CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-044
`
`CHEMISTRY REVIEW! S!
`
`

`

`I of 4
`
`3/4/2007
`
`JanumetTM
`
`(Sitagliptin Phosphate (+) Metformin Hydrochloride)
`Tablets
`NDA 224044
`
`Summary of the Basis for the Recommended Action
`from Chemistry, Manufacturing,- and Controls
`
`Applicant: Merck & Co., Inc.
`UG2CD-48
`PO Box 1000
`
`North Wales, PA 19454-1099
`
`Indication: Adjunct to diet and exercise to improve glycemic control in patients with type 2
`' diabetes mellitus who are not adequately controlled on metformin or sitagliptin
`alone or in patients already being treated with the combination of sitagliptin and
`metformin.
`
`is supplied in two strengths (50 mg sitagliptin/500 mg
`Presentation: The drug product
`metformin hydrochloride or 50 mg sitagliptin/1000 mg metformin hydrochloride)
`as immediate release film-coated tablets packaged in w“ bottles (60, 180 and
`1000-count) and in unit dose ”blister packages (50 count as lO-unit doses
`per foil).
`
`EER Status: Acceptable 24-Jan-2007
`
`Consults:
`
`Methods Validation ~ Agency revalidation not recommended.
`EA — Categorical exclusion granted under 21 CFR §25.31(b) for both drugs.
`Labeling — Under review (multi disciplinary approach).
`
`Original Submission:
`
`31—May-2006
`
`Amendments:
`
`24-Jul-2006
`
`05—Jan—2007
`05-Feb-2007
`05-Feb—2007 '
`
`Post-Approval Agreements: None
`
`Drug Substances:
`
`Sitagliptin Phosphate Monohydrate
`
`inhibitor of the enzyme dipeptidyl
`Sitagliptin is a highly selective and potent
`peptidase 4 (DPP—4). DPP-4 inhibitors act by enhancing the levels of active incretin
`hormones. Sitagliptin is synthesized and present in the drug product as its phosphate
`
`

`

`20f4
`
`3/4/2007
`
`.._._. monohydrate. Sitagliptin phosphate menohydrate has a chemical name is 7-[(3R)-
`3-amino- l -oxo—4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8—tetrahydro—[3 -trifluoromethyl)—
`l,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate, a molecular formula of
`C16H{5F6N50- H304P~H20, and a molecular weight of 523.32 g/mole. Sitagliptin
`
`phosphate monohydrate is a white to off-white solid, melting point
`'
`1°C, and
`'a pKa of ‘J According to the Biopharmaceutics classification system (BCS)
`sitagliptin is a Class III (high solubility, low permeability)/b0rderline Class I (high
`solubility, high permeability) drug. Sitagliptin phosphate monohydrate is the drug
`substance of JanuviaTM Tablets, which is described in and referred to Merck’s
`approved NDA 21-995.
`
`identity, assay, related impurities,
`The release specifications include appearance,
`moisture content, particle size distribution, residual metals, and chiral purity. The '
`proposed regulatory methods have been validated. Residual metals and enantiomeric
`purity will be tested in-process only. However the criteria are retained in the
`specification. Based on development, no testing is performed for Polymorphic Form
`
`and Solvent
`Content. The reference standard, a re—purified commercial
`lot, has been developed, characterized, and purity data provided.
`
`Bulk sitagliptin phosphate monohydrate, packedinW
`W is stable for long-term up to -.years when
`stored at room temperature (25 °C/60 % RH).
`
`Metformin HCl
`
`Metformin is a biguanide class of antihiperglycemic agent that acts primarily by
`decreasing endogenous hepatic output of glucose by inhibition of gluconeogenesis.
`Metformin HCl has a chemical name of l,l-Dimethylbiguanide hydrochloride, a
`molecular formula of C4HHN5-HCI, and a molecular weight of 165.62 g/mole.
`Metformin is a class 3 (high solubility, low permeability) BCS drug.
`
`CMC information on the drug substance, metformin HCl, is described in the Type II
`
`DMF
`5 detailed information on its characterization,
`manufacture,
`in-process controls, analytical procedures and their validation, and
`stability is included.
`
`The release specifications include description, identification, loss on drying, residue
`on ignition, heavy metal, assay, related impurities, residual solvents and particle size.
`These specifications comply with the USP monograph for metformin hydrochloride.
`The drug substance specification differs from the USP monograph in (1) additional
`particle size criteria and (2) more stringent
`limits on impurities. The reference
`standard for metformin HCl is commercially available from USP.
`
`Bulk metformin HCl, packed in W W , is stable
`long-term up to ”years at room temperature (25 °C/60 % RH).
`
`

