CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`200678Orig1s000
`
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`
`
`
`
`
`MEMO TO THE FILE
`
`NDA
`
`Sponsor
`
`Drug Product
`
`Date of Submission
`
`PDUFA goal date
`
`Food and Drug Administration
`Silver Spring, MD 20993-002
`
`200678
`
`Bristol-Myers Squibb
`
`Kombiglyze XR (saxagliptin/metformin extended release) fixed dose
`combination tablets
`
`December 29, 2009
`
`October 29, 2010
`
`
`
`
`Kombiglyze XR is a fixed-dose combination (FDC) tablet of saxagliptin and metformin HCl extended-
`release (met XR). The drug product is a tablet
`
`
`
`
` The
`
`
`
`proposed dosage strengths are:
`• Saxagliptin 5 mg/Metformin XR 500 mg
`• Saxagliptin 5 mg/Metformin XR 1000 mg
`• Saxagliptin 2.5 mg/Metformin XR 1000 mg
`
`
`
`
`
`
`The development of a FDC applies the policy outlined in 21 CFR 300.50 in which “two or more drugs
`may be combined in a single dosage form when each component makes a contribution to the claimed
`effects and the dosage of each component (amount, frequency, duration) is such that the combination is
`safe and effective for a significant patient population requiring such concurrent therapy as defined in the
`labeling for the drug”. In the development of FDC products for the treatment of anti-diabetic agents, the
`applicant would need to provide clinical trial data demonstrating that each of the individual components
`makes a contribution to the claimed effects of the FDC, and that the combination is acceptably safe. Of
`late, it has not been unusual for many companies to develop FDC of two approved anti-diabetic agents.
`In this setting, if clinical efficacy and safety data are available from a trial showing the individual
`components co-administered provide greater efficacy (and are safe) than the individual components alone,
`it may be sufficient for the FDC development program to only demonstrate bioequivalence between the
`FDC and individual components co-administered. This BE study would serve as the bridge between the
`FDC tablet and the clinical efficacy and safety trial of the individual components.
`
`This NDA is a 505(b)(1) application as the applicant is the NDA holder for all drugs relied upon in
`support of efficacy and safety of the FDC. These NDAs include:
`• NDA 22-350 Onglyza (saxagliptin) approved at doses of 2.5 mg and 5.0 mg
`• NDA 20-357 Glucophage (metformin HCl) approved at doses of 500 mg, 850 mg, and 1000 mg
`• NDA 21-202 Glucophage XR (metformin HCl) approved at doses of 500 mg and 750 mg
`
`
`Although it would seem that this NDA is straightforward since Bristol-Myers Squibb has full right of
`reference to all of the referenced NDA, some of the data submitted did not involve a direct bridge
`between the FDC and the referenced product relied upon for labeling. Instead, an indirect bridge was
`
`Reference ID: 2860229
`
`(b) (4)
`
`

`

`relied upon in which an intermediate drug product served as the link between the FDC and the drug
`product studied in the clinical efficacy and safety trial.
`
`This memo will only summarize the bridging clinical data and what has led FDA to conclude an FDC
`product may be approved, even if relying on indirect bridging data. Please see Dr. Joffe’s CDTL memo
`and the Clinical Pharmacology review for complete details of the clinical program.
`
`All clinical efficacy and safety data for saxagliptin plus metformin HCl summarized in this label are from
`NDA 22-350 and involves the immediate-release formulation of metformin HCl. There is no direct
`bridge between Kombiglyze XR and these two individual components nor have there been any clinical
`trials conducted with Kombiglyze XR. Instead the following pivotal BE studies were conducted:
`
`Pivotal BE Study
`CV181111
`
`Test
`FDC of saxagliptin 5 mg and 500
`mg metformin XR manufactured
`in Mt Vernon, IN
`FDC of saxagliptin 5 mg and 1000
`mg metformin XR manufactured
`in Mt Vernon, IN
`
`Comparators
`Marketed Saxagliptin 5 mg and
`metformin XR 500 mg co-
`administered
`Marketed saxagliptin 5 mg and
`metformin XR 500 mg x 2 co-
`administered
`
`CV181112
`
`
`Metformin XR
`from FDC
`
`
`As noted in the review by Dr. Jain and Choe, the FDC of saxagliptin 5mg/metXR 500 mg and saxagliptin
`5 mg/metXR 1000 mg were bioequivalent to their individual components co-administered. A biowaiver
`was granted for the lower dosage strength of saxagliptin 2.5 mg/metXR 1000 mg. These two studies
`allow us to conclude that when the FDC is administered, a similar PK profile can be expected to when
`saxagliptin and metformin XR are co-administered. However, these two studies do not provide a direct
`bridge to clinical efficacy and safety data
`.
