CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`200678Orig1s000
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`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`Addendum to the Clinical Pharmacology Review Dated October 15, 2010
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`NDA: 200678
`Brand Name
`Generic Name
`
`Reviewer
`Team Leader
`OCP Division
`OND division
`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
`
`Proposed Indication
`
`Submission Date(s): 12/29/2009
`Kombiglyze XR
`saxagliptin/metformin HCl extended release fixed dose combination
`(FDC) tablets
`Ritesh Jain, Ph.D.
`Sally Choe, Ph.D.
`Clinical Pharmacology- II
`Metabolism and Endocrinology Products
`Bristol Myers Squibb
`Original NDA 505(b)(1); Standard
`FDC product of saxagliptin/metformin XR at dose strengths
`5 mg/500 mg, 2.5 mg/1000 mg, and 5 mg/1000 mg
`As an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus when treatment with both saxagliptin and
`metformin is appropriate.
`
`
`BACKGROUND:
`NDA 200678 was submitted to seek a marketing approval for Kombiglyze XR (FDC) 5
`mg/500 mg, 2.5 mg/1000 mg, and 5 mg/1000 mg of saxagliptin/metformin hydrochloride
`extended-release tablets. The Clinical Pharmacology review for this NDA was DARRTed
`on October 15, 2010. In this review, under the Summary of Important Clinical
`Pharmacology Findings section, this reviewer mentioned that the proposed FDC product
`was not studied in the Phase 3 trials. Thus, pivotal BE studies provided the link between
`the formulations utilized in Phase 3 trials and the proposed to-be-marketed formulation.
`This addendum to Clinical Pharmacology review dated October 15, 2010 clarifies the
`link between the Kombiglyze XR and the formulations used in Phase 3 clinical trials.
`There were no long term clinical efficacy or safety studies conducted with either
`Kombiglyze XR or metformin hydrochloride XR co-administered with saxagliptin with
`this NDA. The following studies were submitted in support of this NDA:
`• Long term Phase 3 safety and efficacy trials conducted (typically 24-52 week
`long) with metformin hydrochloride immediate-release formulation (Glucophage
`IR) co-administered with saxagliptin under NDA 22350.
`• 4-week, multi-center, randomized, double-blind, placebo-controlled, Phase 3b
`trial (CV181066) conducted with metformin hydrochloride extended-release
`formulation (Glucophage XR) co-administered with saxagliptin under this NDA.
`• Bioequivalence study, CV181111 and CV181112 comparing the rate and extent
`of absorption of saxagliptin and metformin hydrochloride when administered as
`Kombiglyze XR or saxagliptin and metformin hydrochloride XR tablets
`administered together.
`
`
`The duration of 4-week trial (CV181066) mentioned above is not sufficient to evaluate
`the efficacy and safety of metformin hydrochloride extended-release formulation
`(Glucophage XR) co-administered with saxagliptin.
`
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`Reference ID: 2860142
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`

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`Reviewer’s Findings on Pharmacokinetic Link between Glucophage IR vs.
`Glucophage XR:
`Glucophage XR is approved under NDA 21202. In NDA 21202, the steady state
`pharmacokinetics of 4 doses of Glucophage XR was evaluated in study CV138-028. In
`this study, sixteen healthy volunteers were dosed with 500 mg Glucophage XR (referred
`as biphasic in Table 1) as single dose and PK samples were taken. Subjects then received
`nightly doses of 500 mg Glucophage XR for a week and PK samples were again obtained
`after a week of dosing. The 500 mg dose of Glucophage XR increments continued each
`week up to 2000 mg QD. In this study, subjects also received 2 x 500 mg BID
`Glucophage IR tablets for one week to provide comparative PK parameters between
`Glucophage XR and Glucophage IR. The results of the study are summarized in Table 1.
`
`At steady state, the peak plasma concentrations for Glucophage XR (1000 mg QD
`biphasic) were approximately 20% lower compared to the same dose of Glucophage IR
`(1000 mg BID Glucophage). However, the extent of absorption of Glucophage XR (2000
`mg QD biphasic, as measured by AUC) is similar to Glucophage IR (1000 mg BID
`Glucophage) (Table 1).