`

`3 of 4
`
`3/4/2007
`
`Conclusion: Drug substance information is acceptable.
`
`Drug Product:
`
`The drug product is a fixed dose combination tablet, composed of a fixed dose of sitagliptin and
`a variable dose of metformin hydrochloride, and, is available as two strengthswith the following
`description:
`
`The 50/500 tablets contain 50 mg sitagliptin free base /500 mg metformin 'HCl, are
`light pink film-coated, oblong (17.3 mm x 8.4 mm) biconvex tablets debossed “575”
`on one side, blank on the other, and weigh 706.2 mg.
`-
`
`The 50/1000 tablets contain 50 mg sitagliptin free base / 1000 mg metformin HCl, are
`red film-coated, oblong (21.2 mm x 10.3 mm) biconvex tablets debossed “577” on
`one side, blank on the other, and weigh 1333 mg.
`
`ingredients:
`inactive
`following
`the
`JanumetTM contains
`tablet of
`film—coated
`Each
`
`sodium lauryl
`sulfate
`microcrystalline cellulose FM, polyvinylpyrrolidone «ww-w—z:
`‘, and sodium stearyl fiJmarate j“
`.i- The film coating contains the following
`inactive ingredients: polyvinyl alcohol, polyethylene glycol,
`talc, titanium dioxide, red iron
`oxide, and black iron oxide. All excipients, including film coating components, meet compendial
`requirements.
`
`The manufacturing process includes
`L.
`
`i
`
`The specification for the drug, product includes appearance, identification (W
`2’“ ,), assay, degradation products (individual unspecified and total degradation products),
`_ dissolution (both actives are measured in the same media by the same HPLC method), and
`uniformity of dosage units (mass and active content). The proposed regulatory methods have
`been validated. The drug product reference materials are. the same as those used for sitagliptin
`phosphate monohydrate and metformin hydrochloride drug substances.
`
`Stability data indicate that there are no significant changes in terms of appearance, assay, related
`compounds, dissolution, disintegration, hardness and moisture, when tablets are stored at either
`25 °C/60 % RH or at 30 °C/65 '% RH in W bottles with closure and in A“ blister
`
`packages. PhOtostability studies indicate that the tablets are stable when exposed to light.
`
`Based on 12 months of stability data at either 25 °C/60 % RH or 30 °C/65 % RH fortablets
`packaged in ‘ M bottles and blister packages, and 6 months at 40 °C/75 % RH, the requested
`
`expiration dating period of
`.
`is acceptable under the proposed storage conditions:
`“Store at 20 — 25 °C (68 — 77 °F); excursion permitted to 15 — 30 °C (59 — 86 °F) [see USP
`Controlled Room Temperature].”
`
`

`

`4 of4
`
`-
`
`,
`
`3/4/2007
`
`Conclusion: Drug product information is acceptable.
`
`Additional Items:
`
`All associated Drug Master Files (DMFs) are adequate or the pertinent information has
`~ been adequately provided in the application.
`
`The applicant agrees to place at least one batch of each strength annually in the post-
`approval stability program.
`
`Overall Conclusion:
`
`From a CMC perspective, the application is recommended for approval; pending
`agreement on product labeling.
`
`Blair A. Fraser, Ph.D.
`Director
`
`DPA I/ONDQA
`
`Appears This Way
`On’ Original
`
`

`

`This is a representation of an electronic record that was signed electrOnically and
`tMSmmebflmankmmMndflwebdecflmwmm.'
`
`Blair Fraser
`
`3/4/2007 12:49:28 PM
`CHEMIST
`
`Appears This Way
`On Original
`
`