`
`As noted in the reviews of Drs. Joffe and Peneva, the efficacy and safety data for saxagliptin plus
`metformin, in treatment-naïve and as add-on therapy, are from trials using metformin immediate-release
`formulation. To bridge these data to the Kombiglyze XR, the applicant had to rely on the Glucophage
`and Glucophage XR NDAs in which these two different formulations of metformin were evaluated. In
`her addendum to the original Clinical Pharmacology review, Drs. Jain and Choe summarize the different
`PK characteristics between these two metformin formulations. Although the Cmax for Glucophage XR is
`lower than Glucophage by approximately 20%, the extent of absorption (AUC) is comparable between
`these two drug products with the ratio of the geometric means and accompanying 90% CI being 1.00
`(0.93, 1.07). The differences in PK profiles were not considered clinically relevant as a 24-week clinical
`trial comparing efficacy between patients continued on metformin immediate-release versus being
`switched to metformin extended-release did not appear to have marked differences in efficacy. Despite
`this, the label for Glucophage/Glucophage XR does recommend monitoring of glycemic control when
`switching from the immediate-release to the extended-release formulation.
`
`The following diagram depicts the direct and indirect bridging of data to support a conclusion that
`Kombiglyze XR should result in similar efficacy as saxagliptin plus metformin IR.
`
`
`
`
`
`
`
`
`
`
`Metformin XR
`
`
`Metformin IR
`
`
`Reference ID: 2860229
`
`2
`
`(b) (4)
`
`

`

`
`It not uncommon that multiple bridging studies are conducted to link clinical data, even within a single
`development program as drug products undergo different formulation changes or scale up in
`manufacturing. However, there has been a noticeable increase in applications for FDCs for the treatment
`of diabetes and while the rationale for their development is reasonable (majority of diabetics are on
`multiple anti-diabetic therapies), these products are convenience products with no evidence of improved
`patient compliance resulting in better diabetes management. Consequently, labeling for a FDC product
`should accurately summarize the source from which clinical efficacy and safety data are derived. In the
`case of Kombiglyze XR, the following text has been added to Section 14, Clinical Studies:
`
`There have been no clinical efficacy or safety studies conducted with KOMBIGLYZE XR to characterize
`its effect on hemoglobin A1c (A1C) reduction. Bioequivalence of KOMBIGLYZE XR with coadministered
`saxagliptin and metformin hydrochloride extended-release tablets has been demonstrated; however,
`relative bioavailability studies between KOMBIGLYZE XR and coadministered saxagliptin and
`metformin hydrochloride immediate-release tablets have not been conducted. The metformin
`hydrochloride extended-release tablets and metformin hydrochloride immediate-release tablets have a
`similar extent of absorption (as measured by AUC) while peak plasma levels of extended-release tablets
`are approximately 20% lower than those of immediate-release tablets at the same dose.
`
`The Dosage and Administration section of labeling also recommends appropriate monitoring of glycemic
`control after any change in diabetes therapy, specifically when switching of metformin formulations.
`
`
`Reference ID: 2860229
`
`3
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`11/04/2010
`
`Reference ID: 2860229
`
`

`

`CLINICAL REVIEW
`
`Application Type 505(b)(1)
`Application Number(s) NDA 200678
`Priority or Standard Standard
`
`Submit Date(s)
`
`Received Date(s) 12/29/09
`PDUFA Goal Date 10/29/10
`Division / Office DMEP
`
`Reviewer Name(s) Arlet V. Nedeltcheva
`Review Completion Date 08/20/2010
`
`(Saxagliptin + Metformin XR) FDC
`Established Name
`
`(Proposed) Trade Name
`Therapeutic Class DPP4 inhibitor and a biguanide
`Applicant BMS
`
`
`Formulation(s)
`
`5 mg saxagliptin/500 mg metformin XR,
`2.5 mg saxagliptin/1000 mg metformin XR,
`5 mg saxagliptin/1000 mg metformin XR
`Dosing Regimen
`once daily in the evening
`Indication(s) As an adjunct to diet and exercise to improve
`glycemic control in T2DM when treatment with
`both saxagliptin and metformin is appropriate.
