CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`209483Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets: NDA 022350 ONGLYZA (saxagliptin): NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`
`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`(see electronic signature)
`William H. Chon , MD
`Cross-Disci o line Team Leader Review
`
`From
`
`Sub ' ect
`
`NDA/BLA #
`
`NDA 209091
`
`Supplement#
`
`NDA 022350, Suppl 18
`NDA 200678, Su 1 18
`AstraZeneca
`Applicant
`Date of Submission
`
`AOI'l127, 2016
`
`PDUFA Goal Date
`27, 2017
`Feb
`
`
`Proprietary Name /
`
`Established (USAN) names
`
`Dosage forms / Strength
`
`NDA 209091: QTERN (dapagliflozin and saxagliptin)
`NDA 022350: ONGLYZA (saxagliptin)
`NDA 200678: KOMBIGLYZE XR (saxagliptin and
`metfonnin h drochloride extended release
`
`NDA 209091: 10 mg/5 mg (dapagliflozin/saxagliptin)
`tablets
`
`NDA 022350: 5 mg and 2.5 mg tablets (saxagliptin)
`NDA 200678: 5 mg/500 mg, 5 mg/1000 mg, and 2.5
`mg/ 1000 mg (saxagliptin/metfonnin HCl extended release)
`tablets
`
`Proposed Indication(s)
`
`NDA 20901: Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus(m4)
`
`
`
`
`
`
`Recommended Indication(s)
`
`NDA 022350: Not applicable
`
`NDA 200678: Not applicable
`NDA 209091: Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`who have inadequate glycemic control on dapagliflozin or
`who are already treated with dapagliflozin and saxagliptin
`NDA 022350: Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`NDA 200678: Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus
`when treatment with both saxagliptin and metfomlin is
`
`appropriate.
`A roval
`
`Recommendation:
`
`Page 1 of 13
`
`Reference ID: 4061685
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin): NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`
`Cross Discipline Team Leader Review
`
`1. Introduction
`
`AstraZeneca (hereafter referred to as the applicant) submitted a new drug application (NDA)
`for a fixed combination drug product GCDP) that combines saxagliptin, a dipeptidyl
`peptidase4 (DPP4) inhibitor, with dapagliflozin, a sodium glucose cotransporter2 (SGLT2)
`inhibitor for use in adult patients with type 2 diabetes mellitus (T2D1VI). The applicant has
`previously submitted an NDA
`m" for this FCDP, but a Complete Response was
`issued for that application citing a need for more data
`M”
`
`Rather, the applicant has submitted a new NDA with a different
`study to support use of this FDCP. This Cross-Discipline Team Leader (CDTL) review will
`summarize the relevant information fiom the involved review disciplines and their
`recommendations. I will discuss the efficacy data and the relevance to the indication as well
`as safety findings focusing on the additional available data on muscle injury.
`
`2. Background
`
`Type 2 diabetes mellitus is a disease of impaired glucose homeostasis that results in chronic
`hyperglycemia which in turn leads to an increased risk for microvascular (e.g., retinopathy,
`nephropathy) and macrovascular (e.g., myocardial infarction, stroke) complications. Based on
`the results of the Diabetes Control and Complication Trial ODCCT) 1 and the United Kingdom
`Prospective Diabetes study (UKPDS) 2, improved glycemic control (as measured using
`hemoglobin Alc [HbAlc]) is believed to result in improved clinical outcomes.
`
`Many patients with T2DM require multiple antidiabetic drugs to achieve the desired degree of
`glycemic control, and most patients require intensification of therapy (i.e., addition of
`antidiabetic drugs) as the duration of disease progresses. There are currently 11 classes of
`antidiabetic drugs with most classes having multiple members (Table 1). Many of these drug
`products are also available as FCDPs. The FDA has also approved combinations of basal
`insulin with a GLPl receptor agonist.
`
`1 The Diabetes Control and Complications Trial Research Group. “The effect of intensive treatment of diabetes
`on the development and progression of long-term complications in insulin-dependent diabetes mellitus”. NEJM.
`1993: 329 (14): 977-986.