`

`
`
`NDA 22-044
`
`JanumetTM
`
`(Sitagliptin Phosphate (+) Metformin Hydrochloride)
`Tablets
`
`Merck & CO., Inc.
`
`Xavier Ysern, PhD
`CDER/OPS/ONDQA/DPA I
`
`(NDA Clinical Review Division: DMEP)
`
`NDA 22—044 Chemistry Review Page
`
`1 of 87
`
`

`

`V CHEMISTRYREVIE :
`
`Table of Contents
`
`Table of Contents ......................................................................................................................................................... 2
`
`Chemistry Review Data Sheet .................................................................................................................................... 3
`
`The Executive Summary ............................................................................................................................................. 6
`
`I.
`
`Recommendations .......I........................................................................................................... 6
`
`A. Recommendation and Conclusion on Approvability..................................................................................... 6
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management
`Steps, if Approvable ........................................................................................................................................6
`
`
`II. Summary of Chemistry Assessments .......................................................................................................... 6
`
`A. Description of the Drug Product(s) and Drug Substance(s).............................................................................. 6
`
`B. Description of How the Drug Product is Intended to be Used .......................................................................... 8
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................................ 8
`
`III. Administrative ........................................................................................................................................................ 8
`
`A. Reviewer’s Signature ........................................................................................................................................ 8
`
`B. Endorsement Block ................ ........................................................................................................................... 8
`
`C. CC Block .......................................................................................................................................................... 8
`
`ChemistryAssessment
`
`........................ 9
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...................................... 9
`
`S
`
`P
`
`DRUG SUBSTANCES Sitagliptin Phosphate Monohydrate and Metformin Hydrochloride ........................ 9
`
`DRUG PRODUCT JanumetTM (Sitagliptin Phosphate and Metformin HCI) Tablets .................................. 12
`
`A APPENDICES .............................................................................................................................................. 78
`
`R
`
`REGIONAL INFORMATION .........................................'............................................................................ 78
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 .......................................................... 81
`
`A. Labeling & Package Insert............................................................................................................................. 81
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................................... 84
`
`III. List Of Deficiencies To Be Communicated ................................................................................. 84
`
`NDA 22—044 Chemistry Review Page 2 of 87
`
`

`

`
`
`Chemistry Review Data Sheet
`
`1. NDA:
`
`22-044
`
`2. REVIEW #:
`
`l
`
`3. REVIEW DATE:
`
`22-FEB-2007
`
`4. REVIEWER:
`
`Xavier Ysem, PhD
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`IND 65,495 MK-0431 (Sitagliptin)
`NDA 21-995 MK-0431 (Sitagliptin)
`IND 70, 934 MK-0431A (Sitagliptin/Metformin HCl)
`
`12-AUG-2002
`16-DEC-2005 (approved l6-OCT-2006)
`23—MAR-2005
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissions Reviewed
`Original:
`Amendments:
`
`Document Date
`
`31-MAY-2006
`(Labeling)
`24-JUL-2006
`05-JAN—2007 (Additional Stability Data)
`05-FEB-2007 (Validation Summary Report)
`05-FEB-2007 (Labeling)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Merck & Co., Inc.
`Address: UG2CD-48
`.
`PO Box 1000
`North Wales, PA 19454-1099
`Steven A. Aurecchia, MD Director, Regulatory Affairs
`267 305 6669
`
`Representative:
`Telephone:
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`
`Janumetm
`Sitagliptin Phosphate (+) Metformin Hydrochloride fixed dose
`combination tablets
`
`--
`0) Code Name/# (ONDC only):
`d) Chem. Type/Submission Priority (ONDC only):
`0 Chem. Type:
`4 (New Combination)
`0 Submission Priority:
`S (Standard Review, Substantially Equivalent)
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505(b)(2)
`
`10. PHARMACOL. CATEGORY:
`
`Treatment of Type 2 Diabetes Mellitus
`Sitagliptin: dipeptidyl peptidase—4 (DPP-4) inhibitor
`
`11. DOSAGE FORM:
`
`Tablet
`
`NDA 22-044 Chemistry Review Page 3 of 87
`
`

