CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202270Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`NDA:202270
`Brand Name
`
`Generic Name
`
`Reviewer
`Team Leader (Acting)
`OCP Division
`OND Division
`Sponsor
`
`Relevant IND, NDA
`
`Submission Type
`
`Formulation; Strength(s)
`
`Indication
`
`Submission Date: August 02, 2011
`Janumet XR
`Sitagliptin/metformin HCl extended fixed dose
`combination (FDC) tablets
`Jee Eun Lee, Ph.D.
`Jayabharathi Vaidyanathan, Ph.D.
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`Merck Sharp Dohme
`IND 101,964; NDA 22-044 (Janumet®), NDA 21-
`748 (Glumetza®), NDA 21-995 (Januvia®)
`Resubmission NDA 505(b)(1)
`FDC products of sitagliptin/metformin XR at dose
`strengths 50 mg/500 mg, 50 mg/1000 mg, 100
`mg/1000 mg
`Treatment of Type 2 Diabetes Mellitus
`
`
`
`
` 1
`
` Executive Summary
`
`
`This 505(b)(1) application by Merck Sharp Dohme is in pursuit of approval for the fixed
`dose combination (FDC) 50 mg/500 mg, 50 mg/1000 mg, and 100 mg/1000 mg of
`sitagliptin/metformin extended release (MK-0431A XR, Janumet XR) tablets. For
`complete review of clinical pharmacology information from the original NDA, readers
`can refer to the original clinical pharmacology review of NDA 20-2770 in DAARTS
`dated 6/17/2011
`
`Prior to this resubmission, Merck received a complete response letter for the original
`NDA, 20-2270. Janumet XR contains sitagliptin and metformin XR and the registration
`of this product is based on demonstration of bioequivalence (BE) between Janumet XR
`(MK-0431A XR) and co-administration of sitagliptin and an approved metformin XR
`formulation (Glumetza®, NDA 21-748). In the complete response letter issued on July
`22, 2011, the sponsor was asked to submit the updated completed study report (CSR) for
`the pivotal BE study 147. This comment was based on the recommendation of office of
`
`
`
`Reference ID: 3052119
`
`1/5
`
`

`

`scientific investigation (OSI). Division of Bioequivalence and GLP Compliance (DBGC)
`of OSI issued FDA-483 at the bioanalytical laboratory,
`one which analyzed
`blood samples obtained from the pivotal BE study.
`we response to the Form
`FDA-483 was submitted on July 11, 2011, and reviewed by DBGC (see Dr. Gopa
`Biswas’ review dated to July 15, 2011). Deficiencies listed in the Form FDA-483 were
`resolved and consequently the bioanalytical data were updated. Therefore, the sponsor
`repeated the bioequivalence assessment with the reintegrated data and updated the CSR
`accordingly. This review is focused on the updated study results of the pivotal BE study.
`
`2 Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology-II (OCP/DCP—
`II) has reviewed the clinical pharmacology data submitted under NDA 202270
`resubmission dated 8/02/2011 and finds it acceptable to support approval.
`
`3 Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`The pivotal BE study compared the administration of Janumet XR to the co-
`administration of sitagliptin IR and GLUMETZA®, and also the administration of two
`tablets of 50 mg/500 mg and the administration of one tablet of 100 mg/1000 mg in terms
`of pharmacokinetic characteristics. This study was conducted with the final market
`composition (FMC) of Janumet )m tablets, demonstrated BE between the Janumet XR
`tablets for both 50 mg/500 mg and 100 mg/1000 mg strengths, and between the Janumet
`XR tablets
`and co-administration of corresponding doses of
`sitagliptin and
`GLUMETZA®. The treatment arms were:
`
`TRT A: sitagliptin 50 mg + GLUNIETZA® 500 mg
`TRT B: single Janumet XR 50 mg/500 mg tablet
`TRT C: sitagliptin 100 mg + GLUMETZA® 1000 mg
`
`TRT D: single Janumet XR 100 mg/1000 mg tablet
`TRT E: two tablets of Janumet XR 50 mg/500 mg
`
`The resulting data allows for the bridging of the existing safety and efficacy data from
`studies with JANUVIA® (sitagliptin), GLUMETZA® (metformin XR) and the
`combination of sitagliptin and metformin IR (from the JANUVIA® and JANUMET®
`programs) to Janumet XR GVIK-0431A XR).
`
`The sponsor repeated the pharmacokinetic analysis with the revised bioanalytical data
`and the summary statistics for metformin and sitagliptin was updated in the resubmission
`accordingly. The estimated values for PK parameters with revised data are very similar to
`the original estimates, rendering no change in the bioequivalence assessment results.
`As shown in the Tables 1 and 2 that the 90% confidence intervals (CIs) of the geometric
`least square mean ratios for the pharmacokinetic parameters (AUCM, and Cmax) for
`sitagliptin (Table 1) and metformin (Table 2) after administration of single tablet of
`
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`
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`
`