`Intended Population(s) Type 2 Diabetes mellitus
`
`
`
`Template Version: March 6, 2009
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
`
`
` saxagliptin/metformin XR FDC
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Post-market Risk Evaluation and Mitigation Strategies .. 7
`1.4 Recommendations for Post-market Requirements and Commitments............... 7
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7
`2.1 Product Information ............................................................................................ 8
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 9
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 10
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 11
`2.5 Summary of Pre-submission Regulatory Activity Related to Submission ......... 11
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 11
`3.1 Submission Quality and Integrity ...................................................................... 11
`3.2 Compliance with Good Clinical Practices ......................................................... 11
`3.3 Financial Disclosures........................................................................................ 12
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 12
`4.1 Chemistry Manufacturing and Controls ............................................................ 12
`4.2 Clinical Microbiology......................................................................................... 13
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 13
`4.4 Clinical Pharmacology...................................................................................... 13
`5 SOURCES OF CLINICAL DATA............................................................................ 15
`5.1 Tables of Studies/Clinical Trials ....................................................................... 16
`5.2 Review Strategy ............................................................................................... 17
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 18
`6 REVIEW OF EFFICACY......................................................................................... 25
`
`6.1 INDICATION........................................................................................................... 25
`6.1.1 Methods ..................................................................................................... 25
`6.1.2 Demographics............................................................................................ 26
`6.1.3 Subject Disposition .................................................................................... 30
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 34
`SECONDARY OUTPOINT – FASTING PLASMA GLUCOSE ..................................... 38
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 41
`6.1.6 Subpopulations .......................................................................................... 41
`7 REVIEW OF SAFETY............................................................................................. 41
`
`2
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`
`7.1 Methods............................................................................................................ 41
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 42
`7.1.2 Categorization of Adverse Events.............................................................. 42
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 42
`7.2 Adequacy of Safety Assessments .................................................................... 42
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 42
`7.2.2 Explorations for Dose Response................................................................ 42
`7.3 Major Safety Results ........................................................................................ 43
`7.3.1 Deaths........................................................................................................ 43
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 46
`7.3.3 Dropouts and/or Discontinuations: AEs leading to discontinuation ........... 60
`7.3.4 Significant Adverse Events (adverse events of interest) ............................ 67
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 79
`7.4 Supportive Safety Results ................................................................................ 79
`7.4.2 Laboratory Findings ................................................................................... 82
`7.4.3 Vital Signs.................................................................................................. 82
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 82
`7.5 Other Safety Explorations................................................................................. 83
`7.6 Additional Safety Evaluations ........................................................................... 83
`7.6.1 Human Carcinogenicity.............................................................................. 83
`7.6.2 Human Reproduction and Pregnancy Data................................................ 84
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 84
`8 POST-MARKET EXPERIENCE ............................................................................. 84
`
`9 APPENDICES ........................................................................................................ 84
`9.1 Labeling Recommendations............................................................................. 84
`9.2 Advisory Committee Meeting............................................................................ 85
`
`
`
`3
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
`
`
` saxagliptin/metformin XR FDC
`
`Table of Tables
`
`Table 1 The available treatments for Type 2 Diabetes.................................................... 9
`Table 2 Listing of saxagliptin clinical studies that support the FDC NDA ...................... 16
`Table 3 Study CV181038 demographics (Randomized Analysis set) ........................... 26
`Table 4 Study CV181054 demographics (Randomized analysis set)............................ 27
`Table 5 CV181056 demographics (Randomized analysis set)...................................... 28
`Table 6 CV181066 demographics................................................................................. 29
`Table 7 CV181064 demographics................................................................................. 29
`Table 8 Summary table based on ST + LT (LT is complete for all studies below except
`for Study 181054) - Major reason for discontinuation (n, %) in some of the
`studies reviewed for this NDA. Further details are provided for each study
`separately below............................................................................................ 30
`Table 9 Disposition of the subjects in ST + LT treatment period and primary reason for
`discontinuation from study ............................................................................. 31
`Table 10 Disposition of Subjects in ST + LT treatment period and primary reason for
`discontinuation from Study CV181039........................................................... 31
`Table 11 Disposition of the subjects CV 1810156........................................................ 32
`Table 12 Disposition of subjects CV181066 randomized and treated ........................... 32