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`Table 1: Steady State Pharmacokinetics of Glucophage XR *
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` Source: NDA 21202 review by Dr Robert M. Shore
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`The formal PK comparison between the Glucophage XR 2000 mg QD and Glucophage
`IR 1000 mg BID is shown in Table 2. Results from the comparison demonstrated that
`the extent of absorption of Glucophage XR (as measured by AUC) is similar to that of
`Glucophage IR (Table 2).
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`Table 2: Pharmacokinetic Comparison of Glucophage XR 2000 mg QD and Glucophage
`IR 1000 mg BID*.
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` Source: NDA 21202 review by Dr Robert M. Shore
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`Reference ID: 2860142
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`Reviewer’s Findings on Safety and Efficacy Link between Glucophage IR vs.
`Glucophage XR:
`Phase 3 clinical trials in NDA 21202 demonstrated the safety and efficacy of Glucophage
`XR. The efficacy and safety of Glucophage XR was established in a 12-week, double-
`blind, randomized, placebo-controlled trial (CV138010) (Table 3).
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`Table 3: Change in HbA1C at week 12 and 24 week following administration of
`Glucophage XR*.
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`* Source: NDA 21202 review by Dr Robert Misbin
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`The results from another Phase 3 trial (Study 138036) under NDA 21202, a 16-week,
`double-blind, placebo-controlled, dose-response study of Glucophage XR, taken once
`daily with the evening meal or twice daily with meals, in patients with type 2 diabetes
`clearly demonstrated a dose response with increasing dose of Glucophage XR (Table 4).
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`Table 4: Summary of Mean Changes from Baseline in HbA1c, Fasting Plasma Glucose,
`and Body Weight at Final Visit (16 week study)*
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`* Source: Glucophage XR product label
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`Reference ID: 2860142
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`In NDA 21202, the sponsor had a Phase 3 trial (Study 138012) comparing metformin
`Glucophage IR to metformin Glucophage XR. The study was a double blind trial to
`compare two doses of Glucophage XR (1000 mg and 1500 mg) given once daily to
`Glucophage IR 500 mg BID in patients who had already been taking Glucophage IR 500
`mg twice daily for at least 8 weeks. The results from the trial are shown in Table 5.
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`Table 5: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose,
`and Body Weight at Week 12 and at Final Visit (24-week study) ‡
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`‡ Source: Glucophage XR product label
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`Thus, NDA 21202 demonstrated the comparable bioavailability between Glucophage XR
`and Glucophage IR. The differences in Cmax between the two formulations did not appear
`to result marked differences in efficacy based on a clinical trial in which patients with
`T2DM receiving Glucophage IR were either maintained on this regimen or switched to
`Glucophage XR.
`
`Reviewer’s Findings on pivotal BE studies CV181111 and CV181112 submitted
`under NDA 200678:
`Bioequivalence trials, CV181111 and CV181112, comparing Kombiglyze XR to the
`individual components metformin hydrochloride XR and saxagliptin co-administered
`together demonstrated that there is no formulation effect.
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`Reference ID: 2860142
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`CONCLUSIONS:
`NDA 21202 demonstrated the comparable bioavailability between Glucophage XR and
`Glucophage IR. The differences in Cmax between the two formulations did not appear to
`result marked differences in efficacy based on a clinical trial in which patients with
`T2DM receiving Glucophage IR were either maintained on this regimen or switched to
`Glucophage XR. Also, the current product label of GLUCOPHAGE XR states that “In
`a randomized trial, patients currently treated with GLUCOPHAGE were switched
`to GLUCOPHAGE XR. Results of this trial suggest that patients receiving
`GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once
`daily at the same total daily dose, up to 2000 mg once daily”
`
`Figure 1 summarizes the bridging between the metformin extended-release and the
`metformin IR, which was co-administered with saxagliptin in the long term Phase 3
`safety and efficacy trials in support of NDA 200678. In addition, the sponsor conducted
`BE studies comparing metformin XR and saxagliptin co-administered together to the
`FDC combination product and demonstrated that there was no formulation effect
`bridging the individual saxagliptin and metformin extended-release to Kombiglyze XR.
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`Figure 1: Link between FDC product (Kombiglyze XR) and metformin IR and
`saxagliptin co-administration used in the Phase 3 trials.