`

`.. CHEM STRY ‘
`
`12. STRENGTH/POTENCY:
`
`50/500 and 50/1000 mg/mg sitagliptin/metformin hydrochloride
`
`13. ROUTE OF ADMINISTRATION:
`
`Oral
`
`14. Rx/OTC DISPENSED:
`
`Rx
`
`15. SPOTS (SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM):
`
`Not a SPOTS product
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Sitagliptin Phosphate Monohydrate
`
`CmHUFGNSO - H3O4P - H20
`MW = 407.32 + 98.00 + 18.00 = 523.32
`
`CAS 654671-77-9
`
`N/ \
`Y N
`
`CF3
`
`'
`
`Hapoa
`
`'
`
`“20
`
`7-[(3R)~3-amino-1-0xo-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
`
`Metforrnin Hydrochloride
`
`C4HHN5‘HC1
`MW = 129.17 + 36.46 = 165.63
`
`OH,
`
`H
`
`H30 WY 2
`NH
`NH
`
`'
`
`HCl
`
`CAS 657-25-9 (base) 1115-70-4 (hydrochloride)
`
`N,N-Dimethylimidodicarbonimidic
`
`: HCl
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`Type. II
`
`
`
`
`,~
`
`CVICW
`
`.
`-
`‘ dequat O7-APR-2005 10-DEC-2004 Reviewed by
`Mouna P. Selvam,
`HFD-625
`
`
`
`
`26-OCT-2004
`l 6-JUN-2005
`
`29-OCT-2004
`
`OS-APR—2006'
`27-OCT-2004
`
`20-JAN—2006
`
`l 3-APR-2006
`
`l 3-JUN-2003
`
`
`O4-APR-2006
`
`
`
`
`
`08-JAN-2007 24-FEB-2006 X.Ysem
`. dequa -
`
`- . uat
`
`08-IAN-2007 24-FEB-2006 ’ X.Ysem
`
`
`l — DMF Reviewed.
`Action codes for DMF Table:
`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)
`
`AA-h-bAAA-B-bA-h
`
`
`
`
`
`
`>
`
`
`
`NDA 22-044 Chemistry Review Page 4 of 87
`
`

`

`
`
`
`
`
`
`APPLICATION NUMBER DESCRIPTION
`
`
`
`I8. STATUS:
`
`0NDC:
`CONSULTS/ CMC
`
`
`
`
`- mm» REVIEWS
`
`
`-_—_
`
`
`
`
`S. Adams (HFD-322)—— -EES Acceptable 24-JAN-2007 EERsumma Renamed
`
`__—_
`-___—
`Labelin issues still underreview multidisci-Iina a roach) _—
`___——
`——__
`_—
`
`_——
`
`
`
`
`
`
`
`
`
`
`Appears This Way
`On Original
`
`NDA 22-044 ChemiSUy Review Page 5 of 87
`
`

