CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`209091Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`NDA
`
`Submission Date
`
`Brand Name
`
`Generic Names
`
`Reviewer
`
`Team Leader
`
`OCP Division
`
`0ND Division
`
`Sponsor
`
`Formulation; Strength
`
`Indication
`
`CLINICAL PHARMACOLOGY MEMO
`
`209—091 Serial 000
`
`April 5, 2016
`
`QTERN
`
`Saxagliptin and dapagliflozin
`
`S.W. Johnny Lau, R.Ph., Ph.D.
`
`Manoj Khurana, Ph.D.
`
`Clinical Pharmacology 2
`
`Metabolism and Endocrinology Products
`
`AstraZeneca
`
`Fixed dose combination immediate release oral tablet; 5
`mg saxagliptin/10 mg dapagliflozin
`
`Adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus
`
`This memo serves the purpose of referring the Clinical Pharmacology review of NDA 209-091 Serial 000
`to that of NDA
`(I'm as appeared in DARRTS dated August 24, 2015 with the
`Reference ID number of 3810575 for the Office of Clinical Pharmacology (OCP) to assess and
`recommend the clinical pharmacology data cross-referenced under the NDA 209-091.
`
`Executive Summary
`The sponsor submitted NDA 209-091 for QTERN (saxagliptin/dapagliflozin) fixed dose combination
`(FDC) tablets, to support the following proposed indication:
`o QTERN (saxagliptin and dapagliflozin) is indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus (T2DM)
`0')“,
`
`For difficult to control patients with TZDM, who have not met treatment goals with metformin and the
`maximum recommended dose of 10 mg dapagliflozin, there are clinical trial data to support the option of
`adding saxagliptin to the treatment regimen.
`
`The clinical pharmacology information for NDA 209—091 is the same as that reviewed under NDA (hm)
`(hm) This reviewer reviewed portions ofNDA 209-901 that was previously submitted to NDA
`(hm)
`
`The sponsor provided additional safety data for the 24-week short term treatment periods
`of Studies CV181168 and MB102129 in the 4-month safety update (4-MSU, submitted April 15, 2015
`Sequence No. 0003). NDA
`(we) received a complete response letter on October 15, 2015.
`
`01(4)]
`Recommendation for NDA
`(”M’s Clinical
`The OCP/Division of Clinical Pharmacology 2 (DCP2) has reviewed NDA
`Pharmacology data submitted
`M0 The data is acceptable to support approval provided
`
`1 See this reviewer’s Clinical Pharmacology review in DARRTS dated August 24, 2015 with Reference
`ID number 3810575.
`
`1
`
`Reference ID: 4045606
`
`

`

`that a mutual agreement regarding the label language can be reached between the sponsor and the Food
`and Drug Administration.
`
`Recommendation for NDA 209-091
`
`OCP/DCP2 recommends approval of NDA 209-091 provided that a mutual agreement regarding the label
`language can be reached between the sponsor and the Food and Drug Administration.
`
`Notes on Labeling Recommendation
`This note documents the rationale for the recommendation to discontinue QTERN when the eGFR value
`persistently falls between 45 mL/min/1.73 m2 and 60 mL/min/1.73 m2 in the label.
`
`The dapagliflozin GiARXIGA) label states that use of dapagliflozin is not recommended in patients with
`an eGFR persistently between 30 and less than 60 mL/min/ 1.73 m2. Thus, the 60 mL/min/1.73 m2
`recommendation in the QTERN label originates from the dapagliflozin label.
`
`The saxagliptin (ONGLYZA) label recommends that the dosage for patients with moderate or severe
`renal impairment, or end-stage renal disease (CrCl S 50 mL/min) is 2.5 mg once daily regardless of meals.
`QTERN does not have the 2.5 mg saxagliptin strength of FDC. The recommended dose of saxagliptin is
`2.5 or 5 mg once daily taken regardless of meals (ONGLYZA label). The saxagliptin label uses
`creatinine clearance (CrCl) to characterize renal fimction, whereas QTERN label uses eGFR instead.
`Thus, this makes it difficult to directly relate the exposure of saxagliptin at CrCl s 50 mL/min to that at
`eGFR 45 mL/min/ 1.73 m2.
`
`The reanalysis of the original NDA pharmacokinetic data of saxagliptin tablets through current eGFR
`based classification criteria2 and finther subgrouping of moderate renal impairment3 showed that the
`molar ratio of saxagliptin in participants of eGFR 45 — 59 mL/min/1.73 m2 is similar to those of healthy
`participants. However, the molar ratio of saxagliptin in participants of eGFR 30 — 45 mL/min/ l .73 m2 is 2
`fold higher than that of healthy participants. This reanalysis of saxagliptin pharmacokinetic data was
`necessary because of the efforts to align the saxagliptin and metformin FDC tablets’ labels with the
`changes to the metformin safety label changes for the use of metformin in renal impairment subgroups.
`
`Combining the restrictions of saxagliptin and dapagliflozin use in renal impairment, OCP/DCP2
`recommends discontinuing QTERN when the eGFR value persistently falls between 45 mL/min/l .73 m2
`and 60 mL/min/l.73 m2
`"M”
`
`Again, the FDC combinations containing 2.5 mg
`
`saxagliptin component are not available.
`
`2 Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function — Study Design,
`Data Analysis, and Impact on Dosing and Labeling, Issued March 2010
`3 Clinical Pharmacology Memo for NDA 200-678 for KOIVIBIGLYZE XR in DARRTS, Reference
`1]):4043 39 l
`
`2
`
`Reference ID: 4045606
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SZE W LAU
`01/24/2017
`
`MANOJ KHURANA
`01/30/2017
`
`Reference ID: 4045606
`
`