`

`Janumet XR 100 mg/1000 mg tablet and those after administration of sitagliptin 100 mg
`+ GLUMETZA® 1000 mg fell within the range of [0.80, 1.25]. The bioequivalence
`between FDC and co-administration of sitagliptin and Glumetza® has been established
`for two strength levels.
`
`Fmthermore, the BE between two tablets of FDC Janumet XR 50 mg/ 500 mg and one
`tablet of FDC Janumet XR 100 mg/1000 mg has been established in as seen in both
`tables. Likewise, the 90% CIs of the geometric least square mean ratios for AUCM, and
`Cmax of sitagliptin (Table 1) and metformin (Table 2) afier administration of single
`tablet of Janumet XR 100 mg/1000 mg tablet and those after administration of two tablets
`of Janumet XR 50 mg/500 mg fell within the range of [0.80, 1.25].
`
`Table 1. Summary statistics and statistical comparisons for the potency unadjusted plasma PK
`parameters of sitagliptin after administration of a single Janumet XR 100 mg/1000 mg tablet, co—
`administration of corresponding doses of sitagliptin and metformin XR (Glumetza®) in healthy adult
`sub'ects
`
`—__E_E-_
`
`3883, 4161
`
`3849, 4178
`
`7461, 8098
`
`7521, 8166
`
`7520, 8164
`
`Cmax (ng/mL)
`
`3736, 4057
`356
`333 381
`Between-TreahnentC um. .
`'
`
`3758, 4082
`342
`320, 36.
`
`7357, 7989
`778
`727,832
`
`7415. 8054
`780
`728 835
`
`77407, 8044
`76978, 800
`
`
`
`. *n mL
`AUCM,
`AUCW . *n mL
`
`1.00(0.99, 1.02)
`1.01 099,102
`0.96 092,101
`GM: Geometric Meat: CI: Confidence Interval
`
`1.01 (0.99, 1.03)
`1.01 099,102
`1.00 0.96, 1.05
`
`1.00(0.98, 1.02)
`1.00 098,102
`0.96 092,100
`
`Table 2. Summary statistics and statistical comparisons for the potency unadjusted plasma PK
`parameters of metformin after administration of a single Janumet XR 100 mg11000 mg tablet, co—
`administration of corresponding doses of sitagliptin and metformin XR(G1umetza®) in healthy adult
`subjects
`
`_——___
`
`AUCoJ.
`1 *n mL
`
`6614
`(6090, 7184)
`
`7045
`(6492, 7645)
`
`12458
`(11493, 13504)
`
`11963
`(11017, 12990)
`
`12286
`(11339, 13312)
`
`n *n- mL
`
`6093. 7084
`
`6374, 7412
`
`11304, 13139
`
`10976 12772
`
`1113312946
`
`526, 596
`
`570, 646
`
`813, 922
`
`925,105]
`
`937, 1064
`
`Between-Treounentc mm '
`
`Reference ID: 30521 19
`
`3/5
`
`