`

`
`
`
`
`The Chemistry Review for N DA 22-044
`
`The Executive Summafl
`
`l.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`From the CMC point of view this application can be APPROVED. Based on the submitted
`stability data, an expiry of '~—~ s granted under the recommended storage conditions: Store
`at 20—25 °C (68-77 °F); excursions permitted to 15-30 °C (59-86 °F) [see USP Controlled Room
`Temperature]
`
`8.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`None.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product and Drug Substance(s)
`
`The drug product, JanumetTM Tablets is a combination product with two active components: sitagliptin
`and metformin. These two active components are hypoglycemic agents that differ in both chemical class and mode
`of action. Sitagliptin is a highly selective and potent inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4).
`Sitagliptin mechanism of action is well understood, DPP~4 inhibitors act by enhancing the levels 'of active incretin
`hormones. These hormones,
`including glucagon—like peptide-1 (GLP-l) and glucose-dependent
`insulinotropic
`peptide (GlP), are released by the intestine in response to a meal, and are part of an endogenous system involved in
`maintaining glucose homeostasis. Metformin belongs to the biguanide class. Biguanides act primarily by decreasing
`endogenous hepatic output of glucose by inhibition of gluconeogenesis. Due to their complementary mechanisms of
`action, concurrent administration of sitagliptin (JanuviaTM (sitagliptine) tablets) and metformin (Glucophage or
`generic metformin hydrochloride tablets) is prescribed. JanumetTM Tablets has been developed as an immediate
`release product containing a fixed dose of sitagliptin phosphate and a variable dose of metformin hydrochloride
`proposed to be commercialized in two dosage strengths different strengths. 50/500 and 50/ 1000 (mg/mg, Sitagliptin
`free base/Metformin Hydrochloride) immediate release film-coated tablets for oral administration The combination
`drug product will facilitate patient compliance
`
`Drug Substances
`
`
`is synthesized as its phosphate salt monohydrate, sitagliptin
`and it
`Sitagliptin has
`Its chemical name is 7-[(3R)-3-amino-l~oxo-4-(2,4,5'-trifluorophenyl)butyl]-5,6,7,8—
`phosphate monohydrated.
`tetrahydro-[3—(trifluoromethyl)-1,2,4-triazolo[4,3-a]py'razine phosphate (1:1) monohydrate. Sitagliptin phosphate
`monohydrate is a white to off-white solid, melting point m °C, pKa value of "" According to the
`Biopharmaceutics classification system (BCS) sitagliptin is a Class III (high solubility, low permeability)/borderline
`Class I (high solubility, high permeability) drug. Sitagliptin phosphate monohydrate is the drug substance of
`JanuviaTM Tablets, which13 described and referred to approved NDA 21-995.
`
`is aM
`s,
`H
`‘
`Metformin, a
`m to metformin hydroChloride. Metformin hydrochloride is a white to off-white
`crystalline compound. The pKa of metformin is —~. Metformin is a class 3 (high solubility, low permeability) BCS
`drug. Metformin hydrochloride is the drug substance of approved metformin immediate and modified release tablet
`formulations,
`including generic versions, and also in combination with other active components. Metformin
`hydrochloride drug substance employed for JanumetTM Tablets is supplied by m . as described in
`their approved DMF A
`
`NDA 22-044 Chemistry Review Page 6 of 87
`
`

`

`
`
`The two drug substances have the following in common: (1) both are synthesized as salts to improve their
`stability, (2) their quality is controlled by specifications which are consistent with their respective approved drug
`substances, sitagliptin phosphate monohydrate and metformin hydrochloride, (3) no evidence of polymorphism, and
`(4) high stability, showing almost no degradation at room temperature (storage condition) for it proposed retest
`conditions.
`
`Drug Product
`
`The drug product, JanumetlfM (Sitagliptin Phosphate (+) Metformin Hydrochloride) Tablets, has been
`developed as an immediate release product containing a fixed dose of sitagliptin phosphate and a variable dose of
`metformin hydrochloride. JanumetTM Tablets are proposed to be commercialized in two dosage strengths: 50/500
`and 50/1000 (mg/mg, Sitagliptin free base/Metformin Hydrochloride) immediate release film-coated tablets for oral
`administration. In addition of the two ‘drug substances, sitagliptin phosphate in the form of monohydrate and
`metformin hydrochloride, each film-coated tablet of JanumetTM contains the following inactive ingredients:
`
`microcrystalline cellulose p...“ ., polyvinylpyrrolidone v, sodium lauryl sulfate '
`, and sodium
`
`stearyl fumarate
`In addition, the film coating contains the following inactive ingredients: polyvinyl
`alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and black iron oxide. All excipients, including
`film coating components, meet compendial requirements.
`
`Excipient selection throughout pharmaceutical development was initially guided by the experience
`knowledge gained from the MK-0431 development program (JanuviaTM (sitagliptin) Tablets, Merck’s approved
`NDA 21-995) and from the knowledge literature on commercial metformin tablets. Early formulations showed
`dissolution of the drug substances relatively slow when compared to the MK-0431 tablet. The addition of the
`
`disintegrant.
`, used in the MK-0431 tablet formulation, did not significantly enhance the
`dissolution rate. Addition ofa surfactant, sodium lauryl sulfate, significantly and favorably impacted (\d
`a.»- Sodium stearyl fumarate was selected due to ’N relative to similar formulations with
`
`magnesium stearate as the
`
`the formulation and manufacturing process parameters were simultaneously
`Through development
`optimized. The manufacturing process includes ‘
`_
`—”i
`l
`
`L.
`
`.
`
`), assay,
`identification (actives by
`include appearance,
`Drug product specifications
`degradation products (individual unspecified and total degradation products), dissolution (both actives are measured
`
`in the same media by the same
`method), and uniformity of dosage units (mass and active content).
`Justification for the lack of testing for water content, microbial
`limits and hardness are fully justified by
`manufacturing process development. The two active components are very stable in the drug product formulation.
`The criteria of acceptance for any unspecified sitagliptin and metformin degradation products are no more than
`(NMT) —— % and NMT ‘—%, respectively. The total maximum amount of allowed degradation products is NMT
`~ % for either sitagliptin o'r metformin degradation products. The different strengths are distinguished by tablet
`size, color and marking.
`
`
`
`The stability of the drug product has been inferred from the product characterization study (two lots, one of
`each strength) and from the formal stability study (six batches, three of each strength). Although the formal stability
`study is still ongoing, in both studies, 52 weeks stability data have been provided at 25 °C/60 % RH and 30 °C/65 %
`RH storage conditions, and up to 26 weeks for batches stored at 40 °C/75 % RH. Stability studies protocols include
`bracketing. Bracketing for the \ bottle presentations included the worst-case (least protective) and best'case.
`(most protective) conditions of bottle size and fill. Based on the provided stability information an expiry dating of
`——=—e-- is granted under the proposed storage conditions: “Store at 20 - 25 °C (68 - 77 °F); excursions permitted
`to 15 - 30 °C (59 - 86 °F) [see USP Controlled Room Temperature].
`
`NDA 22—044 Chemistry Review Page 7 of 87
`
`