`Table 13 Disposition of Subjects from study CV 181064............................................... 32
`Table 14 Disposition of the subjects in Year 1 of Study CV181054 (randomized and
`treated) .......................................................................................................... 33
`Table 15 Change from baseline to week 76 in HbA1C study CV181038 (LOCF) during
`ST + LT period ............................................................................................... 34
`Table 16 Fasting Plasma glucose Change from baseline to week 24 (LOCF) during ST
`treatment period of study 181038 .................................................................. 35
`Table 17 Change in HbA1C from baseline to week 76 (LOCF) during ST+LT treatment
`period study of study CV181039.................................................................... 36
`Table 18HbA1C (%) results for ST period of study CV181039 using LOCF.................. 36
`Table 19 Fasting plasma glucose Change from baseline to week 76 (LOCF) during ST +
`LT treatment period of study CV181039 ........................................................ 37
`Table 20 Change from baseline to week 24 (ST) in fasting plasma glucose (mg/dL)
`using LOCF.................................................................................................... 37
`Table 21 HbA1C change from baseline at week 18 (LOCF) of the study CV181056 ... 38
`Table 22 Change from baseline fasting plasma glucose from baseline to week 18
`(LOCF) of the study CV181056...................................................................... 38
`Table 23 24 hour mean weighted glucose (MWG-mg/dL) - change from baseline at
`week 4 (LOCF)............................................................................................... 39
`Table 24 4-hour mean weighted postprandial plasma glucose- changes from baseline at
`week 4 (LOCF)............................................................................................... 39
`Table 25 Change in HbA1C (%) from baseline to week 52 (LOCF) .............................. 40
`Table 26 Change in 120-minute postprandial glucose from baseline to week 52 (LOCF)
`....................................................................................................................... 40
`Table 27 Summary table of the deaths in the studies reviewed for this NDA................ 43
`
`4
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`Table 28 Deaths: Study CV181039 (treated patients)................................................... 44
`Table 29 Deaths in study CV181054 (treated subjects) ................................................ 45
`Table 30 Summary table of the SAEs in the studies reviewed for this NDA.................. 46
`Table 31 Serious adverse events by System organ class ST+LT study CV181038
`(treated subjects) ........................................................................................... 47
`Table 32 New SAEs not included in the interim study report for CV181038 (treated
`subjects) ........................................................................................................ 47
`Table 33 Serious Adverse Events during the ST + completed LT period (treated
`subjects) CV181039....................................................................................... 49
`Table 34 SAEs since the interim LT CSR reporting period (treated subjects) CV1810139
`....................................................................................................................... 50
`Table 35 SAEs in CV181056 (treated subjects) ........................................................... 53
`Table 36 SAEs during study CV181064 (24 weeks) ..................................................... 54
`Table 37 SAEs CV181054 (treated subjects) for ST (52 weeks)................................... 55
`Table 38 New data for SAEs reported for CV181014 since 120- day safety update for
`Onglyza NDA ................................................................................................. 56
`Table 39 SAEs during ST + LT period of study CV181014 ........................................... 58
`Table 40 Adverse events leading to discontinuation from entire ST + LT study period of
`CV181038 study by SOC and PT .................................................................. 61
`Table 41 AEs leading to discontinuation during ST + LT (old and new data) of study
`CV1810139.................................................................................................... 62
`Table 42 AEs leading to discontinuation during 18 week treatment period of study
`CV181056...................................................................................................... 62
`Table 43 Subjects who discontinued due to AEs during 24 week study CV181064...... 63
`Table 44 Confirmed hypoglycemia by predefined PT during the ST + LT treatment
`period (new + old data) study CV181038....................................................... 67
`Table 45 Confirmed hypoglycemia - by PT during ST + LT treatment period (old + new
`data)............................................................................................................... 67
`Table 46 Hypoglycemic adverse events by PT of study CV181056 .............................. 67
`Table 47 Hypoglycemic adverse events by PT in CV181066........................................ 68
`Table 48 Reported hypoglycemic adverse events by PT during ST treatment period in
`CV181054 study ............................................................................................ 68
`Table 49 Skin disorders by PT during ST + LT period (new data) of study CV181038 69
`Table 50 Skin disorders by PT during the ST + LT treatment period (old + new data) of
`study CV1810138 .......................................................................................... 69
`Table 51 Skin disorders by PT in study CV1810166 ..................................................... 69
`Table 52 Skin disorders (new data) study CV181014 ................................................... 69
`Table 53 Localized edema AEs by PT during ST + LT treatment (old + new data) period
`of study CV181039 ........................................................................................ 71
`Table 54 AEs of interest: Infections during the ST + LT period (old + new data) study
`CV1810138.................................................................................................... 72
`Table 55 The most common AEs of Infections SOC (incidence > 2 %) (old + new data)
`by PT during study CV181039 ....................................................................... 73
`Table 56 AEs of interest of Infections SOC during study CV181056............................. 74
`
`5
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`Table 57 Most common AEs of interest of Infections SOC during study CV 181066 ... 74
`Table 58 Most common AEs of interest of Infection SOC during study CV181054 ....... 74
`Table 59 Most common AEs with incidence > 5 % during study CV181014 ................. 81
`
`6
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
`
`
` saxagliptin/metformin XR FDC
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1
`
`Recommendation on Regulatory Action
`
`From a clinical perspective, the application is recommended for approval.