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`Phase 3 Trial (under NDA 22350)Phase 3 Trial (under NDA 22350)
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`Metformin IR + Saxagliptin (Co-administration)Metformin IR + Saxagliptin (Co-administration)
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`Link from clinical study suggesting
`Link from clinical study suggesting
`patients receiving GLUCOPHAGE
`patients receiving GLUCOPHAGE
`treatment may be safely switched to
`treatment may be safely switched to
`GLUCOPHAGE XR once daily at the
`GLUCOPHAGE XR once daily at the
`same total daily dose from NDA 21202
`same total daily dose from NDA 21202
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`Comparable Comparable
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`bioavailability between bioavailability between
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`Glucophage XR and Glucophage XR and
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`Glucophage IR from Glucophage IR from
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`NDA 21202NDA 21202
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`Metformin XR + Saxagliptin (Co-administration)Metformin XR + Saxagliptin (Co-administration)
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`BE studies CV181111 and CV181112 bridges BE studies CV181111 and CV181112 bridges
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`FDC product to co-administration of FDC product to co-administration of
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`metformin XR and saxagliptin from NDA metformin XR and saxagliptin from NDA
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`200678200678
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`Metformin XR + Saxagliptin Metformin XR + Saxagliptin
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`(FDC product, Kombiglyze NDA 200678)(FDC product, Kombiglyze NDA 200678)
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`Reference ID: 2860142
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RITESH JAIN
`11/04/2010
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`SALLY Y CHOE
`11/04/2010
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`CHANDRAHAS G G SAHAJWALLA
`11/04/2010
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`Reference ID: 2860142
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`

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`________________________________________________________________________
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`Office of New Drugs Quality Assessment
`BIOPHARMACEUTICS REVIEW
`________________________________________________________________________
`
`NDA
`200-678
`
`Drugs
`Saxagliptin/Metformin
`
`Fixed dose Combination (FDC) Extended Release Tablets
`Formulation
`Strengths
`5 mg/500 mg, 2.5 mg/1000 mg, and 5 mg/1000 mg
`Sponsor
`Bristol Myers Squibb
`
`
`Letter Date
`December 29, 2009
`
`
`Review Type
`Justification for batch size used in the BE studies
`
`Reviewer/Team Leader
`Patrick J. Marroum, Ph.D.
`________________________________________________________________________
`
`Background:
`The Pivotal Phase 3 clinical studies used metformin XR (500 mg) manufactured in Evansville or
`metformin IR formulation; however, the proposed to-be-marketed FDC tablets are being
`manufactured at Mt. Vernon, Indiana. The following figure describes the studies conducted to
`link the currently approved products used in the clinical studies to the proposed to-be-marketed
`formulation.
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`- 1 -
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`(b) (4)
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`

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`Both saxagliptin and metformin are approved products and are marketed by Bristol Myers
`Squibb. Saxagliptin (Onglyza™) was approved in 2009 under NDA 22-350. Metformin
`hydrochloride XR is an extended-release (XR) tablet formulation of metformin hydrochloride
`approved under NDA 21-202 and is currently marketed by Bristol-Myers Squibb under the brand
`name Glucophage® XR (extended release tablets of metformin hydrochloride).
`
`Bristol Myers Squibb conducted two pivotal bioequivalence studies to provide a direct link for
`the to-be-marketed FDC product manufactured at Mt Vernon, Indiana, to the marketed
`Glucophage® XR tablets manufactured at Evansville, Indiana. Bioequivalence study No.
`CV181111 was conducted to link the to-be-marketed 5 mg saxagliptin/500 mg metformin XR
`FDC to the marketed component 500 mg Glucophage® XR. The batch size for this study was
`, which size is considerably less than 100,000 or 10% of the commercial batch size
`typically expected in pivotal bioequivalence studies. Bioequivalence study No. CV181112
`provided the link for the 5 mg saxagliptin/1000 mg metformin XR FDC to the to-be-marketed 5
`mg saxagliptin/1000 mg metformin XR FDC to 2 x 500 mg tablets of marketed Glucophage® XR
`tablets. The batch size for this study was
`.
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`It should be noted that on February 13, 2009 under IND 76500 responses to the questions
`included in the…end of phase 2 (EOP2) meeting package were communicated to the sponsor..
`Bristol Myers Squibb was informed that they were not required to repeat bioequivalence studies
`conducted with smaller batch sizes, as long as the recommendations given in the SUPAC MR
`guidance for batch-scale up were met.