`

`
`
`B. Description of How the Drug Product is Intended to be Used
`
`JanumetTM Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in patients
`with type 2 diabetes mellitus who are not adequately controlled on-metformin or sitagliptin alone or in patients
`already being treated with the combination of sitagliptin and metformin. Two JanumetTM doses are available for oral
`administration as tablets: 50 mg sitagliptin/SOO mg metformin hydrochloride and 50 mg sitagliptin/1000 mg
`metformin hydrochloride.
`‘
`‘
`
`The dosage of antihyperglycemic therapy with JanumetTM Tablets should be individualized on the basis of
`the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily
`dose of 100 mg sitagliptin and 2000 mg metformin. JanumetTM should generally be given twice daily with meals,
`with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.
`
`JanumetTM Tablets are supplied in bottles (50, 60, 180, and 1000 count) and blister packages (10 count per
`foil). Storage is at 20-25 °C (68-77 °F) [see USP Controlled Room Temperature]. The expiration dating period is s
`
`C. Basis for Approvability or Not—Approval Recommendation
`
`Adequate information has been submitted to allow a satisfactory evaluation of the quality of both drug
`substance (DS) and drug product (DP). DS and DP manufactured and packaged in accordance with the procedures
`and recommendations given in the original submission and pertinent amendments were shown, judged by the
`expected compliance to. their proposed specifications, to assure their quality throughout their granted shelf live.
`Based on the evaluation of the provided CMC information, from the chemistry viewpoint this NDA can be
`approved.
`
`III. Administrative
`
`A. Reviewer’s Sign ature
`
`See appended electronic signature page.
`
`B. Endorsement Block
`
`Xavier Ysern, PhD/ ONDQA/ DPA I Reviewer
`Blair Fraser, PhD/ ONDQA/ DPA I Division Director
`
`C. CC Block
`
`Lina Alj ubari, MS/DMEP/ Regulatory Project Manager
`
`NDA 22-044 Chemistry Review Page 8 of 87
`
`

`

`2'2' Page(s) Withheld ‘
`
`.
`
`2:
`
`‘ § 552(b)(4) Trad-e Secret /‘ Confidential
`
`___-_ § 552(b)(4) Draft Labeling '
`
`'
`
`.
`
`I § 552(b)(5) Delibérative Process
`
`