`

`NDA
`Submission Date
`Brand Name
`Generic Names
`Reviewer
`Team Leader (Acting)
`OCP Division
`OND Division
`Sponsor
`Formulation; Strength
`
`Relevant IND
`Indication
`
`CLINICAL PHARMACOLOGY REVIEW
`
`November 17, 2015
`QTERN
`Saxagliptin and dapagliflozin
`S.W. Johnny Lau, R.Ph., Ph.D.
`Manoj Khurana, Ph.D.
`Clinical Pharmacology 2
`Metabolism and Endocrinology Products
`AstraZeneca
`Fixed dose combination immediate release oral tablet; 5
`mg saxagliptin/10 mg dapagliflozin
`118,840
`Adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus
`
`Purpose
`This document reviews the Clinical Pharmacology related questions for the End of Review Meeting for
`immediate release (IR) 5 mg saxagliptin (SAXA) and 10 mg dapagliflozin (DAPA) (5 mg SAXA/10 mg
`DAPA) fixed dose combination (FDC) tablet with the sponsor.
`
`Background
`The sponsor received a Complete Response letter for NDA
` from the Division of Metabolism and
`Endocrinology Products on October 15, 2015 and the letter contains the following salient points:
`
`The currently approved dapagliflozin label recommends starting dapagliflozin at 5 mg with an increase to
`10 mg only for those patients who can tolerate dapagliflozin 5 mg and require additional glucose
`lowering. Initiating dapagliflozin at 5 mg in the general population of patients with type 2 diabetes
`mellitus, naïve to dapagliflozin, was determined to be an essential condition of use for dapagliflozin
`1
`
`Reference ID: 3859076
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`containing products based on review of safety data in NDA 202293 and this condition of use would also
`a
`l
`to our fixed combination
`
`12mm
`
`you will need to submit additional clinical trial data to inform
`the combination use of saxagliptin and dapagliflozin.
`
`
`
`The sponsor requested the End of Review Meeting through this current submission.
`
`Findings
`Integrated safety analysis plan (see Section 7.1)
`
`Reference ID: 3859076
`
`

`

`Question 1: Does the Agency agree with theproposed_ in the
`Safety Update package?
`
`Question 2: Does the Agency agree with the proposed plans for the format and content to be included
`in the Safety Update and Module 2.7.4 Summary of Clinical Safety Addendum and Module 2.5
`Clinical Overview?
`
`Question 3: Does the A enc a ee
`
`?
`
`Prescribing information (see Section 7.2)
`
`Question 4: Does the A enc a ee that 5 m saxa '
`
`tin/10 mg dapagliflozin FDC can be approved
`? Ifyes:
`
`0 Does theA enc a ee
`
`0 Does the Agency agree that approval based on the second scenario (restricted use in patients who
`can tolerate dapagliflozin 10 mg) would be fully supported by the current NDA package, planned
`updated LT safety analyses and individual study ST data from Study CV181168?
`
`
`
`Clinical Pharmacology Response:
`
`Clinical pharmacology defers Questions 1 — 4 and 6 — 8 to Clinical to answer.
`
`_ 3
`
`Reference ID: 3859076
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SZE W LAU
`12/10/2015
`
`MANOJ KHURANA
`12/15/2015
`
`Reference ID: 3859076
`
`

