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

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`Requesting Office or Division:
`
`February 24, 2017
`Division of Metabolism and Endocrinology Products
`(DMEP)
`Application Type and Number: NDA 209091
`Product Name and Strength:
`Qtern (dapagliflozin and saxagliptin), tablets 5 mg/10 mg
`Submission Date:
`February 24, 2017
`Applicant/Sponsor Name:
`AstraZeneca
`OSE RCM #:
`2016-1009-4
`DMEPA Primary Reviewer:
`Ariane O. Conrad, PharmD, BCACP, CDE
`DMEPA Team Leader:
`Hina Mehta, PharmD
`
`PURPOSE OF MEMO
`1
`Division of Metabolism and Endocrinology Products (DMEP) requested that we review the
`revised commercial container label, professional sample carton labeling, and professional
`sample blister cards for Qtern (Appendix A) to determine if they are acceptable from a
`medication error perspective. The revisions are in response to recommendations that we made
`during a previous label and labeling review.a
`
` CONCLUSION
`2
`The revised commercial container labels, professional sample carton labeling, and professional
`sample blister cards for Qtern are acceptable from a medication error perspective. We have no
`further recommendations at this time.
`
`a Conrad A. Label and Labeling Review Memo for Qtern (NDA 209091). Silver Spring (MD): Food and Drug
`Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2017 Feb 21. 4p. OSE RCM No.: 2016-1009-3.
`1
`
`Reference ID: 4060808
`
`

`

`APPENDIX A. LABEL AND LABELING SUBMITTED ON FEBRUARY 24, 2017
`
`Commercial Container Labels
`
`Reference ID: 4060808
`
`2
`
`(b) (4)
`
`

`

`Professional Sample Blister Cards
`
`Professional Sample Carton Labeling
`
`
`
`
`Reference ID: 4060808
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ARIANE O CONRAD
`02/24/2017
`
`HINA S MEHTA
`02/24/2017
`
`Reference ID: 4060808
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
`
`Division of Pediatric and Maternal Health
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Silver Spring, MD 20993
`Telephone: 301-796-2200
`FAX:
` 301-796-9744
`
`PLLR Labeling Review
`
`Date:
`
`From:
`
`February 16, 2017 Date consulted: May 2, 2016
`
`Christos Mastroyannis, M.D., Medical Officer, Maternal Health,
`Division of Pediatric and Maternal Health (DPMH)
`
`Through:
`
`Tamara Johnson, MD, MS, Team Leader, Maternal Health,
`Division of Pediatric and Maternal Health
`
`Lynne P. Yao, MD, OND, Division Director
`Division of Pediatric and Maternal Health
`
`Division of Metabolic and Endocrine Products (DMEP)
`
`QTERN [dapagliflozin /saxagliptin/ fixed dose combination (FDC) tablet]
`for oral use
`
`Sodium glucose cotransporter 2 (SGLT 2) inhibitor/ Dipeptidyl peptidase
`4 (DPP 4) inhibitor, respectively, combination product
`
`To:
`
`Drug:
`
`Class:
`
`NDA:
`
`209091
`
`Applicant:
`
`AstraZeneca Pharmaceuticals LP (AZ)
`
`Subject:
`
`Pregnancy and Lactation Labeling Rule (PLLR) Conversion
`
`Indication(s) Qtern is indicated as an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus (T2DM)
`
`
`Reference ID: 4057405
`
`Page 1 of 17
`
`(b) (4)
`
`

`

`Materials Reviewed:
`
`0 August 4, 2016, Labeling Review of Glyxambi (empagliflozin and linagliptin)
`tablets by Miriam Dinatale, DO, Medical Officer, which belongs to the same
`class as Qtem.
`June 2, 2016, applicant’s response to IR
`May 17, 2016 Division’s Information Request (IR) for a summary of all available
`published literature and pharmacovigilance database to support the PLLR format
`of the labeling,
`
`May 2, 2016, DMEP’s request to DPMH-MHT for labeling review
`April 27, 2016 Applicant’s submission for New NDA 20909lincluding labeling
`in PLLR format
`
`0
`
`January 8, 2014, Summary Review for regulatory Action by Jean—Marc Guettier,
`M.D.C.M., Division Director, DMEP for Farxiga (dapagliflozin)
`
`Consult Question: Assist with Pregnancy and Lactation Labeling
`
`INTRODUCTION
`
`On April 27, 2016, the applicant, AstraZeneca Pharmaceuticals LP (AZ), submitted a New NDA
`209091 for Qtem [dapagliflozin 10 mg/ saxagliptin 5 mg fixed dose combination (FDC) tablet]
`for oral use, as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus (T2DNI)
`0W)
`
`The Division of Metabolic and Endocrine Products (DMEP) consulted the Division of Pediatric
`and Maternal Health (DPMH) on May 2, 2016, to provide input for appropriate labeling of the
`pregnancy and lactation sections of Qtem labeling to comply with the Pregnancy and Lactation
`Labeling Rule (PLLR) format.
`
`This review provides recommended revisions and structuring of existing information related to
`the Pregnancy, Lactation, and Females and Males of Reproductive Potential sections in labeling
`in order to provide clinically relevant information for prescribing decisions and to comply with
`current PLLR regulatory requirements.
`
`BACKGROUND
`
`Regulatory History
`Dapagliflozin (Farxiga) NDA 202293, owned by AZ, is a SGLTZ inhibitor approved for the
`treatment of T2DM on January 8, 2014. Saxagliptin (Onglyza) NDA 022350, also owned by
`AZ, is a dipeptidyl peptidase 4 (DPP 4) inhibitor and was approved on July 31, 2009.
`
`On October 15, 2015, AZ had submitted NDA
`which received a complete response (CR) because
`
`"’""
`
`(on)
`
`Reference ID: 4057405
`
`Page 2 of 17
`
`