`
`1.2
`
`Risk Benefit Assessment
`
`The saxagliptin/metformin XR FDC contains two approved medications with known risks in a
`single tablet. The benefit of the FDC is the convenience of the patients taking less pills, which
`may decrease noncompliance to drug treatment.
`
`1.3
`
`Recommendations for Post-market Risk Evaluation and Mitigation Strategies
`
`There are no Risk Evaluation and Mitigation Strategies (REMS) in place for saxagliptin or
`metformin and no new safety issues were identified with co-administration. Therefore, there is
`no need for a REMS for this FDC.
`
`1.4
`
`Recommendations for Post-market Requirements and Commitments
`
`There are several required postmarketing studies for saxagliptin. For additional information refer
`to the NDA 22350 Approval letter, date July 31, 2009. No distinct required postmarketing
`studies are needed for the FDC.
`
`2
`
`Introduction and Regulatory Background
`
`Saxagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP4) that was developed for treatment of
`hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase 4 inactivates the
`incretin hormone glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic
`polypeptide (GIP). Those incretin hormones are released from the gastrointestinal tract during
`meals and stimulate insulin release from the pancreatic beta-cell in a glucose-dependent manner.
`
`DPP4 inhibitors increase the levels of intact glucagon-like peptide-1 (GLP-1). The intact GLP-1
`regulates blood glucose via stimulation of glucose-dependent insulin secretion, delaying of
`gastric emptying, inhibiting of glucagon secretion, and as a result of all these actions, improves
`the pre-prandial and postprandial glycemic profile.
`
`Metformin is a biguanide, that decreases elevated blood glucose with predominant effect on
`fasting hyperglycemia, reduces hepatic glucose output, improves peripheral glucose uptake and
`utilization, leads to improved insulin sensitivity.
`The combination therapy with DPP4 inhibitor and metformin lowers the glucose via different
`mechanisms of action.
`
`7
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`
`Metformin XR is proposed to be used as the metformin component in the fixed-dose
`saxagliptin/metformin product. This gives an advantage of a saxagliptin/metformin XR fixed-
`dose combination product of being dosed once-daily in the evening , which may improve patient
`compliance over a twice daily dosing product if metformin immediate-release (IR) was used.
`
`2.1
`
`Product Information
`
`Saxagliptin/metformin XR FDC tablets have been developed at dose strengths of 5 mg
`saxagliptin/ 500 mg metformin XR, 2.5 mg saxagliptin/ 1000 mg metformin XR, and 5 mg
`saxagliptin/ 1000 mg metformin XR.
