 3028282
`
`

`

`FDA CDER EES
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`FEI:
`
`
`
`1036761
`
`1036761
`CFN:
`
`MERCK AND CO INC
`
`
`
`4633 MERCK RD W
`
`
`
`WILSON, NC 278939613
`
`
`
`DRUG SUBSTANCE STABILITY TESTER
`
`
`
`FINISHED DOSAGE PACKAGER
`
`
`FINISHED DOSAGE STABILITY TESTER
`
`
`
`
`CONTROL TESTING LABORATORY
`
`
`
`- OC RECOMMENDATION
`
`
`27-DEC-2010
`
`
`
`ACCEPTABLE
`
`BASED ON PROFILE
`
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`OC RECOMMENDATION
`
`
`03-JAN-2011
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`AADA:
`
`
`OAI Status:
`
`NONE
`
`
`OAI Status:
`
`NONE
`
`
`MERCK SHARP & DOHME LTD.
`
`
`
`
`
`
`
`CLONMEL, CO. TIPPERARY, , IRELAND
`
`
`
`
`DRUG SUBSTANCE MANUFACTURER
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`FINISHED DOSAGE RELEASE TESTER
`
`
`
`
`,
`
`AADA:
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`
`
`
`
`
`OAI Status:
`
`NONE
`
`OC RECOMMENDATION
`
`
`30-DEC-2010
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`OC RECOMMENDATION
`
`
`O4-OCT-2011
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`
`
`OAI Status:
`
`NONE
`
`Establishment:
`
`DMF No:
`
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`
`Milestone Date:
`
`
`Decision:
`
`Reason:
`
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`
`Decision:
`
`Reason:
`
`DMF No:
`
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`
`Milestone Date:
`
`
`Decision:
`
`Reason:
`
`Profile:
`
`Last Milestone:
`
`
`Milestone Date:
`
`
`Decision:
`
`Reason:
`
`_________________________________________._______—————
`
`October 4, 2011 3:02 PM
`
`
`
`
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`
`
`Page 2 of 3
`
`Reference ID: 3028282
`Reference ID: 3028282
`
`

`

`
`
`FDA CDER EES
`
`
`ESTABLISHMENT EVALUATION REQUEST
`
`SUMMARY REPORT
`
`EP“‘\Iishment:
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone:
`
`Milestone Date:
`
`Decision:
`
`FEI:
`>
`2623436
`CFN:
`
`
`MERCK SHARP AND DOHME QUIMICA
`
`
`
`
`RD 2, KM 56.7
`
`
`
`BARCELONETA, PR 00617
`
`
`
`2623436
`
`DRUG SUBSTANCE MANUFACTURER
`
`
`DRUG SUBSTANCE PACKAGER
`
`
`DRUG SUBSTANCE RELEASE TESTER
`
`
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`
`
`
`
`OC RECOMMENDATION
`
`
`27-DEC-2010
`
`
`
`ACCEPTABLE
`
`AADA:
`
`OAI Status:
`
`
`NONE
`
`Reason:
`
`BASED ON PROFILE
`
`
`
`Establishment:
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`L’
`
`
`
`“lilestone:
`
`M.
`
`.one Date:
`
`
`Decision:
`
`I
`
`FEI:
`
`CFN:
`MERCK SHARP DOHME
`
`
`SHOTI'EN LANE
`
`CRAMLINGTON, , UNITED KINGDOM
`
`
`
`3002807653
`
`
`
`FINISHED DOSAGE MANUFACTURER
`
`
`TABLETS, PROMPT RELEASE
`
`
`
`OC RECOMMENDATION
`
`
`30-DEC-2010
`
`ACCEPTABLE
`
`AADA:
`
`OAI Status:
`
`
`NONE
`
`Reason:
`DISTRICT RECOMMENDATION
`
`
`Establishment:
`CFN:
`FEI:
`3003431146
`
`
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`Last Milestone;
`
`Milestone Date:
`
`Decision:
`
`MERCK SHARP& DOHME (SINGAPORE), LTD.
`
`
`
`
`21 TUAS SOUTH AVENUE 6
`
`
`
`
`SINGAPORE, , SINGAPORE
`
`
`AADA:
`
`DRUG SUBSTANCE MANUFACTURER
`
`
`NON-STERILE API BY CHEMICAL SYNTHESIS
`
`
`
`
`
`OAI Status:
`
`
`NONE
`
`oc RECOMMENDATION
`
`27-DEC-201O
`
`.
`
`ACCEPTABLE
`
`Reason:
`BASED ON PROFILE
`
`
`
`October 4, 2011 3:02 PM
`
`
`
`
`‘
`
`FDA Confidential - Internal Distribution Only
`
`
`
`
`
`Page 3 of 3
`
`
`Reference ID: 3028282
`Reference ID: 3028282
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NIKOO N MANOCHEHRI-KALANTARI
`10/13/2011
`
`Reference ID: 3028282
`
`