`2 UK Prospective Study Group. “Intensive blood-glucose control with sulphonylureas or insulin compared with
`conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)”. Lancet, 1998:
`352 (9131): 837-853.
`
`Page 2 of 13
`
`Reference ID: 4061685
`
`2
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin): NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`
`Cross Discipline Team Leader Review
`
`Table 1: Summary of FDA approved drugs to improve glycemic control in diabetes
`
`
`
`Insulin and insulin analogs
`
`Multiple products including basal. prandial. and mixed insulin
`products
`Biguanides
`Metformin (as an immediate release and an extended release
`
`formulation)
`
`Chlorpropamide. Glimepilide. Glipizide. Glyburide
`Sulfonylureas
`
`Thiazolidinediones
`Rosiglitazone. Pioglitazone
`
`Meglitinides
`Repaglinide, Nateglinide
`
`Alpha glucosidase inhibitors
`Acarbose. Miglitol
`
`Dipeptidyl peptidase4 (DPP4) inhibitors
`Sitagliptin. Saxagliptin. Alogliptin. Linagliptin
`Glucagonlike peptide] (GLPl) receptor
`Exenatide (as a twice daily and as a once weekly). Liraglutide.
`
`agonists
`Albiglutide, Dulaglutide. Lixisenatide
`Sodium glucose cotransporter2 (SGLT2)
`Canagliflozin, Dapagliflozin, Empagliflozin
`
`inhibitors
`
`Amylin analogs
`Pramlintide
`
`Bile acid sequestrants
`Colesevelam
`
`Dopamine agonists
`Bromocriptine
`Basal insulin and GLPl receptor agonist
`Insulin glargine and lixisenatide, insulin degludec and liraglutide
`combinations
`
`
`
`
`
`
`
`
`The applicant is now proposing to market an FCDP that combines saxagliptin (a DPP4
`inhibitor) with dapagliflozin (an SGLT2 inhibitor). The DPP4 inhibitors prolong the
`circulation of endogenous incretin hormones by preventing DPP4 mediated degradation. This
`in tum is believed to increase insulin secretion in response to a glucose load and decrease
`glucagon secretion. The SGLT2 inhibitors block glucose reabsorption in the kidney, thus
`resulting in an insulin independent reduction in plasma glucose levels. The applicant believes
`that this FCDP offers patients with T2DM a way to combine two drugs which improve
`glycemic control through different mechanisms of action in a manner that will be convenient
`and that may improve compliance.
`
`An NDA for this FCDP was previously submitted (NDA
`was issued for that NDA
`
`(mo), but a Complete Response
`(”(4)
`
`mm).
`(see Complete Response Letter issued on October 15, 2015 under NDA
`Following receipt of the Complete Response Letter, an End of Review meeting was held on
`December 17, 2015 to discuss potential paths forward for the FCDP. Options includedmm
`
`or submitting a new NDA with data from a study of adding saxagliptin to
`patients with inadequate glycemic control on dapagliflozin (see Meeting Minutes issued on
`January 14, 2016). The applicant has opted to do the latter
`
`mm)
`
`Page 3 of 13
`
`Reference ID: 4061685
`
`3
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`3. CMC/Device
`
`There is no new Chemistry, Manufacturing, and Controls (CMC) data for NDA 022350 or
`NDA 200678. For the CMC information of these two drug products, see the currently
`approved prescribing information. This section will discuss data relevant to NDA 209091.
`
`The Chemistry, Manufacturing, and Controls (CMC) review of the FCDP was previously
`completed during review of NDA
`The drug substance and drug product review was
`completed by John Amartey, the man acturing process and microbiology review was
`completed by Daniel Peng, the manufacturing facilities review was completed by Vipul
`Dholakia, and the biopharmaceutics review was completed by Peng Duan.
`
`The reviewers from the Office of Product Quality recommended Approval of the NDA during
`review ofNDA- In the current submission, the a
`licant has made onl minor
`
`chan es to the CMC information.
`
`
`y e CMC rev1ewers an were oun to be
`acceptable. The Office of Product Quality recommends Approval for NDA 209091.