`

`
`
`AUC04.
`
`1.07 (1.01, 1.13)
`
`0.96 (0.91. 1.01)
`
`1.03 (0.97. 1.08)
`
`
`
`1.08 1031.14
`GM: Geometric Mean; CI: Confidence Interval
`
`1.14 1.09.1.19
`
`1.01 097 106
`
`1.05 (1.00. 1.09)
`
`0.97 (0.93. 1.02)
`
`1.01 (0.97. 1.06)
`
`Reviewer’s Comments:
`
`The key results from the revised data indicate that co-administration of sitagliptin and
`GLUMETZA® and administration of Janumet XR are bioequivalent, and the Janumet
`XR tablets for both 50 mg/SOO mg and 100 mg/ 1000 mg strengths are bioequivalent for
`both sitagliptin and metformin XR components. The results obtained from reviewer’s
`independent analysis with raw data provided by the sponsor are in agreement with the
`sponsor’s results. The conclusions made from the original submission regarding BE
`assessment have not changed by revised bioanalytical data.
`
`Appendix: Synopsis Summary of Pivotal BE Study (Protocol 147)
`
`Title: A Definitive Bioequivalence Study for Sitagliptin/Metformin XR FDC Tablets in
`Healthy Subjects
`
`Objectives
`
`Primary:
`0 To demonstrate bioequivalence between the final market
`composition (FMC) sitagliptin/metformin (Janumet) extended
`release (XR) 50 mg/500 mg tablet and co—administration of
`corresponding doses of sitagliptin and Glumetza as individual
`tablets
`
`Form
`
`To demonstrate bioequivalence between the FMC Janumet XR
`100 mg/ 1000 mg tablet and co-administration of corresponding
`doses of sitagliptin and Glumetza as individual tablets
`To demonstrate bioequivalence between two FMC Janumet XR
`50 mg/SOO mg tablets and a single FMC Janlnnet XR 100
`mg/1000 mg tablet
`
`O en-label, randomized, five- eriod crossover
`
`Study
`u o ulation
`
`Forty-eight (male 28, female 20, age 18—45 years) enrolled and 39
`sub'ects com o leted.
`
`drug
`
`#
`
`Reference ID: 30521 19
`
`4/5
`
`

`

`100 ..- 1000 m WL00034323
`
`FDC tablet WL00034976
`
`*Sitagliptin was the sponsor’s approved product. Januvia®
`**Glumetza® (a registered product of Depomed Inc) required for the study was
`purchased by the sponsor
`T n=2 for Janumet XR tablet: n=10 for Glumetza; n=72 for lOO-mg sitagliptin tablet
`and n=l 68 for 50-mg sitagliptin tablet
`
`Treatments
`
`' 5
`
`—-_ FDC MK-0431 AXR
`—-_—
`——-1!__
`—--—
`——-_'13_-
`—— 2x 50m-n-soo
`
`
`PK
`Assessment
`
`PK parameters such as AUCom, AUCMm, Cmax, Tmax and apparent
`terminal half-life for sitagliptin and metfonnin after administration of a
`single Janumet XR 50 mg/SOO mg or 100 mg/1000 mg tablet, co—
`administration of corresponding doses of sitagliptin and Glumetza as
`individual tablets, and two Janumet XR 50 mg/500 mg tablets were
`
`Safety
`Assessment
`
`The safety and tolerability afier administration of each treatment were
`assessed by clinical
`evaluation,
`including Vital
`signs, physical
`examination, ECGs, and stande laboratory safety tests (hematology,
`chemis
`, and urinal
`
`Reference ID: 30521 19
`
`/5
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEE E LEE
`11/30/2011
`
`JAYABHARATHI VAIDYANATHAN
`11/30/2011
`
`Reference ID: 3052119
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA:202270
`Brand Name
`
`Generic Name
`
`Reviewer
`Team Leader (Acting)
`OCP Division
`OND Division
`Sponsor
`
`Relevant IND, NDA
`
`Submission Type
`
`Formulation; Strength(s)
`
`Indication
`
`Submission Date: September 23, 2010
`Janumet XR
`Sitagliptin/metformin HCl extended fixed dose
`combination (FDC) tablets
`Jee Eun Lee, Ph.D.
`Jayabharathi Vaidyanathan, Ph.D.
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`Merck Sharp Dohme
`IND 101,964; NDA 22-044 (Janumet®), NDA 21-
`748 (Glumetza®), NDA 21-995 (Januvia®)
`Original NDA 505(b)(2)
`FDC products of sitagliptin/metformin XR at dose
`strengths 50 mg/500 mg, 50 mg/1000 mg, 100
`mg/1000 mg
`Glycemic Control for Type 2 Diabetes Mellitus
`
`
`
`
`
`
`
`Table of Contents
`
`
`
` 1
`
`EXECUTIVE SUMMARY.......................................................................3
`
`Recommendation ............................................................................................... 3
`1.1
`Phase IV Commitments .................................................................................... 3
`1.2
`Summary of Important Clinical Pharmacology and Biopharmaceutics
`1.3
`Findings......................................................................................................................... 3
`
`2
`2.1
`
`
`
`Reference ID: 2962437
`
`QUESTION BASED REVIEW.................................................................6
`General Attributes............................................................................................. 6
`
`1/43
`
`