`

`
`
`NDA #202-343
`
`(I!) (4)
`
`(sitagliptin phosphate (+) simvastatin) tablet: immediate
`release, 100/10, 100/20, 100/40 mg/mg
`
`Merck Sharp & Dohme Corp.
`
`Chemistry Review #2
`
`John C. Hill, Ph.D.
`
`ONDQA/DNDQA—III/Branch VII and OND/ODE II/DMEP
`
`. On 22-JUN-2011. DMEPA denied the proprietary name
`name has not been approved.
`
`(5)“). As of the date of this review a new proprietary
`
`Reference ID: 2983191
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`1. Recommendations ...................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 8
`
`II. Summary of Chemistry Assessments......................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used........................................................ 10
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 11
`
`III. Administrative ......................................................................................................................... 11
`
`A. Reviewer’s Signature ...................................................................................................................... 11
`
`B. Endorsement Block ......................................................................................................................... 11
`
`C. CC Block ........................................................................................................................................ 11
`
`Chemistry Assessment ........................................................................................... 12
`
`Reference ID: 29831 91
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA: 202—343
`
`2. REVIEW # 2
`
`3. REVIEW DATE: 02—AUG—201 l
`
`4. REVIEWER: John C. Hill, PhD.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`Original NDA Application
`Response to IR Request: (Manufacturing contact information)
`
`07-DEC-201 0
`l 6—DEC-201 0
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions 5 1 Reviewed
`Response to IR Request: (Manufacturing contact information)
`Response to IR Request: (Mannficnning contact infonnation)
`
`Document Date
`22—JUN—201 1
`01—AUG-201 1
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Merck Sharp & Dohme Corp.
`
`RC. Box 1000. UG2CD-48
`North Wales. PA 19454-1099
`
`Representative;
`
`111°th 1- Swanson Ph.D..
`
`Senior Director. WW Regulatory
`Afiairs
`
`Telephone:
`
`267-305-687 1
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`(51(4)
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`
`Reference ID: 29831 91
`
`Page 3 of 40
`
`