`
`For detailed discussion of the CMC findings, see the completed Quality Review from NDA
`and the Dr. Amartey’s Memorandum for NDA 209091. A brief summary of the CMC
`ta is included below.
`
`
`The saxa 1i tin and da a iflozin FCDP is manufactured as a film coated tablet
`
`
`
`see Figure 1 .
`
`Fi
`
`
`re 1: Saxa li tin and da a liflozin tablet
`
`
`
`Source: Excerpted from page 11 of the Quality Review for NDA-
`
`Page 4 of 13
`
`Reference ID: 4061685
`
`4
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin): NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`
`Cross Discipline Team Leader Review
`
`(I!) (4)
`
`The applicant is proposing to manufacture/market only the 10 mg dapagliflozin/S mg
`saxagliptin dosage strength.
`
`Long-term stability studies were performed with three batches in blister packs and four batches
`of in high density polyethylene bottles. Based on review of the stability data, the Quality
`Review concludes that the proposed 36month shelf life is justified.
`
`I agree with the CMC reviewers that the CMC data support Approval.
`
`4. Nonclinical Pharmacology/Toxicology
`
`There is no new nonclinical data for NDA 022350 or NDA 200678. For the nonclinical
`
`information of these two drug products, see the currently approved prescribing information.
`This section will discuss data relevant to NDA 209091.
`
`one was completed by Dr. Fred Alavi. An updated
`The nonclinical review for NDA
`review for this NDA was completed by Dr. Jeffery Quinn. Both Dr. Alavi and Dr. Quinn
`recommend Approval. For detailed discussion of the nonclinical findings, see Dr. Alavi’s
`completed review in NDA
`W0 and Dr. Quinn’s completed review in NDA 209091.
`
`The nonclinical data to support the fixed combination drug product is drawn primarily from
`the individual components (see primary nonclinical reviews under NDA 022350 [saxagliptin]
`and NDA 202293 [dapagliflozin]). Additional safety findings to support the combination of
`saxagliptin + dapagliflozin come from a 3 month rat toxicology study and an in vitro hlunan
`liver microsomal metabolism study. In these two studies, coadministration of the two drugs
`was studied. The combination of dapagliflozin + saxagliptin did not result in a synergistic
`effect on the toxicity profile with the exception of increased proteinuria in male rats at doses
`6x the maximum recommended human dose. Based on the data reviewed, Dr. Alavi and Dr.
`Quinn conclude that the nonclinical data support approval of this FCDP.
`
`I agree that the nonclinical data support Approval.
`
`Page 5 of 13
`
`Reference ID: 4061685
`
`5
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin): NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`
`Cross Discipline Team Leader Review
`
`5. Clinical Pharmacologleiopharmaceutics
`
`There is no new clinical pharmacology data for NDA 022350 or NDA 200678. For the
`clinical pharmacology information of these two drug products, see the currently approved
`prescribing information. This section will discuss data relevant to NDA 209091.
`
`The clinical pharmacology review was completed by Dr. SW. Johnny Lau with additional
`biopharmaceutics review by Dr. Peng Duan. Based on review of the submitted data, the
`clinical pharmacology reviewer recommends Approval. For detailed discussion of the clinical
`pharmacology findings, see Dr. Lau’s completed review in NDA
`(m4)
`
`Two clinical pharmacology studies were submitted to support the NDA. The first (study
`CV181191) was a drug-drug interaction study of dapagliflozin 10 mg and saxagliptin 5 mg.
`The second (study CV181341) was designed to demonstrate the bioequivalence of the
`combination tablet with the coadministration of the individual components. This study also
`included an assessment of food effect. Study CV181341 was reviewed by Biopharmaceutics.
`
`Results from study CV181191 showed that coadministration of dapagliflozin 10 mg and
`saxagliptin 5 mg does not result in a significant interaction.
`
`(mm) was included in the submission
`An additional clinical pharmacology study (study
`(m4)
`for NDA 209091. This study was conducted
`and was submitted as complementary data for the previously reviewed studies. This
`study was not reviewed as part of the NDA review.
`
`(m4)
`While the clinical pharmacology reviewer recommends Approval,
`I agree that the data support Approval.