`

`NDA
`Submission Dates
`Brand Name
`Generic Names
`Reviewer
`Team Leader (Acting)
`OCP Division
`OND Division
`Sponsor
`Formulation; Strength
`
`Relevant IND
`Indication
`
`CLINICAL PHARMACOLOGY REVIEW
`
` August 11, 2015
`
`QTERN
`Saxagliptin and dapagliflozin
`S.W. Johnny Lau, R.Ph., Ph.D.
`Manoj Khurana, Ph.D.
`Clinical Pharmacology 2
`Metabolism and Endocrinology Products
`AstraZeneca
`Fixed dose combination immediate release oral tablet; 5
`mg saxagliptin/10 mg dapagliflozin
`118,840
`Adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus
`
`Page
`1
`2
`2
`2
`
`Table of Contents
`1 Executive Summary
`1.1 Recommendations
`1.2 Post Marketing Requirement
`1.3 Summary of Important Clinical Pharmacology Findings
`2 Question Based Review
`2.1 Background
`2.2 General Attributes
`2.3 General Clinical Pharmacology
`2.4 Intrinsic Factors
`2.5 Extrinsic Factors
`2.6 General Biopharmaceutics
`2.7 Bioanalytical
`3 Labeling Recommendations
`1 Executive Summary
`The sponsor is seeking approval for immediate release (IR) 5 mg saxagliptin (SAXA) and 10 mg
`dapagliflozin (DAPA) (5 mg SAXA/10 mg DAPA) fixed dose combination (FDC) tablet as an adjunct to
`improve glycemic control in adults with type 2 diabetes mellitus (T2DM).
`
`3
`3
`5
`7
`7
`9
`10
`11
`
`Saxagliptin (ONGLYZA; 5 and 2.5 mg tablets) has an approved indication to improve glycemic control in
`adults with T2DM (NDA 22-350, approval on July 31, 2009). Dapagliflozin propanediol (FARXIGA; 5
`and 10 mg tablets) also has an approved indication to improve glycemic control in adults with T2DM
`(NDA 20-702, approval on January 8, 2014).
`1.1 Recommendations
`
`Reference ID: 3810575
`
`1
`
`(b) (4)
`
`(b) (4)
`
`

`

`2 OCP/DCP2) has reviewed
`The Office of Clinical Pharmacology/Division of Clinical Pharmacolo
`The data is acceptable to
`NDA-’s Clinical Pharmacology data submitted
`support approval provided that a mutual agreement regarding the label language can be reached between
`the sponsor and the Food and Drug Administration.
`
`1.2 Post Marketing Requirement
`None.
`
`1.3 Summary of Important Clinical Pharmacology Findings
`
`The sponsor submitted the results of 2 clinical pharmacology studies (CVl8l 191 and CVl8l34l), a
`pivotal efficac stud CV181169), and 2 clinical safety studies (CV181169 and D1690C00010) to
`support NDA
`Study CV181191 assesses the mutual interaction upon oral administration
`between a 5 mg SAXA tablet and a 10 mg DAPA tablet. Study CVl8l34l assesses the bioequivalence
`between coadministration of 5 m SAXA tablet
`lus 10 m DAPA tablet and 5 m SAXA/10 m DAPA
`
`FDC tablet
`
`
`
`
`Study CVl8l34l also has 2 additional arms to
`assess the food effect on the 5 mg SAXA/10 mg DAPA FDC tablet
`- See Biopharmaceutics reviewer’s review for Stud CVl8l34l. Also, the s
`a
`
`roval for the 5 m SAXA/10 m DAPA FDC
`
`nsor onl
`
`seeks
`
`
`
`The 5 mg SAXA/10 mg DAPA FDC tablets used in the pivotal
`bioequivalence study were the same as the to-be-marketed 5 mg SAXA/10 mg DAPA FDC tablets.
`
`According to the results of Study CV181191, SAXA and DAPA do not significantly interact with each
`other upon coadministration of 5 mg SAXA and 10 mg DAPA tablets.
`
`
`
`S.W. Johnny Lau, R.Ph., PhD.
`OCP/DCP2
`
`FT signed by Manoj Khurana, Ph.D., Acting Team Leader,
`
`8/
`
`/15
`
`Reference ID: 381 0575
`
`