`
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`Justification for Acceptance of a smaller batch size
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`1- The new saxagliptin/metformin extended release fixed dose combination formulation has
`exactly the same
` as the approved extended release formulation of
`metformin with the only difference being the
`.
`2- The new manufacturing site for the
` as well as the fixed dose combination Mt. Vernon,
`Indiana has been qualified via a bioequivalence study for the metformin
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`3- The requirements described in the SUPAC MR guidance in terms of batch-scale up were
`met. The sponsor provided the supportive in vitro comparative dissolution profile data
`showing that the release characteristics of a pilot small scale batch are similar to the release
`characteristics of a full scale batch in three media (0.1 N HCl and phosphate buffer pH4.5
`and 6.8).
`4- The batch size requirement of 100,000 units or 10 % of the production batch size (whichever
`is greater), is not a CFR regulatory requirement but it is only a recommendation cited in a
`regulatory guidance to avoid issues that can arise from using smaller size batches. It is
`recommended to increase the probability of passing the confidence interval criteria for
`bioequivalence.
`5- In general, the probability of a formulation to be bio-inequivalent when scaled to a full scale
`batch is very small when the pilot scale batch has shown to be bioequivalent to the reference
`formulation.
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`- 2 -
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Conclusion:
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`For all the above reasons, the Biopharmaceutics group within ONDQA considers that the
`recommendation given to Bristol Myers Squibb during the EOP2 meeting of not to repeat
`bioequivalence studies conducted with the small scale batches is adequate and justified.
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`__________________________
`Patrick Marroum, Ph. D.
`Office of New Drug Quality Assessment
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`cc: NDA 200-678, A Dorantes, A Al Hakim, Choe, Mahayni, Chikhale
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`Date________________
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`- 3 -
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICK J MARROUM
`10/20/2010
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`Reference ID: 2852344
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`

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`CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA: 200678
`Brand Name
`Generic Name
`
`Reviewer
`Team Leader
`OCP Division
`OND division
`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
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`Proposed Indication
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`release
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`fixed dose
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`Submission Date(s): 12/29/2009
`Kombiglyze
`saxagliptin/metformin HCl extended
`combination (FDC) tablets
`Ritesh Jain, Ph.D.
`Sally Choe, Ph.D.
`Clinical Pharmacology- II
`Metabolism and Endocrinology Products
`Bristol Myers Squibb
`Original NDA 505(b)(1); Standard
`FDC product of saxagliptin/metformin XR at dose strengths
`5 mg/500 mg, 2.5 mg/1000 mg, and 5 mg/1000 mg
`As an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when
`treatment with both saxagliptin and metformin is
`appropriate.
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` 1
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` EXECUTIVE SUMMARY .................................................................................................................. 4
`1.1
`RECOMMENDATION......................................................................................................................... 4
`1.2
`PHASE IV COMMITMENTS ............................................................................................................... 4
`1.3
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS .................................................. 4
`2 QUESTION-BASED REVIEW (QBR)............................................................................................. 10
`2.1
`GENERAL ATTRIBUTES OF THE DRUG AND DRUG PRODUCT ......................................................... 10
`2.1.1 What are the 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?.....................................................................10
`2.1.2 What pertinent regulatory background or history contributes to the current assessment of the clinical pharmacology and
`Biopharmaceutics of the drug? .........................................................................................................................................................12
`2.1.3 What is the proposed therapeutic indication and route of administration?............................................................................13
`2.1.4 Is any DSI (Division of Scientific Investigation) inspection requested for any of the clinical studies? ...............................13