`

`2.1.1 What are highlights of the chemistry and physicochemical properties of the drug
`substance and the formulation of the drug product as they relate to clinical pharmacology
`and biopharmaceutics review?.................................................................................................. 7
`2.1.2 What pertinent regulatory background or history contributes to the current assessment of
`the clinical pharmacology and Biopharmaceutics of the drug? ............................................. 7
`2.1.3 What is the proposed indication and route of administration?.............................................. 8
`Is there any DSI inspection requested for any of the clinical studies?................................... 8
`2.1.4
`2.2
`General Clinical Pharmacology ....................................................................... 9
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?.......................................................................................................... 9
`2.2.2 What is the pharmacokinetic characteristics of the FDC and the comparison results of the
`BE? ............................................................................................................................................ 10
`2.2.3 What is the pediatric plan for NDA 202270?......................................................................... 12
`2.2.4 What are the characteristics of multiple-dose PK?............................................................... 12
`2.3
`Intrinsic factors................................................................................................ 12
`2.3.1 What intrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety response?........................................................ 12
`Extrinsic factors............................................................................................... 12
`2.4
`2.4.1 What extrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety responses? ...................................................... 12
`General Biopharmaceutics ............................................................................. 14
`2.5
`2.5.1 What is the impact of fixed dose combination formulation on systemic exposure of
`sitagliptin and metformin? ...................................................................................................... 14
`2.5.2 What are the batch size of the FDC formulation in the pivotal BE study?......................... 15
`2.5.3 What are the dose dumping potential of FDC product?....................................................... 15
`2.6
`Analytical Section ............................................................................................ 15
`2.6.1 How are the active moieties identified and measured in the plasma/serum?...................... 15
`2.6.2 What bioanalytical methods are used to assess concentrations?.......................................... 15
`
`3
`
`LABELING ...........................................................................................16
`
`APPENDIX............................................................................................16
`4
`Individual Clinical Study Review................................................................... 16
`4.1
`Pivotal BE Study: Protocol 147............................................................................................... 16
`4.1.1
`Food Effect Study: Protocol 164 ............................................................................................. 21
`4.1.2
`4.1.3 Multiple-Dose Study: Protocol 165......................................................................................... 27
`4.1.4 Low Dose Probe Formulation Biocomparison Study: Protocol 112 .................................... 28
`4.1.5 Drug Interaction between Metformin XR and Sitagliptin: Protocol 012............................ 31
`4.1.6
`Phase I Mechanism-of-Action Study in Healthy Subjects: Protocol 050............................. 32
`4.1.7
`Phase I PD study in T2DM Patients: Protocol 110................................................................ 36
`4.2
`Cover Sheet and OCP Filing .......................................................................... 40
`
`
`
`
`
`Reference ID: 2962437
`
`2/43
`
`

`

`1 Executive Summary
`
`Merck Sharp Dohme submitted the NDA 20-2270 for Janumet XR (MK-0431A XR) as a
`fixed-dose combination (FDC) product, which contains sitagliptin and metformin XR.
`The sponsor is in pursuit of registration of this product based on 505(b)(2) application by
`demonstration of bioequivalence between Janumet XR (MK-0431A XR) and co-
`administration of sitagliptin and an approved metformin XR formulation (Glumetza®,
`NDA 21-748).
`
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology-II (OCP/DCP-
`II) has reviewed the clinical pharmacology data submitted under NDA 202270 dated
`9/23/2010 and finds it acceptable.
`
`
`1.2 Phase IV Commitments
`
`None
`
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`
`This 505(b)(2) application by Merck Sharp Dohme is in pursuit of approval for the fixed
`dose combination (FDC) 50 mg/500 mg, 50 mg/1000 mg, and 100 mg/1000 mg of
`sitagliptin/metformin extended release (MK-0431A XR, Janumet XR) tablets.
`
`Pivotal Bioequivalence (BE)
`
`The pivotal BE study compared Janumet XR to co-administration of sitagliptin IR and
`GLUMETZA®, and also the administration of two tablets of 50 mg/500 mg and the
`administration of one tablet of 100 mg/1000 mg as per the Agency recommendation via
`comments on the questions submitted in EOP2 meeting package on October 31, 2008
`(See Dr. Sang Chung’s review dated February 18, 2009). This study was conducted with
`the final market composition (FMC) of Janumet XR tablets, demonstrated BE between
`the Janumet XR tablets for both 50 mg/500 mg and 100 mg/1000 mg strengths, and
`between the Janumet XR tablets and co-administration of corresponding doses of
`sitagliptin and GLUMETZA®. The treatment arms were:
`
`
` TRT A: sitagliptin 50 mg + GLUMETZA® 500 mg
` TRT B: single Janumet XR 50 mg/500 mg tablet
` TRT C: sitagliptin 100 mg + GLUMETZA® 1000 mg
` TRT D: single Janumet XR 100 mg/1000 mg tablet
` TRT E: two tablets of Janumet XR 50 mg/500 mg
`
`
`
`
`
`
`
`
`Reference ID: 2962437
`
`3/43
`
`