`

`2 Question-Based Review
`2.1 Background
`The sponsor developed the following strengths of FDC immediate release tablets:
`5 mg SAXA/10 mg DAPA
`
`
`The sponsor submitted this 505(b)(1) new drug application to seek marketing approval only for the 5 mg
`SAXA/10 mg DAPA FDC oral tablet as an adjunct to diet and exercise to improve glycemic control in
`adults with T2DM.
`
`2.2 General Attributes
`2.2.1 What are SAXA and DAPA’s key physicochemical properties?
`SAXA has a molecular weight of 333.43, empirical formula of C18H25N3O2•H2O. See Figure 1 for the
`chemical structure of SAXA. SAXA is sparingly soluble in water with an aqueous solubility of 17.6
`mg/mL at 24ºC ± 3ºC. SAXA has a pKa of 7.3. SAXA’s apparent octanol/water distribution coefficient
`(Do/w) is 0.015 at pH 1.2, 0.04 at pH 4.5, and 0.607 at pH 7.
`
`Figure 1. Chemical structure of SAXA.
`
`DAPA has a molecular weight of 502.98, empirical formula of C21H25ClO6•C3H8O2•H2O. See Figure 2
`for the chemical structure of DAPA. The solubility of DAPA in water at 24C ± 3C is 1.6 mg/mL.
`DAPA’s octanol/water partition coefficient is 2.45 at pH 7.4.
`
`Figure 2. Chemical structure of DAPA.
`
`Reference ID: 3810575
`
`3
`
`(b) (4)
`
`

`

`2.2.2 What is the formulation for the to-be-marketed SAXA/DAPA FDC oral tablet?
`
`Table 1 below details the formulation of the to-be-marketed 5 mg SAXA/10 mg DAPA FDC oral tablets.
`
`Cow
`
`Qflily Stalk-d
`
`Functi- M per Tablet
`
`(90"!)
`
`(
`
`Table 1. Composition of the to-be-marketed 5 mg SAXA/lo mg DAPA Film-Coated Tablet.
`
`
`
`Source: Sponsor’s Table 3.2.P.l—6
`
`Reference ID: 3810575
`
`

`

`2.2.3 How does SAXA/DAPA FDC tablet work for the proposed indications?
`Both drugs lower blood glucose concentrations in the body through the following mechanisms:
`Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and
`
`glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the
`small intestine in response to meals. These hormones cause insulin release from the pancreatic
`beta cells in a glucose-dependent manner but are inactivated by the (dipeptidyl peptidase-4) DPP4
`enzyme within minutes. SAXA is a DPP4 inhibitor that slows the inactivation of the incretin
`hormones, thereby increasing their bloodstream concentrations and reducing fasting and
`postprandial glucose concentrations in a glucose-dependent manner in patients with T2DM.
` Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible
`for the majority of the reabsorption of filtered glucose from the tubular lumen. DAPA is an
`inhibitor of SGLT2. By inhibiting SGLT2, DAPA reduces reabsorption of filtered glucose and
`lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
`
`2.2.4 What are the sponsor’s proposed indication and dosing regimen for SAXA/DAPA FDC
`tablet?
`The 5 mg SAXA/10 mg DAPA FDC tablet’s proposed indication is an adjunct to diet and exercise to
`improve glycemic control in adults with T2DM
`
`
`The 5 mg SAXA/10 mg DAPA FDC tablet’s proposed dosing regimen is:
`a tablet taken once daily in the morning with or without food, but:
`
`o Do not initiate the tablet if eGFR is < 60 mL/min/1.73 m2.
`o Discontinue the tablet if eGFR falls persistently < 60 mL/min/1.73 m2.
`o Do not coadminister the tablet with strong cytochrome P450 3A4/5 inhibitors.
`
`2.3 General Clinical Pharmacology
`2.3.1 What are SAXA and DAPA’s clinical pharmacokinetic (PK) characteristics?
`Besides SAXA and DAPA’s product labels, the following publications detail SAXA and DAPA’s clinical
`PK and interactions:
` Scheen A.J. Dipeptidylpeptitase-4 Inhibitors (Gliptins) Focus on Drug-Drug Interactions. Clin
`Pharmacokinet 2010;49: 573-88.
` Scheen A.J. Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2)
`Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus.
`Clin Pharmacokinet 2014;53:295–304.
` Amin M and Suksomboon N. Pharmacotherapy of Type 2 Diabetes Mellitus: An Update on Drug–
`Drug Interactions. Drug Saf 2014;37:903–19.
`
`2.3.2 How is the proposed daily SAXA/DAPA FDC tablet dosing regimen determined for patients
`with T2DM?
`The proposed dosing regimen of SAXA/DAPA FDC tablet follows the dosing recommendations of
`individual SAXA and DAPA tablets. The recommended starting dose of SAXA is 2.5 mg or 5 mg once
`daily taken regardless of meals (see saxagliptin product label). The recommended starting dose of DAPA
`is 5 mg once daily taken in the morning with or without food and can be increased to 10 mg once daily in
`patients who require additional glycemic control (see dapagliflozin product label).
`
`2.3.3 What is the efficacy response of coadministration of SAXA and DAPA tablets?
`The sponsor conducted Study CV181169 to show the efficacy response of the coadministered 5 mg
`SAXA tablet and 10 mg DAPA tablet. This was a Phase 3, double-blind, randomized, placebo-controlled
`
`Reference ID: 3810575
`
`5
`
`(b) (4)
`
`