`mu) there is sufficient data to support
`the proposed dosage strength of dapagliflozin 10 mg/saxagliptin 5 mg.
`
`6. Clinical Microbiology
`
`Not applicable.
`
`7. Clinical/Statistical Efficacy
`
`The statistical review of this NDA (and efiicacy supplements) was completed by Dr. Anna
`Kettermann.
`
`The applicant has submitted three clinical studies (study CV181 168, study CV181169, and
`study MB102129) in support of NDA 209091. Each of the studies and the findings will be
`briefly discussed here. Only one (study CV181168) is proposed for inclusion in labeling to
`
`Page 6 of 13
`
`Reference ID: 4061685
`
`6
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`support the proposed indication. This study has also been submitted to NDA 022350 and
`NDA 200678 for inclusion in section 14 of the prescribing information. While Dr.
`Kettermann has reviewed all three studies, my discussion of efficacy will focus on study
`CV181168.
`
`Study CV181168 was a randomized, double-blind, placebo-controlled study comparing the
`effect of sequentially adding saxagliptin vs. placebo to a background of dapagliflozin and
`metformin. The study enrolled patients needing additional glycemic control despite therapy
`with metformin, treated them with dapagliflozin 10 mg for 8 weeks, and then randomized
`those patients requiring additional glycemic control to either saxagliptin 5 mg or placebo
`(Figure 2).
`
`Figure 2: Study schematic for study CV181168
`
`Source: Excerpted from Figure 3.11 of the study report for CV181168
`
`The primary endpoint was change in HbA1c from baseline (i.e., Day 1) to week 24 (i.e., after
`24 weeks of saxagliptin or placebo). Secondary endpoints included change in 2hour
`postprandial glucose, change over time in HbA1c and fasting glucose, and percentage of
`subjects achieving HbA1c < 7%.
`
`The applicant utilized a longitudinal repeated measures analysis to estimate change from
`baseline for HbA1c. The primary analysis population consisted of all randomized subjects that
`received at least one dose of double-blind study drug (i.e., saxagliptin or placebo). Data on
`HbA1c collected after discontinuation of study drug was excluded from the primary analysis
`by the applicant.
`
`Dr. Kettermann does not believe that excluding data after discontinuation will yield a realistic
`estimate of the effect. As such, Dr. Kettermann has conducted analyses including data
`regardless of adherence which she believes will more appropriately describe real world
`outcomes.
`
`Page 7 of 13
`
`Reference ID: 4061685
`
`7
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`Both the applicant and Dr. Kettermann conclude that the addition of saxagliptin on top of a
`background of dapagliflozin and metformin demonstrated a statistically significant greater
`reduction in HbA1c at week 24 compared to the addition of placebo (Table 2). Dr. Ketterman
`conducted various analyses using alternative approaches to the handling of missing data
`examining the difference for change in HbA1c. All analyses supported the conclusion that
`addition of saxagliptin led to greater reduction in HbA1c than addition of placebo.
`
`Table 2: Summary of HbA1c findings for study CV181168
`- Compared addition of saxagliptin vs. addition of placebo in patients inadequately
`controlled following addition of dapagliflozin 10 mg in patients on metformin therapy
`Difference for change in HbA1c
`95% CI
`at 24 weeks
`-0.35%
`-0.52, -0.18
`
`Applicant’s analysis1
`FDA analyses
`- MI (J2R)
`- MI (CR)
`- MI (retrieved dropouts, ANCOVA)
`- MMRM
`1 mixed effect model repeat measurement without data after rescue
`MI (J2R) = missing data imputation, jump-to-reference; MI (CR) = missing data imputation, copy reference; MI
`(retrieved dropouts, ANCOVA) = missing data imputation using retrieved dropouts, analysis of covariance;
`MMRM = mixed model repeated measures
`Source: Adapted from Table 7 and Table 8 of Dr. Kettermann’s statistical review
`
`-0.336
`-0.334
`-0.395%
`-0.337
`
`-0.504, -0.166
`-0.505, -0.167
`-0.54, -0.233
`-0.504, -0.171
`
`No statistically significant difference was seen for either fasting plasma glucose or 2hour
`postprandial glucose (Table 3).