`

`The resulting data allows for the bridging of the existing safety and efficacy data from
`studies with JANUVIA® (sitagliptin), GLUMETZA® (metfonnin XR) and the
`combination of sitagliptin and metformin 1R (from the JANUVIA® and JANUMET®
`programs) to Janumet XR (MK-0431A XR).
`
`The key results indicate that that co-administration of sitagliptin and GLUMETZA® and
`administration of Janumet XR are bioequivalent, and the Janumet XR tablets for both 50
`mg/500 mg and 100 mg/ 1000 mg strengths are bioequivalent for both sitagliptin and
`metformin XR components (See Figures 1 and 2)
`
`Sitagliptin Cmax -
`
`Sitagliptin AUC—
`
`Metformin Cmax ‘
`
`I +
`
`Metformin AUC —
`
`I
`0.7
`
`T
`0.8
`
`I
`0.9
`
`1.0
`
`I
`1.1
`
`'
`
`I
`1.2
`
`I
`1.3
`
`Figure 1. Forest plot for the geometric least square mean ratio for PK parameters comparing em
`administration of sitagliptin and GLUMETZA® and administration of Janumet XR
`
`Reference ID: 2962437
`
`4/43
`
`

`

`Sitagliptin Cmax -
`
`Sitagliptin AUC '
`
`Metformin Cmax —
`
`Metformin AUC —
`
`I
`0.7
`
`I
`0.8
`
`I
`0.9
`
`1.0
`
`I
`1.1
`
`'
`
`I
`1.2
`
`I
`1.3
`
`Figure 2. Forest plot for the geometric least square mean ratio for PK parameters comparing two
`tablets of 50 mg/500 mg and one tablet of 100 mg11000 mg of Janumet XR
`
`Food Effect
`
`The
`
`food effect was
`
`evaluated for both Janumet® and Janumet XR. The
`
`pharmacokinetics O’K) of sitagliptin and metformin from Janumet® and Janumet XR
`was evaluated when given with or without high—fat diet. The treatment arms were:
`
`TRT A: Two tablets Janumet XR 50 mg/1000 mg fasted
`TRT B: Two tablets Janumet H 50 mg/ 1000 mg afler high—fat breakfast
`TRT C: Two tablets JANUMET® 50 mg/1000 mg fasted
`TRT D: Two tablets JANUMET® 50 mg/ 1000 mg after high-fat breakfast
`
`The results indicated that there was a significant food effect on metformin PK following
`administration of Janumet XR. After administration of 2 Janumet XR 50 mg/1000 mg
`tablets after consumption of a high-fat breakfast, the AUC04,o for metformin increased by
`62% compared to that under the fasted state. The AUCM, and Cmax for sitagliptin and
`the Cmax for metformin decreased by approximately 6%, 17%, and 9%, respectively, as
`compared to that under
`the fasted state. The observed effect of food on the
`phannacokinetics of metformin was generally consistent with the effect of food for
`marketed metformin XR formulations (e.g., GLUCOPHAGE® XR: fed state metformin
`AUC increased by 50%, no food effect on Cmax). After administration of two tablets of
`Janumet® 50 mg/1000 mg afier consumption of a high-fat breakfast, the AUCOm and
`Cmax for sitagliptin increased by approximately 6%, and 12%, respectively, compared
`with fasted state. The AUC04, and Cmax for metformin decreased by approximately 6%,
`
`Reference ID: 2962437
`
`5/43
`
`