`

`study in 534 subjects with T2DM and with a screening HbA1c > 8% and ≤ 12%, who did get adequate
`glycemic control on metformin monotherapy. This study compared the primary efficacy endpoint as the
`mean change from baseline in HbA1c achieved with the following treatments after 24 weeks of double-
`blind treatment:
`5 mg SAXA + 10 mg DAPA + metformin XR
`
`5 mg SAXA + metformin
`
`10 mg DAPA + metformin
`
`The sponsor claimed that the 5 mg SAXA + 10 mg DAPA + metformin treatment group showed
`superiority against the other treatment groups, 5 mg SAXA + metformin, and 10 mg DAPA + metformin,
`respectively (See Table 2 and Figure 3 below).
`Table 2. Study CV181169’s efficacy endpoint at Week 24.
`
`Source: Study CV181169’s report Table -3.
`Figure 3. Longitudinal plot of change from baseline in HbA1c - 24-Week double blind period –
`randomized participants
`
`Source: Study CV181169’s report Figure 7.2-1.
`
`6
`
`Reference ID: 3810575
`
`

`

`For detailed discussion of Study CV181169’s results and acceptability of the sponsor’s claims on
`efficacy, see Dr. Suchitra Balakrishnan’s medical review and Dr. Anna Kettermann’s statistical review in
`DARRTS.
`
`2.4 Intrinsic Factors
`2.4.1 What intrinsic factors may affect the use of SAXA/DAPA FDC tablet?
`See the individual SAXA and DAPA product labels for further information.
`2.5 Extrinsic Factors
`2.5.1 How does food affect the bioavailability (BA) of SAXA and DAPA from the FDC tablet?
`Study CV181341 examined the effect of food on the BA of SAXA and DAPA from the FDC tablet. See
`Biopharmaceutics reviewer’s (Dr. Peng Duan) review in DARRTS.
`2.5.2 What is the potential for mutual interactions between SAXA and DAPA?
`The sponsor conducted the following 2 studies to assess the interaction potential between SAXA and
`DAPA:
` Study 930059456
` Study CV181191
`Study 930059456 is an in vitro study to assess the potential of SAXA and 5-OH SAXA (major active
`metabolite) to inhibit UGT1A9 to glucuronidate DAPA. The IC50 values for SAXA and 5-OH SAXA
`were  50 µM, which was the highest concentration tested. In the same test systems, the positive control
`inhibitor, niflumic acid, inhibited DAPA and propofol glucuronidation with IC50 values of 0.2 µM and
`0.42 µM, respectively. These data suggest that SAXA and 5-OH SAXA have little or no potential to
`inhibit UGT1A9 and the metabolism of DAPA to its 3-O-glucuronide. See Dr. Fred Alavi’s
`pharmacology/toxicology review in DARRTS dated June 15, 2015.
`Study CV181191 was a single-dose, 3-period, 3-treatment, crossover study to assess the mutual
`interaction of SAXA and DAPA in 42 randomized healthy volunteers (29 men, 13 women, body mass
`index of 19.5 – 30.1 kg/m2, and aged 19 – 43 years). The 3 treatments are the following with 6 days of
`washout period between treatments:
`5 mg SAXA
`
`10 mg DAPA
`
`5 mg SAXA coadministered with 10 mg DAPA
`
`Serial blood samples were collected predose and 60 hours postdose to determine SAXA, 5-OH SAXA,
`and DAPA via validated liquid chromatography tandem mass spectrometry (LC/MS/MS) bioanalytical
`assays.
`
`Reference ID: 3810575
`
`7
`
`