`2.2
`GENERAL CLINICAL PHARMACOLOGY .......................................................................................... 14
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support dosing or claims? ............14
`2.2.2 Are the active moieties in the plasma appropriately identified and measured?.....................................................................15
`2.2.3 What is the steady-state pharmacokinetics of the new 5 mg/1000 mg strength tablets?.......................................................15
`2.3
`INTRINSIC FACTORS ...................................................................................................................... 17
`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 responses? ............................................................................................................................................................17
`2.4
`EXTRINSIC FACTORS ..................................................................................................................... 17
`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? ............................................................................................................................................................17
`2.5
`GENERAL BIOPHARMACEUTICS..................................................................................................... 20
`2.5.1 What is the impact of fixed dose combination formulation, containing saxagliptin and metformin XR as a tablet, on
`systemic exposures of saxagliptin and metformin?..........................................................................................................................20
`2.5.2 What is the batch size of the FDC formulation used in the pivotal BE studies CV181111 and CV181112?.......................23
`2.5.3 What is the dose dumping potential of FDC product? ...........................................................................................................25
`2.6
`ANALYTICAL................................................................................................................................. 25
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`2.6.1 How are the active moieties identified and measured in the plasma/serum?.........................................................................25
`2.6.2 What bioanalytical methods are used to assess concentrations?............................................................................................25
`3 DETAILED LABELING RECOMMENDATION.......................................................................... 27
`4 APPENDIX ......................................................................................................................................... 35
`4.1
`COMPOSITION OF TO-BE-MARKETED FORMULATION AT DIFFERENT DOSE STRENGTHS............... 35
`4.2
`OCP FILING MEMO ................................................................................................................... 41
`4.3
`INDIVIDUAL STUDY REVIEW ................................................................................................ 51
`4.3.1 Bioequivalence Study CV181111...........................................................................................................................................51
`4.3.2 Bioequivalence Study CV181112...........................................................................................................................................66
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`List of Figures and Tables:
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`FIGURE 1: RATIOS OF GEOMETRIC MEANS (TREATMENT B/ TREATMENT A) AND THE 90% CONFIDENCE
`INTERVALS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND METFORMIN FOLLOWING
`CO-ADMINISTRATION OF SAXAGLIPTIN 5 MG AND METFORMIN XR 500 MG (TREATMENT A) AND FDC
`PRODUCT (TREATMENT B) UNDER LOW FAT MEAL CONDITION. ............................................................ 6
`FIGURE 2: RATIOS OF GEOMETRIC MEANS (TREATMENT B/ TREATMENT A) AND THE 90% CONFIDENCE
`INTERVALS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND METFORMIN FOLLOWING
`CO-ADMINISTRATION OF SAXAGLIPTIN 5 MG AND METFORMIN XR 2 X 500 MG (TREATMENT A) AND
`FDC PRODUCT (TREATMENT B) UNDER LOW FAT MEAL CONDITION..................................................... 7
`FIGURE 3: RATIOS OF GEOMETRIC MEANS (TREATMENT B/ TREATMENT A) AND THE 90% CONFIDENCE
`INTERVALS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND METFORMIN FOLLOWING
`ADMINISTRATION OF FDC PRODUCT (5/500 MG SAXAGLIPTIN/METFORMIN) UNDER FASTED (TREATMENT
`A) AND FED (TREATMENT B)................................................................................................................... 8
`FIGURE 4 : SCHEMATIC REPRESENTATION OF SAXAGLIPTIN/METFORMIN FDC TABLET............................... 11
`FIGURE 5: SPONSOR DEVELOPMENT PROGRAM LINKING THE PROPOSED TO-BE-MARKETED FORMULATION TO
`THE CURRENTLY APPROVED FORMULATION. ......................................................................................... 12
`TABLE 1: SUPPORTING CLINICAL PHARMACOLOGY STUDIES OF SAXAGLIPTIN/METFORMIN XR FDC