`

`and 28%, respectively, compared with fasted state. The observed effect of food on the
`pharmacokinetics of metformin was somewhat less than the effect of food for marketed
`metformin IR formulations (e.g., GLUCOPHAGE®, AUC decreased by 25%, Cmax
`decreased by 40% with food, and 35 minutes prolongation of time to peak plasma
`concentration following 850 mg metformin).
`
`
`
` Question Based Review
`
` 2
`
`
`
`2.1 General Attributes
`
`The sponsor submitted the NDA 20-2270 for Janumet XR (MK-0431A XR) as a fixed-
`dose combination (FDC) product, which contains sitagliptin and metformin XR. The
`sponsor is in pursuit of registration of this product based on 505(b)(2) application by
`demonstration of bioequivalence between Janumet XR (MK-0431A XR) and co-
`administration of sitagliptin and an approved metformin XR formulation (Glumetza®,
`NDA 21-748). The safety and efficacy data from studies with sitagliptin (Januvia®, NDA
`21-995), metformin XR (Janumet®, NDA 22-044), and the combination of sitagliptin and
`metformin IR (from the JANUVIA® and Janumet® programs) are utilized to bridge to
`those of Janumet XR (MK-0431A XR).
`Janumet® (MK-0431A) was approved as a fixed dose combination (FDC) tablet that
`contains sitagliptin and metformin IR for glycemic control in T2DM. It is administered
`twice a day because of IR formulation of metformin was used for the FDC. The sponsor
`developed Janumet XR formulation, which replaces metformin IR with metformin XR
`enabling once a day dosing regimen.
`Janumet® was approved based on bridging with a Canadian metformin IR,
` was bridged with Glucophage IR in ANDA 75984)
`
`
`
`
`Metformin: Metformin is a biguanide. There are several metformin products approved
`and marketed as follows:
`– Glucophage (metformin IR, BMS)
`– Glucophage XR (metformin XR, BMS)
`– Glumetza (metformin XR, Depomed)
`– Fortamet (metformin ER, Andrx labs)
`– Riomet (solution, Ranbaxy)
`
`
`The following FDC tablets containing metformin have been approved:
`– ActoPlus Met (pioglitazone/metformin, Takeda)
`– ActoPlus Met XR (pioglitazone/metformin ER, Takeda)
`– Glucovance (glyburide/metformin, BMS)
`– Metaglip (glipizide/metformin, BMS)
`– Avandamet (rosiglitazone/metformin, SB PHARMCO)
`– Janumet (sitagliptin/metformin, Merck)
`– Prandimet (repaglinide/metformin, Novo Nordisk)
`
`
`
`Reference ID: 2962437
`
`6/43
`
`(b) (4)
`
`(b) (4)
`
`