`

`
`
`Chemistry Review Data Sheet
`
`c) Code Name/# (ONDC only): MK-0431D Tablet
`d) Ch... Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`Reference is made to the approved NDA 21995 Januvia (sitagliptin) Tablets (same applicant) for
`all CMC information on the sitagliptin phosphate monohydrate drug substance.
`
`Reference is made to the approved NDA 19766 Zocor (simvastatin) Tablets (same applicant) for
`all CMC information on the simvastatin drug substance.
`
`10. PHARMACOL. CATEGORY: TX of type H diabetes mellitus /
`Hypercholesterolemia-cardiovascular disease
`
`11. DOSAGE FORM:
`
`Fixed dose combination (FDC), bilayer, Immediate
`release tablet
`
`12. STRENGTH/POTENCY: 100/ 10, 100/20, 100/40, mg/mg sitagliptin
`anhydrous free base/ simvastatin)
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM I:
`_SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Sitagliptin phosphate:
`
`Molecular Weight: 523.32
`Chemical Formula: C15H15F5N§0 . H3P04 . H20
`Chemical Name: 7-[(3R)-3-amino-l-oxo-4-(2.4.5-
`trifluorophenyl)butyl]-5.6,7,8-
`tetrahydro-[3 -(t1ifluoromethyl)- l ,2,4-t1iazolo[4,3-a]
`pyrazine phosphate (1:1) mnohydrateT
`
`. H30
`
`- H3PO4
`
`Reference ID: 29831 91
`
`Page 4 of 40
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Laboratory Code: MK-043 1D
`
`Simvastatin
`
`Molecular Weight: 418.57
`Chemical Formula: C25H3805
`Chemical Name: a. [1S-[1(1.3a,7fl,8[3(28*.4S*),8afl]]-1,2.3,7,8,8a-
`Hexahydro-3.7-
`
`dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-
`yl) ethyl]-1-naphthalenyl-2 .2-dimethylbutanoate
`
`b. Butanoic acid. 2,2-dimethyl-.1,2,3,7.8,8a,hexahydro-3.7-
`dimethyl—S—[2{tetrahydro-4-hydroxy—6-oxo—2H-pyran-Z—
`yl)ethyl]-l-naphthalenyl ester,[lS-[ la,3a.7fi,
`8B(ZS*.4S*), 835]]
`
`
`
`c. 2,2—dimethylbutyric acid, 8—ester with (4R.6R)—6-[2-
`[(lS,ZS,6R,8S,8aR)— l,2,6,7,8,8a-hexahydro-8-hydroxy—2,6—
`dimethyl-l-napthyl]elhyl]telrahydro—4—hydroxy—2H-pyran— -
`one
`
`d. (lS,3R,7S,8S.8aR)-8-[2-[(2R,4R)—4-hydroxy-6-oxotetrahydro-
`2H-pyran-2-yl]ethyl]-3,7-dimethyl- l ,2.3 ,7,8,8a-hexahydronaphthalen—
`1-yl 2,2,-dimethylbutanoate
`Laboratory Code: MK-0733
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`TYPE HOLDER
`
`REFEITE CED
`REN
`
`CODEl
`
`STATUS2
`
`REVIEW
`
`COMMENTS
`
`Adequate
`
`APR-20 10
`
`COMPLETED (”m 4
`
`—1-.-
`
`Reference ID: 29831 91
`
`Page 5 of 40
`
`