`TABLETS SUBMITTED UNDER THIS NDA............................................................................................... 15
`TABLE 2: GEOMETRIC MEANS (CV) FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN, METFORMIN
`AND SAXAGLIPTIN METABOLITE (BMS 510849) FOLLOWING SINGLE AND MULTIPLE DOSE
`ADMINISTRATION OF FDC PRODUCT UNDER LOW FAT MEAL CONDITION........................................... 16
`TABLE 3: GEOMETRIC MEANS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND METFORMIN
`FOLLOWING ADMINISTRATION OF FDC PRODUCT IN FED (LOW FAT MEAL) AND FASTED CONDITIONS.18
`TABLE 4: GEOMETRIC MEANS, RATIOS OF GEOMETRIC MEANS AND THEIR 90% CONFIDENCE INTERVALS
`FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND METFORMIN FOLLOWING
`ADMINISTRATION OF FDC PRODUCT IN FED (LOW FAT MEAL) AND FASTED CONDITIONS.................... 19
`TABLE 5: GEOMETRIC MEAN, RATIOS OF GEOMETRIC MEANS (TREATMENT B/ TREATMENT A) AND THE
`90% CONFIDENCE INTERVALS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND
`METFORMIN FOLLOWING CO-ADMINISTRATION OF SAXAGLIPTIN 5 MG AND METFORMIN XR 500 MG
`(TREATMENT A) AND FDC PRODUCT (TREATMENT B) UNDER LOW FAT MEAL CONDITION. ............... 21
`TABLE 6: GEOMETRIC MEAN, RATIOS OF GEOMETRIC MEANS (TREATMENT B/ TREATMENT A) AND THE
`90% CONFIDENCE INTERVALS FOR THE PHARMACOKINETIC PARAMETER OF SAXAGLIPTIN AND
`METFORMIN FOLLOWING CO-ADMINISTRATION OF SAXAGLIPTIN 5 MG AND METFORMIN XR 2X500 MG
`(TREATMENT A) AND FDC PRODUCT (TREATMENT B) UNDER LOW FAT MEAL CONDITION. ............... 22
`TABLE 7: BATCH SIZE OF THE TABLETS USED IN PIVOTAL BE STUDIES.......................................................... 23
`TABLE 8: ASSAY VALIDATION RESULTS FOR SAXAGLIPTIN AND METFORMIN.............................................. 26
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`1 Executive Summary
`
`1.1
`Recommendation
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology II
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`(OCP/DCP-II) has reviewed the clinical pharmacology data submitted under NDA
`200678, dated 12/29/2009, and finds it not acceptable because of the following
`deficiency:
`1) The batch sizes of the formulation that were utilized in the pivotal bioequivalence
`(BE) studies, CV181111 and CV181112, do not meet the biobatch size criteria of
`10% or greater than that of the proposed commercial production batch or at least
`100,000 units, whichever is greater.
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`Comments to the Clinical Division: These findings on the batch sizes used in the pivotal
`BE studies have been communicated to the Office of New Drug Quality Assessment
`(ONDQA) Biopharmaceutics and Chemistry Manufacturing and Controls (CMC) groups.
`They are in the process of evaluating these findings and will be finalizing their reviews
`on assessing the impact of using batch sizes lower than SUPAC-MR guidance and
`general criteria used by FDA.
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`Phase IV Commitments
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`1.2
`None
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`1.3
`Summary of Important Clinical Pharmacology Findings
`The purpose of this application (NDA 200678) by Bristol Myers Squibb is to seek
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`a marketing approval for the Fixed Dose Combination (FDC) 5 mg/500 mg, 2.5 mg/1000
`mg, and 5 mg/1000 mg of saxagliptin/metformin hydrochloride extended-release tablets.
`The FDC product is indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus (T2DM) when treatment with both
`saxagliptin and metformin is appropriate.
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`Both saxagliptin and metformin are approved products and are marketed by
`Bristol Myers Squibb. Saxagliptin (Onglyza™) has been approved in the United States in
`2009 under NDA 22350. Saxagliptin is currently indicated as an adjunct to diet and
`exercise to improve glycemic control in adults with T2DM, both as monotherapy and as
`combination therapy with other anti-diabetic agents, including metformin. Saxagliptin is
`a highly potent, selective, reversible, competitive, dipeptidyl peptidase-4 (DPP4)
`inhibitor and is currently marketed as immediate-release tablets of 2.5 mg and 5 mg dose
`strengths.
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`Metformin hydrochloride is an oral anti-hyperglycemic agent also used in the
`treatment of T2DM. Metformin hydrochloride XR is an extended-release (XR) tablet
`formulation of metformin hydrochloride approved under NDA 21202 and is currently
`marketed by Bristol-Myers Squibb under the brand name Glucophage® XR (extended
`release tablets of metformin hydrochloride). In the United States, Glucophage® XR is
`marketed in the 500 and 750 mg dose strengths and is approved for doses up to 2000 mg
`to be taken once daily with the evening meal.
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`The safety and efficacy of the FDC product is supported by Phase 3 trials that
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`were submitted under saxagliptin NDA (NDA 22350). In the Phase 3 trials the
`saxagliptin and metformin IR was found to be safe and efficacious when they were co-
`administered together.