`

`(SOPG&k4SD&17.27c66F 26—FEB—2007
`Page 1 of 3
`
`FDA
`
`CDER EES
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`Ab
`
`lcation:
`
`NDA
`
`22044/000
`
`Action Goal:
`
`Stamp:
`
`Regulatory Due:
`METEOR
`
`31—MAY—2006
`
`31—MAR—2007
`
`Applicant:
`
`MERCK
`
`1000
`
`District Goal:
`
`30—JAN—2007
`
`Brand Name:
`
`JANUMET(PHOSPHATE
`
`Estab; Name:
`
`MIN HCL FIXED DO
`
`Generic Name:
`
`SITAGLIPTIN
`
`N HCL
`
`NORTH WALES,
`
`PA
`
`19454
`
`PHOSPHATE/METFORM
`
`Priority:
`
`Org Code:
`
`4S
`
`510
`
`/MG
`
`TABS
`
`Dosage Form:
`
`(TABLET)
`
`Strength:
`
`50/500, 50/1000 M
`
`Application Comment:
`
`DRUG NAME:
`
`SITAGLIPTIN PHOSPHATE/METFORMIN HCL
`
`REFER TO NDA 21—995 FOR INFO ON SITAGLIPTIN. BOTH NDA 21
`
`995 AND
`
`{OVED
`
`A.
`
`(on
`
`NDA 22—044 INITIALLY GOT "NME" DESIGNATION; THE FIRST ON
`
`KEEPS "NME" AND THE SECOND ONE APPROVED BECOMES TYPE 6 N
`
`20—JUN—2006 by s.
`
`TRAN () 301—796—1764)
`
`FDA Contacts:
`anager
`
`L.
`
`ALJUBURI
`
`emist
`
`er
`
`X.
`
`YSERN
`
`S.
`
`TRAN
`
`301—796—1168
`
`, Project
`
`301—796—2410
`
`, Review C
`
`301—796—1764
`
`, Team Lea
`
`3verall Recommendation:
`27—9051
`
`ACCEPTABLE on 24—JAN—2007by S.
`
`ADAMS
`
`(HFD—322)30l—
`
`ZS
`
`‘blishment:
`
`CFN
`
`V
`
`9613092
`
`FEI
`
`,_.-"*
`
`

`

`DMF No:
`
`F_#__.
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE MANUFACTURER
`
`E
`
`.le:
`
`CSN
`
`OAI Status:
`
`NONE
`
`EMilestone Name
`eator
`
`Date
`
`Type
`
`Insp. Date
`
`Decision & Reason
`
`C
`
`SUBMITTED TO OC
`TRANS
`
`.SUBMITTED TO DO
`ADAMSS
`
`20-JUN-2006
`
`20—JUN-ZOO6
`
`GMP
`
`ASSIGNED INSPECTION T 22—JUN-2006
`ADAMSS
`
`GMP
`
`INSPECTION SCHEDULED O7—SEP—2006
`IRIVERA
`
`09—Nov—2006
`
`INSPECTION PERFORMED
`S.DUNNI
`
`09—Nov-2006
`
`09—Nov—2006
`
`JAM
`
`The inspection of this active pharmaceutical
`in
`
`3
`
`ingredient
`
`(API) manufacturer was ma
`
`ponse to a FACTS inspection request
`
`from HEB—322 regarding the manufacturing 0
`
`Metformin Hydrochloride, as well as a general GMP inspection of this facility.
`
`The previous FDA inspection of this site was conducted on 06/03407/2002 and was
`
`
`That
`
`inspection was a pre—approval
`
`classified as VAI.
`
`inspection for
`
`A,~,~d—sa_-_;_________ and Metformin Hydrochloride.
`six
`
`That
`
`inspection disclosed
`
`objectionable conditions in the areas of Materials, Production, and the Laborator
`
`Control systems.
`:tive
`
`The firm?s management committed to follow—up and implement corr
`
`actions as soon as possible.
`
`There was one objectionable condition noted during the current
`A~483
`
`inspection and a F
`
`

`

`26—FEB—2007
`2 of 3
`
`FDA CDER EES
`
`Page
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`was
`an
`
`issued.
`
`The observation was that although the Metfomin Hydrochloride API has
`
`expiry time of five years, effective 4/13/06,
`
`the firm had reduced the long term
`
`stability test duration from five years to three years.
`
`Based upon the results of the inspection,
`
`the firm should remain acceptable for t
`
`e
`
`manufacturing of Metformin Hydrochloride (API).
`
`DO RECOMMENDATION
`ADAMSS
`
`24—JAN—2007
`
`ACCEPTABLE
`
`OC RECOMMENDATION
`ADAMSS
`
`24—JAN—2007
`
`ADEQUATE FIRM RESPONSE
`
`INSPECTION
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`Establishment:
`
`CFN
`
`1036761
`
`FEI
`
`1036761
`
`MERCK AND CO INC
`
`4633 MERCK RD W
`
`WILSON, NC
`
`278939613
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`DRUG SUBSTANCE STABILITY TESTER
`
`Profile:
`
`CTL
`
`OAI Status:
`
`NONE
`
`FINISHED DOSAGE PACKAGER
`
`EMilestone Name
`
`Date
`
`' Type
`
`Insp. Date
`
`Decision & Reason
`
`C
`
`