`

`LOA: 20-
`
`APR-2010
`
`LOA: 01-
`APR—2010
`
`
`
`Adequate*
`
`. 1|.
`... maceordanoewifluwicwpolicyforconhim—clostnsystuns u sol? u. n
`+ Puminfomufimonmufimmhudmdchfldmishmdmmybefiomdml01-104,601-604,901-938,1001—1015,1101-1125,11 51,1201-1202,1211,
`13 01-13129,13 02.13 301.111 15 01(onevolnme, submiuedtoFDAoany9,2003)IMAnmlUpdminfilfl(onevohlne,wbmdmtheFDAouAugxst24,2009)
`@ 11mm“
`00(4) Mainlykfomdoul’lges2 002-2997,301-30L501-505,601-
`602,701,801—809,1001,1111“!01(onevohnne,mbmifledtoFDAon1me30,2004)andAnmalUpdatesubnimdmfl1eFDAouAnglst24,2009
`& Produdinfionnlfimlouwdonplgelo,submimdouhly2&2009
`s
`00(4) Winfmm‘ionfwfllis
`FDAon ”April 1993 :11de 1993, respectively)
`
`(5)“)mybefomdonpngsG—VH—b—lde—H-nn—l,13,&4(whidrwueswmmedbfile
`
`1Action codes for DMF Table:
`l — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`18. STATUS:
`
`0ND 0A:
`
`
`
`Reference ID: 29831 91
`
`Page 6 of 40
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Methods Validation
`
`John C. Hill
`
`20-JUL-2011
`21-JUL-2011
`21-JUL-2011
`21-JUL-2011
`
`Patricia M Brunda - e
`John C. Hill
`John C. Hill
`
`Reference ID: 29831 91
`
`Page 7 of 40
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202-343
`
`The Executive Summaa
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The final CMC recommendation is Approve; however we note that the facility inspection is
`still outstanding and that the CMC recommendation does not incorporate any
`potential facility inspection issues.
`
`Based on the provided real-time stability data, a two and a half (2 1/2) year expiry period is
`granted for the 100/10. 100/20 and 100/40 mg ling
`(5X4) tablets supplied in 30 and 90 count
`bottles. This expiry period can be extended vial the annual report according to the stability
`protocol.
`
`Based on the provided real-time stability data. a one (1) year expiry period is granted for the
`100/10. 100/20 and 100/40 mg /mg m“) tablets supplied in the 1000 count bottle. This expiry
`period can be extended vial the annual report according to the stability protocol.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`H.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substancc(s)
`
`Drug Substance:
`
`Two approved drug substances are used in the manufacturing process:
`
`1 .
`
`Sitagliptin phosphate has been reviewed in support of NDA 21-995 for Januvia. This
`NDA is active and up-to-date.
`
`Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-a1nino-l-oxo-4-
`(2.4.5-t1ifluorophenyl)butyl]-5 .6.7,8-tetrahydro-3-(trifluoromethyl)- 1 ,2,4-triazolo[4.3-
`a]pyrazine phosphate (1:1) monohydrate. Sitagliptin phosphate monohydrate is a white to
`ofl-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. The empirical formula is
`C16H15F6N50'H3P04'H20 and the molecular weight is 523.32. The structural formula is:
`
`
`
`Page 8 of 40
`
`Reference ID: 29831 91
`
`

`

`FEE“
`.mL‘
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`.2“:\
`
`Afier oral ingestion, Simvastatin, which is an inactive lactone, is hydrolyzed to the
`corresponding B-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-
`coenzyme A (I-IMG-CoA) reductase. This enzyme catalyzes the conversion of
`I-IMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of
`cholesterol.
`
`2. Simvastatin has been reviewed in support of NDA 19-766 for Zocor. This NDA
`is active and up-to-date.
`
`Simvastatin is butanoic acid, 2,2-dimethyl-,l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-
`(tetrahydro-4-hydroxy-6-oxo-ZH-pyran-2-yl)-ethyl]-l-naphthalenyl ester, [13-
`[l(1,3(x,7B,8B(ZS*,4S*),-8afl]]. Simvastatin is a white to off-white, nonhygroscopic,
`crystalline powder that is practically insoluble in water, and freely soluble in chloroform,
`methanol and ethanol. The empirical formula of Simvastatin is CstuOS and its
`molecular weight is 418.57. Its structural formula is:
`
`
`
`Drug Product:
`
`0') (9 tablets (sitagliptin phosphate (+) Simvastatin) are supplied as a bi-layer, film coated
`tablet.
`
`(b)(4) contains 128.5 mg of sitagliptin phosphate monohydrate,
`Each bilayer tablet of
`which is equivalent to 100 mg of free base, either 10 mg, 20 mg, or 40 mg of Simvastatin and
`the following inactive ingredients: anhydrous dibasic calcium phosphate, microcrystalline
`cellulose, croscarmellose sodium, sodium stearyl furnarate, magnesium stearate, ascorbic
`acid, citric acid monohydrate, lactose monohydrate, and pre-gelatinized corn starch. In
`addition, the film coating contains the following inactive ingredients: polyvinyl alcohol,
`polyethylene glycol, talc, titanium dioxide, red iron oxide, yellow iron oxide, and black iron
`oxide. Butylated hydroxyanisole is added as a preservative.
`
`(b) (4’ tablets, with the exception of
`The inactive excipientsts used in the manufacture of
`0')(4), are the subjects of monographs in the
`USP-NF, Ph. Eur. and meet the requirements found therein, as applicable.
`(5)“)
`00(4) is the subject of the 8 monograph and is approved in the manufacture of
`(5)(4) film coatings have been reviewed and found to be acceptable.
`
`Zocor. The
`
`Note: The 100 mg/ 80 mg strength was used during product development; however the
`Applicant does not intend to market this strength.
`
`The product will be packaged in high-density polyethylene (HDPE) bottles containing silica
`gel desiccant with closures (either child resistant or non-child resistant). The inclusion of a
`
`Reference ID: 29831 91
`
`Page 9 of 40
`
`