`

`Figure 4. Mean (+SD) DAPA plasma concentration versus time profile (PK evaluable population)
`
`Treatment B = 10 mg DAPA
`Treament C = 5 mg SAXA + 10 mg DAPA
`Source: Study CV181191’s report Figure 11.1
`
`Figure 5. Mean (+SD) SAXA and 5-OH SAXA plasma concentration versus time profile (PK
`evaluable population).
`SAXA
`
`5-OH SAXA
`
`Source: Study CV181191’s report Figures 11.2 (SAXA) and 1.31 (5-OH SAXA)
`
`Table 3. Effect of concomitant administration of SAXA on DAPA PK.
`
`Treatment B = 10 mg DAPA; Treatment C = 5 mg SAXA + 10 mg DAPA
`Source: Section 2.7.2 Table 2.
`The ratios of adjusted geometric mean (GM) for DAPA Cmax, AUC(0-T), and AUC(INF) indicated a decrease
`of 6, 1, and 2%, respectively, with concomitant administration of SAXA (Table 3). The 90% CI of ratios
`of adjusted GM for DAPA Cmax, AUC(0-T), and AUC(INF) with concomitant administration of SAXA
`contained 1 and were all within the 0.8 – 1.25 bioequivalent goalpost (Table 3).
`8
`
`Reference ID: 3810575
`
`

`

`Table 4. Effect of concomitant administration of DAPA on SAXA and 5-OH SAXA PK.
`
`Analyte
`
`[Treatment
`and
`Comparison
`
`Cmax
`(ng/mL)
`Adjusted GM [11]
`
`AUC (0-1)
`(ng h/mL)
`Adjusted GM [11]
`
`AUC (INF)
`(ng h/mL)
`Adjusted GM [11]
`
`Saxagliptin
`
`A
`
`C
`
`23.6 [42]
`
`21.9 [42]
`
`87.8 [42]
`
`87.0 [42]
`Ratio of Adjusted GM (90% Cl)
`
`89.0 [42]
`
`88.2 [42]
`
`C vs A
`
`0.927 (0.883. 0.972)
`
`0.991 (0.960. 1.022)
`
`0.991 (0.961. 1.022)
`
`5—OH
`
`Saxagliptin
`
`A
`
`C
`
`47.0 [42]
`
`267 [42]
`
`273 [42]
`
`49.6 [42]
`
`289 [42]
`
`296 [42]
`
`Ratio of Adjusted GM (90% Cl)
`
`C VS A
`
`1.055 (1.004. 1.109)
`
`1.085(1.058. 1.113)
`
`1.085(1.058. 1.113)
`
`Treatment A = 5 mg SAXA: Treatment C = 5 mg SAXA + 10 mg DAPA
`Source: Section 2.7.2 Table 3.
`
`The ratios of adjusted GM for SAXA Cm, AUC(M), and AUCONB indicated a decrease of 7, 1, and 1%,
`respectively, with concomitant administration of DAPA (1"able 4). The 90% CI of ratios of adjusted GM
`for SAXA Cm, AUC(0_1), and AUCGNE) with concomitant administration of DAPA were, however, all
`within the 0.8 — 1.25 bioequivalent goalpost (Table 4) and contained l. The ratios of adjusted GM for 5-
`0H SAXA Cm, AUCan), and AUCGNF) indicated an increase of 6, 9, and 9%, respectively, with
`concomitant administration of DAPA (Table 4). The 90% CI of ratios of adjusted GM for 5-OH SAXA
`Cm, AUCQD, and AUCGNB with concomitant administration of DAPA were, however, all within the 0.8
`— 1.25 bioequivalent goalpost (Table 4) and contained 1.
`
`This reviewer’s statistical analyses results for DAPA and SAXA are consistent with the sponsor’s
`analyses. See Attachment.
`
`According to the above analyses, SAXA and DAPA do not significantly interact with each other upon
`coadministration of 5 mg SAXA and 10 mg DAPA.
`
`2.6 General Biopharmaceutics
`2.6.1 Are the clinically tested SAXA oral tablets and DAPA oral tablets identical to the marketed
`commercial SAXA oral tablets and DAPA oral tablets?
`
`(we)
`
`bioequivalence study (CV181341) used commercial SAXA tablets and DAPA tablets (see Project
`Manager, A. Adeolu’s memo in DARRTS dated January 30, 2015).
`
`The
`
`2.6.2 Are the clinically tested SAXA/DAPA FDC tablets identical to the to-be-marketed
`SAXA/DAPA FDC tablets?
`(mo 5 mg SAXA/ 10 mg DAPA FDC tablets
`Except for
`on» the
`used in the pivotal bioequivalence study were the same as the to-be—marketed FDC tablets (Section
`3.2.P.2.2 Page 18/20).
`
`Reference ID: 381 0575
`
`