`

`SUBMITTED To OC
`TRANS
`
`20—JUN—2006
`
`B.
`
`iECOMMENDATION
`IOJ
`
`20—JUN—2006
`
`ACCEPTABLE
`
`DA
`
`BASED ON PROFILE
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`EMilestone Name
`eator
`
`Date
`
`Decision & Reason
`
`SUBMITTED TO OC
`TRANS
`
`20—JUN—2006
`
`OC RECOMMENDATION
`BROGIOJ
`
`20—JUN—2006
`
`ACCEPTABLE
`
`DA
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN
`
`2650235
`
`FEI
`
`1000131917
`
`MERCK CO INC
`
`RD 2 KM 60.3 BO SAB HOYO
`
`ARECIBO,
`
`PR
`
`00688
`
`DMF NO:
`
`AADA:
`
`

`

`26—FEB—2007
`3 of 3
`
`FDA CDER EES
`
`'
`
`Page
`
`Rf onsibilities:
`
`FINISHED DOSAGE PACKAGER
`
`ESTABLISHMENT EVALUATION REQUEST
`
`DETAIL REPORT
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`EMilestone Name
`eator
`
`Date
`
`Type
`
`Insp. Date
`
`Decision & Reason
`
`.
`
`C
`
`SUBMITTED TO 00
`TRANS
`
`20—JUN—2006
`
`OC RECOMMENDATION
`BROGIOJ
`
`20—JUN—2006
`
`ACCEPTABLE
`
`DA
`
`BASED ON PROFILE
`
`Establishment:
`
`CFN
`
`2623436
`
`FEI
`
`2623436
`
`MERCK SHARP AND DOHME QUIMICA
`
`RD 2, KM 56.7
`
`BARCELONETA,
`
`PR
`
`00617
`
`DMF No:
`
`AADA:
`
`Responsibilities
`
`DRUG SUBSTANCE MANUFACTURER
`
`Profile:
`
`CSN
`
`OAI Status:
`
`NONE
`
`EMilestone Name
`eator
`
`Date
`
`Type
`
`Insp. Date
`
`Decision & Reason
`
`C
`
`SUBMITTED TO OC
`TRANS
`
`20—JUN—2006
`
`OC RECOMMENDATION
`BROGIOJ
`
`20—JUN-2006
`
`ACCEPTABLE
`
`DA
`
`BASED ON PROFILE
`
`

`

`Establishment:
`
`CFN
`
`FEI
`
`_——————
`
`V
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE MANUFACTURER
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`EMilestone Name
`eator
`
`Date
`
`Type
`
`Insp. Date
`
`Decision & Reason
`
`C
`
`SUBMITTED TO OC
`TRANS
`
`SUBMITTED TO DO
`BROGIOJ
`
`20—JUN—2006
`
`20—JUN-2006
`
`10D
`
`INSPECTION SCHEDULED
`MSOSA
`
`28—AUG—2006
`
`25—SEP—2006
`
`'EECTION PERFORMED
`DSA
`
`28—SEP42OO6
`
`28—SEP—2006
`
`DO RECOMMENDATION
`MSOSA
`
`O7—DEC—2006
`
`OC RECOMMENDATION
`RGUSONS
`
`O7—DEC—2006
`
`DA
`
`ACCEPTABLE
`
`INSPECTION
`
`ACCEPTABLE
`
`F
`
`DISTRICT RECOMMENDATION
`
`

`

`ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Xavier Ysern
`
`2/27/2007 03:29:38 PM
`CHEMIST
`
`Blair Fraser
`
`2/28/2007 05:52:58 AM
`CHEMIST
`
`