`

`'“E'X
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`desiccant is important in that the
`The proposed packaging is:
`
`f'fi"
`
`(5)(4)
`
`“M0 100 mg/10 mg tablets are pink-beige, bi—convex round, film-coated tablets,
`coded 8753 on one side and plain on the other. They are supplied as follows:
`
`NDC 0006-0753-31 unit of use bottles of 30
`NBC 0006-0753-54 unit of use bottles of 90
`NBC 0006-0753-82 bottles of 1000.
`
`(I'm, 100 mg/20 mg tablets are pink-beige, bi-convex modified capsule-shaped,
`film-coated tablets, coded 8757 on one side and plain on the other. They are supplied as
`follows:
`
`NDC 0006-0757-31 unit of use bottles of 30
`NBC 0006—0757-54 unit of use bottles of 90
`NBC 0006-0757—82 bottles of 1000.
`
`(5)“) 100 mg/40 mg tablets are orange-beige, bi-convex modified capsule-shaped,
`film-coated tablets, codedg773 on one side and plain on the other. They are supplied as
`follows:
`
`NDC 0006-0773-31 1mit of use bottles of 30
`NBC 0006-0773-54 unit of use bottles of 90
`NBC 0006-0773-82 bottles of 1000.
`
`30 and 90 count bottles are to be stored at 20-25°C (GS-77°F), excursions permitted to 15-
`30°C (59-86°F), in a dry place with cap tightly closed.
`
`The contents of the 1000 count bottles are to be dispensed into a USP tightly closed. moisture-
`resistant container(s).
`
`B. Description of How the Drug Product is Intended to be Used
`
`(5) (4) (sitagliptin phosphate (+) simvastatin) is indicated in patients for whom treatment with
`both sitagliptin and simvastatin is appropriate.
`m (4) is intended to be taken orally, in the
`evening, with or without food.
`
`Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet
`to:
`
`0
`
`0
`
`0
`
`0
`
`Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-
`fatal myocardial infarction, stroke, and the need for revasculan'zation procedures in
`patients at high risk of coronary events.
`Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL—C in patients with
`primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.
`Reduce elevated T6 in patients with hypertriglyceridemia and reduce TG and VLDL—C
`in patients with primary dysbeta—lipoproteinemia.
`Reduce total-C and LDL—C in adult patients with homozygous familial
`hypercholesterolemia.
`
`Reference ID: 29831 91
`
`Page 10 of 40
`
`

`

`
`
`Executive Summary Section
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The final CMC recommendation is Approve: however we note that the facility inspection is
`still outstanding and that the CMC recommendation does not incorporate any
`potential facility inspection issues.
`
`111. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`ChemistName/Date: Same date as draft review
`
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
`
`C. CC Block
`
`29 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 29831 91
`
`Page 11 of 40
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN C HILL
`08/03/2011
`
`ALI H AL HAKIM
`08/03/2011
`
`ERIC P DUFFY
`08/04/2011
`
`Reference ID: 2983191
`
`