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`FDC tablets of saxagliptin with metformin XR have been developed in the
`following 3 different dose strengths to allow once-daily dosing of saxagliptin with
`metformin at total daily doses up to 5 mg saxagliptin and 2000 mg metformin (i.e., the
`highest recommended once-daily doses of saxagliptin and metformin):
`(cid:57) 5 mg saxagliptin/500 mg metformin XR
`(cid:57) 5 mg saxagliptin/1000 mg metformin XR
`(cid:57) 2.5 mg saxagliptin/1000 mg metformin XR
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`The clinical pharmacology program for the FDC product consists of two pivotal
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`and five supporting clinical pharmacology studies. Two pivotal clinical pharmacology
`studies evaluated the bioequivalence (BE) between the FDC product and saxagliptin and
`metformin XR tablets when administered together. The BE was assessed at two different
`dose strengths of FDC product (5/500mg, 5/1000mg as saxagliptin/metformin FDC) and
`individual components co-administered together (5 mg saxagliptin + 500 mg metformin
`and 5 mg saxagliptin + 1000 mg metformin). These pivotal studies also evaluated the
`effect of food and steady state pharmacokinetics of saxagliptin and metformin when
`administered as FDC product.
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`The proposed FDC product was not studied in the Phase 3 trials. Thus, pivotal BE
`studies provided the link between the formulations utilized in Phase 3 trials and the
`proposed to-be-marketed formulation. This review will focus on the following two
`pivotal Clinical Pharmacology studies.
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`(cid:153) Study CV181111: Bioequivalence study of the fixed-dose combination of 5 mg
`saxagliptin and 500 mg metformin XR Tablet (manufactured in Mt Vernon, IN)
`relative to equivalent dose strengths of the currently marketed individual
`component formulations of 5 mg saxagliptin tablet and 500 mg metformin XR
`tablet co-administered to healthy subjects in a fed condition. The study also
`evaluated the effect of food on the FDC product. This study was an open-label,
`randomized, 3-period, 3-treatment, crossover study in healthy subjects.
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`(cid:153) Study CV181112: Bioequivalence study of the fixed-dose combination of 5 mg
`saxagliptin and 1000 mg metformin XR (manufactured in Mt Vernon, IN) relative
`to 5 mg of saxagliptin and 2 × 500 mg metformin XR co-administered to healthy
`subjects in the fed state. This study also evaluated the single dose and steady state
`pharmacokinetics of saxagliptin and metformin when administered as FDC
`tablets. This study was an open-label, randomized, 3-period, 3-treatment,
`crossover study in healthy subjects.
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`Bioequivalence studies were conducted with the FDC product containing 5 mg
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`saxagliptin. No clinical bioequivalence study was conducted for
`the 2.5 mg
`saxagliptin/1000 mg metformin XR FDC
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`The batch sizes of the formulation that were utilized in bioequivalence studies,
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`CV181111 and CV181112, do not meet the biobatch size criteria of 10% or greater than
`that of the proposed commercial production batch or at least 100,000 units, whichever is
`greater. In this NDA, the proposed commercial batch size is
` tablets
`and the sponsor used batch sizes of
`in trials CV181111 and CV181112,
`respectively. These batch sizes do not meet the criteria of biobatch,
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`, for the pivotal BE studies.
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`Fixed-Dose Combination vs. Individual Component Bioequivalence
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`Two pivotal bioequivalence studies (CV181111 and CV181112) were conducted
`to compare the rate and extent of absorption of saxagliptin and metformin when
`administered as FDC product or saxagliptin and metformin XR tablets administered
`together.
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`Study CV181111 evaluated the rate and extent of absorption of saxagliptin and
`metformin from the to-be-marketed 5 mg saxagliptin/500 mg metformin XR FDC
`formulation relative to the equivalent dose strengths of the currently marketed individual
`component formulations (5 mg saxagliptin and 500 mg metformin XR) under low fat
`meal condition (324 kcal).
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`The 90% confidence intervals (CIs) of the ratios of geometric least square (LS) means for
`AUC0-t, AUC0-inf, and Cmax were entirely contained within 0.80 to 1.25 for both
`saxagliptin and metformin (Figure 1). Therefore,
`the FDC
`tablet, which was
`manufactured at Mt Vernon was bioequivalent to the co-administered 5 mg saxagliptin
`and 500 mg metformin XR tablets, w