`

`2.6.3 What is the relative BA of the SAXA/DAPA FDC oral tablets to the coadministration of
`corresponding individual innovator SAXA oral tablets and DAPA oral tablets?
`Study CV181341 examined the relative bioavailability of SAXA/DAPA FDC oral tablets to individual
`innovator SAXA oral tablets and DAPA oral tablets. See Dr. Peng Duan’s Biopharmaceutics review in
`DARRTS.
`
`2.7 Bioanalytical
`Are the bioanalytical methods properly validated for Study CV181191 in NDA
`?
`Table 5 below summarizes the bioanalytical method validation for saxagliptin, 5-OH saxagliptin, and
`dapagliflozin for Study CV181191.
`
`Table 5. Validation of LC/MS/MS bioanalytical assays for saxagliptin, 5-OH saxagliptin, and
`dapagliflozin for Study CV181191.
`Saxagliptin
`plasma
`100
`0.1
`0.1 – 50
`
`Matrix
`Sample volume, µL
`LLOQ, ng/mL
`Linear range, ng/mL
`Assay Precision (% CV)
`Inter-
` 4.9
` 4.4
` 2.8
`Intra-
` 3.8
` 5.2
` 9.2
`± 2.0
`± 4.2
`± 4.3
`Accuracy (% deviation)
`These are LC/MS/MS bioanalytical assays. Ethylenediaminetetra acetic acid was the anticoagulant for the blood samples.
`LLOQ = lower limit of quantitation Source: This reviewer’s modified version of the sponsor’s submission, Section 2.7.1, Table 8.
`
`5-OH saxagliptin
`plasma
`100
`0.2
`0.2 – 100
`
`Dapagliflozin
`plasma
`50
`0.2
`0.2 – 100
`
`Stability data were established for saxagliptin and 5-OH saxagliptin as the following:
`benchtop stability in human plasma for at least 24 hours for saxagliptin and at least 42 hours
`
`for 5-OH saxagliptin
`6 freeze thaw cycles and autosampler stability for at least 31 hours at room temperature
`long term stability at -20°C for 401 days
`
`
`
`
`Stability data were established for dapagliflozin as the following:
`bench-top stability of dapagliflozin in human plasma for at least 24 hours
`
`5 freeze-thaw cycles at -20°C and -70°C post-preparative extract stability for at least 72 hours
`
`at room temperature and 141 hours at 2 to 8°C
`long term stability at -20°C and -70°C for 337 days
`
`
`
`All validations for the LC/MS/MS bioanalytical methods for Study CV181191 appear acceptable with
`reasonable precision and accuracy. For the review of bioanalytical methods validation of Study
`CV181341, see Dr. Peng Duan’s Biopharmaceutics review in DARRTS.
`
`Reference ID: 3810575
`
`10
`
`2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`Reviewer’s Analysis:
`
`Attachment
`
`Source: Reviewer’s analysis
`
`Source: Reviewer’s analysis
`
`These results were consistent with the sponsor’s analysis except some minor differences in the GMR and
`90% CI estimates, which did not alter the interpretation of the results. This reviewer used the SAS PROC
`GLM procedure to calculate the GMR and 90% CI, whereas the sponsor used the SAS PROC MIXED
`procedure.
`
`Reference ID: 3810575
`
`13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SZE W LAU
`08/24/2015
`
`MANOJ KHURANA
`08/24/2015
`
`Reference ID: 3810575
`
`