`

`
`
`NDA #202-343
`
`(5) (4)
`
`(sitagliptin phosphate (+) simvastatin) tablet: immediate
`release, 100/10, 100/20, 100/40 mg/mg
`
`Merck Sharp & Dohme Corp.
`
`John C. Hill, Ph.D.
`
`Theodore Carver, Ph.D.
`
`ONDQA/DNDQA—III/Branch VII and OND/ODE II/DMEP
`
`Reference ID: 2943314
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`1. Recommendations ...................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps, if Approvable ................................................................................................... 8
`
`II. Summary of Chemistry Assessments......................................................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
`
`B. Description of How the Drug Product is Intended to be Used.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 10
`
`III. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature ...................................................................................................................... 10
`
`B. Endorsement Block ......................................................................................................................... 10
`
`C. CC Block ........................................................................................................................................ 10
`
`Chemistry Assessment ........................................................................................... l 1
`
`I. Review Of Common Technical Document-Quality (Ctd—Q) Module 3.2: Body Of Data ......... ll
`
`S-A. DRUG SUBSTANCE [(sitagliptin phosphate, Merck & Co., Inc.] ...................................... 11
`
`S-B. DRUG SUBSTANCE [(simvastatin, Merck & Co., Inc.] ..................................................... 14
`
`P DRUG PRODUCT [Name, Dosage form] ..................................................................................... 17
`
`RI Description and Composition of the Drug Product [name, dosage ................................................ 17
`
`form] ..................................................................................................................................................... 17
`
`A APPENDICES ............................................................................................................................. 120
`
`R REGIONAL INFORMATION ................................................................................................... 120
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 .................................. 147
`
`A. Labeling & Package Insert ........................................................................................................... 147
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................ 147
`
`III. List Of Deficiencies To Be Communicated ........................................................................... 148
`
`Reference ID: 2943314
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA: 202—343
`
`2. REVIEW # l
`
`3. REVIEW DATE: 25-APR—2011 (Mid—Cycle 03-MAY—201 1)
`
`4. REVIEWERS: Theodore Carver, Ph.D. and John C- Hill, Ph.D-
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions 5! Reviewed
`Original NDA Application
`Response to IR Request: (Manufacturing contact information)
`
`Document Date
`07-DEC-2010
`l6—DEC-201 0
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Merck Sharp & Dohme Corp.
`
`PO. Box 1000. UG2CD-48
`Add‘ess:
`North Wales. PA 19454-1099
`Representative: Richard J. Swanson. Ph.D.. Semor Director. WW Regg‘lg:g
`
`Telephone:
`
`267-305-6871
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`(01(4)
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`c) Code Name/# (0NDC only): MK—043 lD Tablet
`
`Reference ID: 2943314
`
`Page 3 of 150
`
`