`
`Table 3: Summary of fasting glucose and postprandial glucose findings for study
`CV181168
`- Compared addition of saxagliptin vs. addition of placebo in patients inadequately
`controlled following addition of dapagliflozin 10 mg in patients on metformin therapy
`Difference at 24 weeks
`95% CI
`-3.7 mg/dL
`-14.9, 3.1
`Fasting glucose
`-5.9 mg/dL
`-11, 3.6
`2-hour postprandial glucose
`Source: Adapted from Table 9 of Dr. Kettermann’s statistical review
`
`At week 24, a greater proportion of subjects randomized to receive saxagliptin had an HbA1c
`< 7% (35.3% vs. 23.1%).
`
`Subgroup analyses were generally consistent with the findings for the population as a whole.
`While the nonwhite subjects did not demonstrate a statistically significant difference, this is
`likely due to the small number of nonwhite subjects (nearly 90% of subjects in study
`CV181168 were classified as white). The treatment difference was smaller for subjects from
`the North America region (-0.25%, 95% CI [-0.48, -0.01]). Subjects from Latin America had
`the largest difference (-0.56%, 95% CI [-1.02, -0.1]). Reasons for this are unclear.
`
`Page 8 of 13
`
`Reference ID: 4061685
`
`8
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`Dr. Kettermann concludes that adding saxagliptin to dapagliflozin results in a statistically
`significantly greater reduction in HbA1c compared to placebo at 24 weeks, and that the
`efficacy findings support approval of this NDA. I agree with this assessment.
`
`8. Safety
`
`The discussion of safety will primarily focus on the data as it relates to NDA 209091. No new
`safety concerns relevant to ONGLYZA or KOMBIGLYZE XR were identified from the
`submitted data for NDA 022350 or NDA 200678.
`
`The safety review was completed by Dr. Frank Pucino. Dr. Pucino did not identify any safety
`issues which would preclude approval.
`
`The overall safety profile of combining dapagliflozin and saxagliptin is consistent with what
`would be expected if combining the safety profiles of the individual drug products.
`Combining dapagliflozin and saxagliptin did not appear to exacerbate any of the previously
`identified safety concerns for the two drug products. Overall, no concerning findings in terms
`of deaths or serious adverse events were observed. For a detailed discussion of the safety
`findings from the development program, see Dr. Pucino’s clinical review.
`
`One safety concern which I will discuss here was the potential for muscle injury. During
`review of the small safety database included with NDA
` it was noted that the incidence
`of marked elevation of creatine kinase was higher in the arm which combined dapagliflozin
`and saxagliptin compared to the individual treatments. There was one event of
`rhabdomyolysis in the database without a clear explanation. In this NDA, the safety database
`is expanded to include the long-term safety data from studies CV181168 and MB102129
`which adds approximately an additional 100 patient-years of exposure. Additionally, non-
`serious adverse event data are unblinded for review.
`
`No notable changes were seen when looking at mean changes from baseline for creatine
`kinase. There remains in imbalance in marked elevations of creatine kinase in subjects treated
`with both dapagliflozin and saxagliptin compared to subjects treated with either of the
`components (Table 4). The clinical significance of this is unclear.
`
`Table 4: Summary of Marked Elevations in Creatine Kinase in the Pooled Safety
`Database
`
`Creatine kinase > 5x ULRR
`Creatine kinase > 10x ULRR
`ULRR = upper limit of reference range
`Source: Adapted from Table 19 of Dr. Pucino’s Clinical Review
`
`Dapa + Saxa
`N=486
`N (%)
`7 (1.4)
`4 (0.8)
`
`Saxa
`N=334
`N (%)
`0
`0
`
`Dapa
`N=334
`N (%)
`1 (0.3)
`1 (0.3)
`
`Page 9 of 13
`
`Reference ID: 4061685
`
`9
`
`(b) (4)
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`The subjects treated with dapagliflozin and saxagliptin did not have an increased incidence of
`serious adverse events from the ‘Musculoskeletal and connective tissue disorders’ system
`organ class (Table 5).