`

`Sitagliptin: This is the first compound as a DPP-4 inhibitor. The sponsor’s sitagliptin
`product, JANUVIA® (NDA 21—995) was approved in 2006.
`
`2.1.1 What are highlights of the chemistry and physicochemical properties of the
`drug substance and the formulation of the drug product as they relate to
`
`clinical pharmacology and biopharmaceutics review?
`
`Formulation: Janumet XR tablets are fihn coated tablets containing an immediate release
`dose of sitagliptin phosphate and an extended release dose of metfonnin hydrochloride
`(core) for once daily use (Figure l). The FDC formulation can be separated into three
`main components as follows:
`
`1. A matrix release tablet (MRT) core that provides an extended release (ER) profile
`of metformin hydrochloride.
`2. A sitagliptin active coating over the MRT core designed to provide immediate
`release of sitagliptin.
`3. A polymeric film coating over the active coating to provide taste masking and
`product differentiation by color.
`
` J
`
`/
`
`Polymer“- film rooting {or
`
`(II) (4)
`
`Figure 3. Schematic representation of Janumet XR tablets
`
`2.1.2 What pertinent regulatory background or history contributes to the current
`assessment of the clinical pharmacology and Biopharmaceutics of the drug?
`
`While the sponsor owns an approved product of sitagliptin IR (Januvia®), they do not
`have their own approved product for metfonnin XR formulation. Thus the performance
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`of the metformin XR incorporated in the FDC is compared to an approved metformin XR
`product, Glmnetza® in the pivotal BE study.
`
`Figure 2 shows the bridging information for metfonnin XR component. NDA 22044
`(Janumet®) was approved based on bridging with a Canadian metformin IR
`one)
`which was approved based on bridging with Glucophage IR (ANDA 75984). The bridge
`between metformin IR (Glucophage®) and metformin XR is supported by NDA 21748
`(Glumetza®).
`
`Januvia
`(silaglipt'n IR)
`
`m4)
`mdbmin IR
`
`Janumet® was approved based
`On Phase 3 bridging with a
`Canadian metformin IR
`
`.
`
`NDA 22-044
`
`(5) (4)
`
`vs. Glucophage IR
`
`ANDA75984
`
`Metformin product
`
`(sitaglipt'n IR)
`
`mafomlin XR
`
`Glumetza vs. Glucophase IR
`NDA 21-748
`
`Merck does not own approved
`
`Figure 4. Bridging history for relevant formulations
`
`2.1.3 What is the proposed indication and route of administration?
`
`The proposed indication for the FDC formulations is to improve glycemic control in type
`2 diabetes mellitus patients.
`
`2.1.4
`
`Is there any DSI inspection requested for any of the clinical studies?
`
`Yes. The Division of Scientific Investigation’s inspection was requested for the pivotal
`BE study (P147). The clinical site inspection indicated that the study was conducted
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`following Good Clinical Practice. The final report from DSI regarding pivotal BE study
`is still pending.
`
`2.2 General Clinical Pharmacology
`
`
`2.2.1 What are the design features of the clinical pharmacology and clinical
`studies used to support dosing or claims?
`
`
`The safety and efficacy of the FDC product (Janumet®), is supported by Phase 3 clinical
`trials that were submitted under NDA 22-044, where sitagliptin and metformin IR was
`found to be safe and efficacious when co-administered. FDC tablets of sitagliptin with
`metformin XR have been developed in three different dose strengths (50/500 mg to be
`given as 2 tablets, 50/1000 mg to be given as 2 tablets, and 100/1000 mg to be given as 1
`tablet) to allow once-daily (QD) dosing of sitagliptin with metformin.
`
`The clinical pharmacology program includes a pivotal BE study that demonstrates BE
`between MK-0341 XR and co-administration of sitagliptin and an approved metformin
`XR product (GLUMETZA®). In the study, BE between two tablets of 50 mg/500 mg and
`one tablet of 100 mg/1000 mg was demonstrated as well. A biowaiver for the 50 mg/1000
`mg tablet was requested. The biopharmaceutics reviewer has found the biowaiver request
`acceptable and agreed for the dissolution specification (See Dr. Sandra Suarez’s review).
`
`The submission also includes a food effect study where the in vivo performance of MK-
`0431 XR with and without high-fat breakfast was compared. This study also compares
`the PK of JANUMET® IR 50 mg/1000 mg and JANUMET® XR 50 mg/1000 mg under
`either fasted or fed condition.
`
`Eight Clinical Pharmacology studies, including four biopharmaceutics studies (P112,
`P163, P164, and P147), two pharmacokinetic studies (P012 and P165), and two
`pharmacodynamic studies (P050 and P 110) were submitted to support the application.
`A list of completed clinical pharmacology is provided in the Table 1 below and the
`summary of the studies are provided in the appendix.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`9