`

`
`
`Chemistry Review Data Sheet
`
`d) Chem. Type!Submission Priority (ONDC only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`Reference is made to the approved NDA 21995 Januvia (sitagliptin) Tablets (same applicant) for
`all CMC information on the sitagliptin phosphate monohydrate drug substance.
`
`Reference is made to the approved NDA 19766 Zocor (simvastatin) Tablets (same applicant) for
`all CMC information on the simvastatin drug substance.
`
`10. PHARMACOL. CATEGORY: TX of type H diabetes mellitus /
`Hypercholesterolemia-cardiovascular disease
`
`11. DOSAGE FORM:
`
`Fixed dose combination (FDC), bilayer, Immediate
`release tablet
`
`12. STRENGTH/POTENCY: 100/ 10, 100/20, 100/40, mg/mg sitagliptin
`anhydrous free base/ simvastatin)
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. RX/OTC DISPENSED:
`
`_X_Rx
`
`OTC
`
`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM [2
`
`_SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Sitagliptin phosphate:
`
`Molecular Weight: 523.32
`Chemical Formula: C15H15F5N50 . H3P04 . H20
`Chemical Name: 7-[(3R)-3-amino-l-oxo-4—(2.4.5-
`t1ifluorophenyl)butyl]-5.6,7,8-
`tetrahydro-[3 -(t1ifluoromethyl)- l ,2,4-t1iazolo[4,3-a]
`pyrazine phosphate (1:1) mnohydratef
`Laboratory Code: MK-0431D
`
`. H20
`
`- H3PO4
`
`Reference ID: 2943314
`
`Page 4 of 150
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Simvastatin
`
`Molecular Weight: 418.57
`Chemical Formula: C25H3305
`Chemical Name: a. [lS-[lm3a,7fi,8|3(2$*,4$*),8afl]]-1,2,3,7,8,8a-Hexahydro-
`3,7-
`
`dimelhyl-S-[2-(teIIahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)
`ethyl]- l -naphthalenyl-2.2-dimethylbutanoate
`
`b. Butanoic acid. 2,2-dimethyl-_.1.2,3,7_.8.8a.hexahydro-3_.7-
`dimethyl-S-[2{telrahydro-4-hydroxy—6-oxo—2H-pyran-Z-
`yl)ethyl]-l-naphthalenyl ester,[lS-[lu,3a.7fi,8[3(2$*,4S*). -
`8343]]
`
`c. 2,2—dimethylbutyric acid, 8-ester with (4R.6R)—6-[2—
`[(1S,2$,6R,8S,80LR)— l,2,6,7,8,8a-hexahydro-8-hydroxy—2,6-
`dimelhyl-1-napthyl]eflnyl]te1rahydro—4—hydroxy—2H-pyran- -
`one
`
`H
`
`
`
`d. (lS,3R,7S,8S,8aR)-8-[2-[(2R,4R)—4-hydroxy-6-oxotetrahydro-
`2H-pyran-2-yl]ethyl]-3,7-dimethyl- l ,2,3 ,7,8,8a-hexahydronaphthalen-
`1-yl 2,2,-dimethylbutanoate
`Laboratory Code: MK-0733
`
`17. RELATED/SUPPORTING DOCUlVIENTS:
`
`A. DMFs:
`
`ITEM
`
`REFERENCED
`W"
`
`CODEl
`
`STATUS2
`
`4
`
`Adequate
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
`
`LOA: 20—
`APR-2010
`
` 4
`
`Adequate*
`
`LOA:13-
`MAY-201 0
`
`Reference ID: 2943314
`
`Page 5 of 150
`
`

`

`
`
`
`
`Adequate*
`
`Adequate
`
`Adequate*
`
`Adequate*
`
`Adequate*
`
`Adequate*
`
`Adequate*
`
`Adequate*
`
`LOA: 20-
`APR-2010
`
`LOA: 01-
`APR-2010
`LOA: ll—
`MAY-2010
`LOA: 01-
`APR-2010
`LOA: 21-
`APR-2010
`
`LOA: l9-
`APR—2010
`LOA: 15-JUL-
`2010
`
`LOA: 19-
`APR-2010
`
`ge
`um-acoordancewiflamtiewpolicyforcomainfl-closnesystuns u sor?‘ u.
`+ WMmemdchfldmdmm-yhemml01-104,601-604,901-938,1001-1015,1101-1125,1151,1201-1202,1211,
`13 01-13 129,13 02-13 307,:111‘115 01 (omvolnm, 9113mmFDAoany9,2003)andAnmlUpdminfilfl(onevohmc,sWtolheFDAonAugust24,2009)
`@ Patinentinfixmnimon
`09(4) mnaiflmybefiomdoul’lgeIZ 002-2997,301-302,501—505,601—
`601701,!!01-809, 1001,1111!“01(oncvolm,mbn|i1tedwFDAonJme30,2004)mdAnnnalUpdnesnbnimdtoflle1-'DAouAngm24,2009
`& mmmuupgclo,mmum2uoo9
`S
`(5)“) Wmfafi:
`FDAon 15AM 1993 :11de 1993, rapecfively)
`
`(5X4) mybefonndonpnguG—VH—b—lde—II—nn—l,2,3,&4(whidlwuesubmimdbthe
`
`1Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previome and no revision since last review
`4 — Sufficient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2 Adequate, Inadequate. or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`18. STATUS:
`
`0ND 0A:
`CONSULTS/ CMC
`RELATED REVIEWS
`
`REVIEWER Biometrics
`
`RECOMMENDATION
`The ONDQA
`Biopharmaceuties Review
`Staff will review all
`dissolution-related
`
`Reference ID: 2943314
`
`Page 6 of 150
`
`