`
`In looking at treatment emergent adverse events from the ‘Musculoskeletal and connective
`tissues disorder’ system organ class, subjects treated with dapagliflozin and saxagliptin had a
`higher incidence than those treated with dapagliflozin but lower than those treated with
`saxagliptin. During review of NDA
` these data were not available for review.
`“Arthralgia’ was reported more commonly for subjects treated with the combination of
`dapagliflozin and saxagliptin compared to the individual components (2.4% dapagliflozin +
`saxagliptin vs. 1.2% saxagliptin vs. 0.9% dapagliflozin), as was ‘Myalgia’ (0.8% dapagliflozin
`+ saxagliptin vs. 0.3% saxagliptin vs. 0.9% dapagliflozin). While there is the case of
`rhabdomyolysis without clear explanation or obvious confounders that was identified
`previously during review of NDA
` no additional such cases were identified in review
`of the expanded safety database.
`
`Table 5: Summary of Treatment Emergent Adverse Events Reported from the
`‘Musculoskeletal and Connective Tissue Disorders’ System Organ Class in the Pooled
`Safety Database
`-
`Includes events from long-term period
`
`Saxa
`N=336
`N
`%
`1
`(0.3)
`1
`(0.3)
`0
`(0)
`51
`(15.2)
`12
`(3.6)
`4
`(1.2)
`7
`(2.1)
`7
`(2.1)
`1
`(0.3)
`7
`(2.1)
`1
`(0.3)
`5
`(1.5)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`2
`(0.6)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`1
`(0.3)
`1
`(0.3)
`
`Dapa
`N=341
`N
`%
`0
`(0)
`0
`(0)
`0
`(0)
`37
`(10.9)
`8
`(2.3)
`3
`(0.9)
`2
`(0.6)
`6
`(1.8)
`2
`(0.6)
`2
`(0.6)
`1
`(0.3)
`5
`(1.5)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`1
`(0.3)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`
`SERIOUS ADVERSE EVENTS
`- ARTHRITIS
`- RHABDOMYOLYSIS
`TREATMENT EMERGENT ADVERSE EVENTS
`- BACK PAIN
`- ARTHRALGIA
`- MUSCULOSKELETAL PAIN
`- PAIN IN EXTREMITY
`- MYALGIA
`- MUSCLE SPASMS
`- ARTHRITIS
`- NECK PAIN
`- SPINAL OSTEOARTHRITIS
`- FLANK PAIN
`- INTERVERTEBRAL DISC DEGENERATION
`- INTERVERTEBRAL DISC PROTRUSION
`MUSCLE FATIGUE
`- MUSCULOSKELETAL CHEST PAIN
`- OSTEOARTHRITIS
`- OSTEOCHONDROSIS
`- PAIN IN JAW
`- PERIARTHRITIS
`- PERIOSTITIS
`- RHABDOMYOLYSIS
`- ROTATOR CUFF SYNDROME
`- ANKLE IMPINGEMENT
`- BONE PAIN
`
`Dapa + Saxa
`N=492
`N
`%
`1
`(0.2)
`0
`(0)
`1
`(0.2)
`64
`(13.0)
`16
`(3.3)
`12
`(2.4)
`6
`(1.2)
`5
`(1.0)
`4
`(0.8)
`3
`(0.6)
`2
`(0.4)
`2
`(0.4)
`2
`(0.4)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0 2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`1
`(0.2)
`0
`(0)
`0
`(0)
`
`Page 10 of 13
`
`Reference ID: 4061685
`
`10
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`Dapa
`Saxa
`Dapa + Saxa
`N=341
`N=336
`N=492
`N
`%
`N
`%
`N
`%
`- BURSITIS
`1
`(0.3)
`1
`(0.3)
`0
`(0)
`- COSTOCHONDRITIS
`1
`(0.3)
`0
`0
`0
`(0)
`- INTERVERTEBRAL DISC DISORDER
`1
`(0.3)
`0
`(0)
`0
`(0)
`- JOINT SWELLING
`0
`(0)
`1
`(0.3)
`0
`(0)
`- OSTEOPENIA
`1
`(0.3)
`0
`(0)
`0
`(0)
`- SPINAL PAIN
`1
`(0.3)
`0
`(0)
`0
`(0)
`- TENDONITIS
`1
`(0.3)
`0
`(0)
`0
`(0)
`- TRIGGER FINGER
`1
`(0.3)
`1
`(0.3)
`0
`(0)
`Source: Reviewer generated based on review of adae.xpt file in module 5.3.5.3 st-lt-pool – Pooled datasets short
`term plus long term
`
`The lack of additional cases of rhabdomyolysis without an apparent alternative etiology is
`reassuring given the additional patient-years of exposure in the updated safety database. The
`absence of a clear imbalance in muscle related treatment emergent adverse events also
`provides some reassurance that an effect on muscle tissue (if any) is not likely to be substantial
`or of severe. There remains some uncertainty, however, due to the continued observation of a
`higher incidence of marked increases in creatine kinase with dapagliflozin + saxagliptin
`compared to what was seen with the individual treatment with saxagliptin or dapagliflozin.