`
`In the saxagliptin/metformin XR FDC tablets,
`
`
`
`
`
`
`
`
`
`
`
`
`
`Drug class: DPP4 inhibitor (dipeptidyl peptidase-4 inhibitor) and a biguanide
`
`Established name: saxagliptin and metformin XR FDC
`
`Proposed trade name:
`
`Target patient population and indication: Treatment of type 2 diabetes mellitus
`
`Formulation: Film coated tablets for oral administration
`
`Dosage forms and strengths for saxagliptin/metformin HCl extended-release available:
`• saxagliptin/metformin HCl XR 5mg/500 mg tablets are light brown, capsule-shaped, film-
`coated tablets with “5/500” printed on one side and “4221” printed on the reverse side
`in blue ink
`• saxagliptin/metformin HCl XR 5 mg/1000 mg tablets are pink, capsule-shaped, film-
`coated tablets with “5/1000” printed on one side and “4223” printed on the reverse side,
`in blue ink
`• saxagliptin/metformin HCl XR 2.5 mg /1000 mg tablets are yellow, capsule-shaped, film-
`coated tablets with “2.5/1000” printed on one side and “4222” printed on the reverse
`side, in blue ink
`Proposed dosing: The dosage of antihyperglycemic therapy should be individualized based on
`the effectiveness and tolerability in each patient with type 2 diabetes mellitus. When the
`saxagliptin/metformin XR FDC is considered appropriate treatment by the physician, the
`recommended starting dose of saxagliptin is 2.5 mg or 5 mg once daily and the recommended
`starting dose of metformin XR is 500 mg once daily, which can be gradually titrated to 2000 mg
`once daily to reduce the gastrointestinal side effects associated with metformin. The maximum
`
`8
`
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`dose is saxagliptin 5 mg /metformin XR 2000 mg taken as two 2.5 mg/1000 mg tablets once daily
`with the evening meal.
`
`Proposed indication: saxagliptin/ metformin XR FDC is indicated 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.
`
`2.2
`
`Tables of Currently Available Treatments for Proposed Indications
`
`Table 1 The available treatments for Type 2 Diabetes
`Drug class
`Drug Mechanism
`of action
`
`Metformin
`
`Biguanides
`
`
`
`
`
`Sufonylureas
`
`
`
`Thiazolidinediones
`
`
`Insulin
`
`
`
`
`
`Glimepiride
`Glyburide
`Glipizide
`
`Rosiglitazone
`Pioglitazone
`
`Lispro
`NPH insulin
`Glargine
`
`Alpha-glucosidase
`inhibitors
`
`
`Acarbose
`Miglitol
`
`Repaglinide
`Nateglinide
`Pramlintide
`
`Meglitides
`
`Amylin analogues
`
`
`
`
`Decrease
`hepatic
`glucose
`production
`Increase
`insulin
`sensitivity
`Insulin
`secretagogue
`
`Increases
`insulin
`sensitivity
`Stimulates
`glucose
`uptake
`in muscle and
`adipose
`tissue
`Slow GI
`absorption of
`carbohydrates
`
`Insulin
`secretagogue
`Slow gastric
`emptying
`Suppresses
`glucagon
`
`9
`
`HbA1c
`(%)
`decrease*
`
`
`
` 1.5
`
`Advantage
`
`Disadvantage
`
`Weight
`neutral
`Inexpensive
`
`GI side effects
`Lactic acidosis
`Contraindicated
`in renal failure
`
` 1.5 Inexpensive
`
`0.5-1.4
`
`
`
`1.5-2.5
`
`Lower risk of
`hypoglycemia
`
`No dose limit
`Inexpensive
`Improve lipid
`profile
`
`
`
`0.5-0.8
`
`1-1.5
`
`
`
`
` 0.5-1.0
`
`Weight
`neutral
`
`Short
`duration
`
`
`
`Weight loss
`
`Hypoglycemia
`Weight gain
`
`Fluid retention
`Weight gain
`Expensive
`Injections
`Frequent
`monitoring
`Hypoglycemia
`Weight gain
`
`Frequent GI
`side effects
`TID dosing
`Expensive
`TID dosing
`Expensive
`TID dosing
`GI side effects
`Expensive
`Limited
`
`(b) (4)
`
`

`

`Clinical Review
`Arlet V. Nedeltcheva, M.D.
`NDA 200678
`
` saxagliptin/metformin XR FDC
`
`
`
`
`
`
`
`GLP-1 analogues
`
`Exenatide
`
`experience
`
`
`
`
`
`0.5-1.0
`
`Weight loss
`Lower risk of
`hypoglycemia
`except when
`used with
`insulin
`secretagogues
`
`GI side effects
`Expensive
`Limited
`clinical
`experience
`Pancreatitis
`
`
`secretion
`Promotes
`satiety
`Decreases
`appetite
`Stimulated
`glucose-
`
`
`dependent
`insulin
`release
`Slows gastric
`emptying
`Inhibits
`glucagon
`secretion
`Reduces food
`intake
`Inhibits the
`enzyme DPP-
`IV
`
`prolonging
`the action of
`
`endogenous
`GLP-1 and
`GIP
`Unknown
`
`DPP-IV inhibitors Sitagliptin
`Saxagliptin
`
`Bile acid
`seques