`
`A Sitagliptin-Metformin Drug Interaction Study
`A Multiple-Dose Safety. Tolerability and Pharmacokinetic Study
`
`Clinical P11armacology/Pharmacokinetic Studies _
`PharmacodvnamicStudies
`=
`
`Table 1. Clinical Pharmacology Studies Supporting NDA 202270
`
`Study Type
`
`Protocol Number
`
`Biopbarmaceutics Studies
`
`A Low—Dose Probe Formulation Biocomparison Study
`A Hi - h-Dose Probe Formulation Biocom narison Study?
`A Food-Effect Study
`A Definitive Bioequivalence Study
`
`112
`163
`
`A Mechanism-of—Action Study1n Healthy Subjects
`A Mechanism-of—Action Study in Treatment-Nat“ Patients with TEDM‘
`Studies where MK—043 1A XR was administered
`Studies where metformin IR was administered
`
`2.2.2 What is the pharmacokinetic characteristics of the FDC and the comparison
`results of the BE?
`
`Pivotal BE study @3147) characterized the single dose PK of sitagliptin and metformin
`following administration of 50 mg/500 mg or 100 mg/1000 mg of Janumet XR in healthy
`subjects. As shown in the Table 2 that the 90% CIs of the geometric mean ratios for the
`pharmacokinetic parameters (AUCM and Cmax) for sitagliptin and metformin after
`administration of single tablet of Janumet XR 100 mg/1000 mg tablet and those after
`administration of sitagliptin 100 mg + GLUMETZA® 1000 mg fell within the range of
`[0.80, 1.25]. The bioequivalence between FDC and co-administration of sitagliptin and
`Glumetza® has been established for two strength levels (details are are provided in
`Appendix).
`
`Table 2. Summary statistics and statistical comparisons for the plasma PK parameters of sitagliptin
`after administration of a single Janumet XR 100 mg/1000 mg tablet, co—administration of
`ondin_ doses of sita_ ‘ utill and metformin XR Glumetza® in health adult sub 'ects
`
` AUCM u *n- mL
`
`7766 (7449, 8097)
`
`7831 (7511, 8166)
`
`1.01 (0.99, 1.03)
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`
`AUCW (hr*ng/mL)
`7661 (7346, 7989)
`7721 (7403, 8052)
`1.01 (0.99, 1.02)
`
`Cmax (ng/mL)
`778 (727, 833)
`778 (727, 834)
`1.00 (0.95, 1.05)
`Tmax
`201070
`3010 50
`12.3 2.8
`12.2 3.1 —
`
`1.15 (1.08 1.22)
`
`. *n mL
`AUCOJ,
`AUCM“, (hr*ng/mL)
`Cmax (ng/mL)
`Tmax (hr)
`
`12490(11540, 13519)
`12194 (11305, 13 152)
`868 (815, 924)
`10.0 (5.0, 16.0)
`
`Apparent tm (hr **
`
`12.2
`
`12009 (11077, 13019)
`1 1845 (10976, 12783)
`988 (927, 1052)
`7.0 (4.0, 12.0)
`
`12.0 (6.8)
`
`0.97(0.91,1.02)
`0.97 (0.94, 1.01)
`
`Furthermore, the BE between two tablets of FDC Janumet XR 50 mg/ 500 mg and one
`tablet of FDC Janumet XR 100 mg/1000 mg has been established in this pivotal BE
`study. Likewise, The 90% CIs of the geometric least square mean ratios for the
`pharmacokinetic parameters (AUCM, and Cmax) for sitagliptin and metformin after
`administration of single tablet of Janumet XR 100 mg/ 1000 mg tablet and those after
`administration of two tablets of Janumet XR 50 mg/500 mg fell within the range of [0.80,
`1.25] (Table 3).
`
`Table 3. Summary statistics and statistical comparisons for the plasma PK parameters of sitagliptin
`after administration of two Janumet XR 50 mg/500 mg tablets, or one Janumet XR 100 mgl1000 mg
`tablet in health adult sub'ects
`Pharmacokinetic
`
`parameters
`
`Two tablet of Janumet One tablet of Janumet Test/Ref Ratio
`“song/500mg
`xnioo mylooomg
`(90%Cl)
`est
`reference
`
`AUCM . *1] mL
`AUCW . *11 mL
`
`7828 (7508,8162)
`7712 7395. 8042
`746 697. 799
`3.0 1.06.0
`12.2 3.1
`
`1.00(0.98,1.02)
`7831(7511,8166)
`1.00 0.98.1.02
`7721 7403,8052
`0.96 0.92.1.00
`778 727.834
`3.0 1.0, 5.0 —
`12.2 3.1 —
`
`
`
`m—
`m—n—m—
`
`Reviewer’s Comments: The resulting data allows bridging of the existing safety and
`efficacy data from studies with JANUVIA® (sitagliptin), GLUIVIETZA® (metformin
`XR) and the combination of sitagliptin and metformin IR (from the JANUVIA® and
`JANUMET® programs) to Janumet XR. The key results of the pivotal pharmacokinetic
`BE study showed that co-administration of sitagliptin and GLUMETZA® and
`administration of Janumet XR are equivalent for both dose levels tested.
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`2.2.3 What is the pediatric plan for NBA 202270?
`
`The sponsor will have a pediatn'c post-marketing requirement (PMR) to evaluate dosing,
`safety, and eflicacy of sitagliptin/metformin XR in pediatiic atients 10 through 17 years
`(inclusive) of age with T2DM. This PNIR will include one
`clinical trial and a
`single dose PK study. (1) A -, randomized, double-blind placebo-controlled trial
`to evaluate the efficacy and safety of Janumet XR vs. metformin—
`in pediatric patients who are inadequately controlled. As
`art of this
`the swallowabili
`
`of the formulation will be evaluated.
`
`stud ,
`
`
`
`17 years
`Janumet XR m pe atrlc patlents 10 throu
`p armaco
`et1c stu y o
`(inclusive) of age with T2DM. As part of this study the sponsor will e