`
`9. Advisory Committee Meeting
`
`Not applicable. No Advisory Committee Meeting was convened to discuss this NDA.
`
`10.
`
`Pediatrics
`
`The applicant has requested a full waiver for pediatric studies. This request was discussed
`with the Pediatric Review Committee on October 5, 2016. A full waiver for pediatric studies
`was granted as appropriate studies to inform the use of this FDCP in the pediatric population
`would be impossible or highly impracticable.
`
`11.
`
`Other Relevant Regulatory Issues
`
`Not applicable.
`
`12.
`
`Labeling
`
`The proposed proprietary name (QTERN) was reviewed and found acceptable.
`
`Page 11 of 13
`
`Reference ID: 4061685
`
`11
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
`The applicant proposed the following indication:
`“Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus
`”
`
`I do not believe that study CV181168 is sufficient to support this indication. I recommend
`granting the following indication:
`
`“Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus who have inadequate glycemic control on dapagliflozin or who are already treated
`with dapagliflozin and saxagliptin”
`
`Given the increased incidence of marked elevations in creatine kinase and case of
`rhabdomyolysis without clear explanation, I recommend including a discussion of this finding
`in section 6 of the prescribing information.
`
`The presentation of safety information should be updated to be consistent with recent Safety
`Labeling Changes and safety findings not captured in the FDCP development program but
`associated with the two individual drug products should be included in the prescribing
`information.
`Recommendations/Risk Benefit Assessment
`13.
` Recommended Regulatory Action
`
`I recommend approval for NDA 209091 and the associated supplemental NDAs.
`
` Risk Benefit Assessment
`
`Safety findings from the studies of combining dapagliflozin and saxagliptin were generally
`consistent with what would be expected if one combined these two products. No substantial
`safety concerns were identified which would preclude or contraindicate combining
`dapagliflozin with saxagliptin. The addition of saxagliptin to patients with inadequate
`glycemic control while being treated with dapagliflozin 10 mg demonstrated a statistically
`significant greater reduction in HbA1c compared to the addition of placebo. Overall, the
`benefit of additional glycemic control weighs favorably when compared to the safety profile of
`these two drugs.
`
` Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`I do not recommend a Risk Evaluation and Management Strategy.
`
`Page 12 of 13
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`Reference ID: 4061685
`
`12
`
`(b) (4)
`
`

`

`NDA 209091 QTERN (dapagliflozin and saxagliptin) tablets; NDA 022350 ONGLYZA (saxagliptin); NDA
`200678 KOMBIGLYZE XR (saxagliptin and metformin hydrochloride extended release)
`Cross Discipline Team Leader Review
`
` Recommendation for other Postmarketing Requirements and Commitments
`
`I do not recommend any Postmarketing Requirements of Commitments.
`
` Recommended Comments to Applicant
`
`None.
`
`Page 13 of 13
`
`Reference ID: 4061685
`
`13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H CHONG
`02/27/2017
`
`JEAN-MARC P GUETTIER
`02/27/2017
`I concur.
`
`Reference ID: 4061685
`
`