`

`
`
`Methods Validation
`
`Microbiology
`
`information and biowaiver
`r uests.
`
`EER was sent to Compliance
`on 22-DEC-2010 by ONDQA
`PM.
`
`Labeling consult request
`will be sent as part of
`DMEP’s reuest.
`
`Evaluation of the genotoxicity
`potential of identified
`de u dants.
`
`Validation may be requested
`of FDA labs after test
`methods are finalized.
`
`The categorical exclusion
`claim will be assessed by
`P 'n . Reviewer.
`
`May Not Be Applicable: solid
`oral dosa ' e form.
`
`Reference ID: 2943314
`
`Page 7 of 150
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 202-343
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`From a CMC perspective a complete review of this Application cannot be approved at this time.
`The following information is required:
`
`1.
`
`Satisfactory responses to the identified CMC deficiencies. These deficiencies include
`clarification of a manufacturing failure that has a potential negative impact on any
`approved expiry period.
`
`2. Completion of the outstanding CGlVIP inspection(s)
`
`3. Completion of the Biopharmaceutics review.
`
`4. Completion of the final labeling.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`11.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Substance:
`
`Two approved drug substances are used in the manufacturing process:
`
`1. Sitagliptin phosphate has been reviewed in support of NDA 21—995 for Januvia.
`This NDA is active and up-to-date.
`
`2. Simvastatin has been reviewed in support of NDA 19-766 for Zocor. This NDA
`is active and up-to-date.
`
`Drug Product:
`
`(5) ‘0 tablets (sitagliptin phosphate (+) simvastatin) are supplied as a bi-layer, film coated tablet.
`Each bi—layer tablet contains 100 mg of sitagliptin and 10. 20. 40. or 80 mg of simvastatin drug
`substance. The 100 mg/ 80 mg strength was used during product development; however the
`Applicant does not intend to market this strength. The inactive excipientsts used in the
`manufacture of M“) tablets. with the exception of
`(”(0
`are the subjects of monographs in the USP—NF, Ph. Eur. and meet the
`requirements found therein. as applicable
`(”(4) is the subject of the 8
`monograph and is approved in the manufacture of Zocor. The
`(5K4) film coatings have been
`
`Reference ID: 2943314
`
`Page 8 of 150
`
`

`

`
`
`Executive Summary Section
`
`reviewed and found to be acceptable. The drug product manufacturing process includes a number
`ofproposed QbD elements including
`(5)(0
`
`mathematical modeling.
`
`supported by DOES and
`
`The product will be packaged in high-density polyethylene (I-IDPE) bottles containing silica gel
`desiccant with closures (either child resistant or non-child resistant). The inclusion of a desiccant
`is important inthat
`(W). The
`proposed packaging is:
`
`(5)“) 100 mg/10 mg tablets are pink-beige. bi-convex round, film-coated tablets.
`coded 8753 on one side and plain on the other. They are supplied as follows:
`
`NDC 0006-0753-31 unit of use bottles of 30
`NBC 0006—0753-54 unit of use bottles of 90
`NBC 0006—0753-82 bottles of 1000.
`
`(m4) 100 mg/20 mg tablets are pink-beige. bi-convex modified capsule-shaped,
`film-coated tablets, codedg757 on one side and plain on the other. They are supplied as
`follows:
`
`NDC 0006-0757-31 unit of use bottles of 30
`NBC 0006-0757-54 unit of use bottles of 90
`NBC 0006-0757-82 bottles of 1000.
`
`(I'm, 100 mg/40 mg tablets are orange-beige, bi-convex modified capsule-shaped,
`film-coated tablets, coded8773 on one side and plain on the other. They are supplied as
`follows:
`
`NDC 0006-0773-31 Imit of use b