`

`On April 27, 2016, the applicant, AZ, submitted a New NDA 209091including labeling in PLLR
`format for Qtern [dapagliflozin/ saxagliptin fixed dose combination a:DC) tablet] for oral use.
`
`The current submission does not address the deficiencies outlined in the CR letter; therefore, the
`applicant in agreement with the Division was required to submit a new NDA 209091.
`(km
`
`During the clinical trials, the primary safety assessment of the combined use of dapagliflozin and
`saxagliptin in adults with T2DM was based on pooled data from 3 Phase 3, randomized, double-
`blind, active/placebo-controlled, parallel group, multicenter clinical studies.
`0
`Study CV181168: This Phase 3 clinical study compared the addition of saxagliptin 5 mg
`versus placebo when administered sequentially to metformin 21500 mg and dapagliflozin
`10 mg in adults with T2DM who had inadequate glycemic control on metformin plus
`dapagliflozin therapy. It was a 24—week, 2—arm, randomized, double—blind, placebo-
`controlled, parallel-group study.
`Study MB]02129: This Phase 3 clinical study compared the addition of dapagliflozin 10
`mg versus placebo when administered sequentially to metformin 21500 mg and
`saxagliptin 5 mg in adults with T2DM who had inadequate glycemic control on
`metformin plus saxagliptin therapy. It was a 24-week, 2-arm, randomized, doubleblind,
`placebo-controlled, parallel—group study.
`
`0
`
`0
`
`Study CV181169: This Phase 3 clinical study compared the addition of saxagliptin 5 mg
`plus dapagliflozin 10 mg versus placebo plus saxagliptin 5 mg and versus placebo plus
`dapagliflozin 10 mg when administered concomitantly with metformin 21500 mg in
`adults with T2DM who had inadequate glycemic control on a stable dose of metformin
`monotherapy. It was a 24-week, 3-arm, randomized, double-blind, active-controlled,
`parallel—group study
`
`Three pregnancies were reported during the CV181169 study. No cases of pregnancy were
`reported in Studies CV181168 and MBlOZ 129.
`
`During the observational study NIB102242 for dapagliflozin, a case series analysis of foreign and
`domestic spontaneously reported events of pregnancy outcomes from January 8, 2015 through
`January 7, 2016, 5 pregnancies were reported, one premature delivery, one congenital anomaly
`and 3 unknown outcomes.
`
`Drug’s Characteristics
`Dapagliflozin (Farxiga)
`SGLT2 inhibitors reduce hyperglycemia by targeting the kidney to promote urinary glucose
`excretion. Dapagliflozin is a sodium—glucose cotransporter 2 (SGLT2) inhibitor. SGLT2 is
`expressed in the proximal renal tubules, and it is responsible for the majority of the reabsorption
`of filtered glucose from the tubular lumen. By inhibiting SGLT2, dapagliflozin reduces
`reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases
`urinary glucose excretion. Dapagliflozin has a molecular weight of 502.98 Daltons. The mean
`
`Reference ID: 4057405
`
`Page 3 of 17
`
`

`

`plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single
`oral dose of Farxiga 10 mg.
`
`Saxagliptin (Onglyza)
`DPP4 inhibitor class of antihyperglycemic agents targets the incretin defect in T2DM by
`improving the β-cell sensitivity to glucose, increasing insulin secretion, and decreasing glucagon
`secretion. The DPP4 inhibitors are associated with a low intrinsic risk of hypoglycemia and are
`neutral on patient’s weight. Saxagliptin is a competitive 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 type 2 diabetes mellitus. It has a molecular weight of 333.43 Daltons. Following a
`single oral dose of Onglyza 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2)
`for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
`
`Background on Current Treatments
`In 2015, the American Diabetes Association (ADA)1 and the European Association for the Study
`of Diabetes (EASD) issued an update to their joint position statement including SGLT2
`inhibitors use among the options for second-line therapy after metformin.2 Balancing the
`benefits of glycemic control with its potential risks, taking into account the adverse effects of
`glucose-lowering medications (particularly hypoglycemia) is a cornerstone of diabetes treatment.
`Initial combination therapy with metformin plus a second agent may allow patients to achieve
`HbA1c targets more quickly than sequential therapy. While the SGLT2 inhibitors are approved
`as monotherapy, they are mainly used in combination with metformin and/or other agents.3
`When compared with most standard oral agents, they appear to be as efficacious with regard to
`initial HbA1c lowering.4,5
`
`Similar to most combinations, efficacy may be less than additive when SGLT2 inhibitors are
`used in combination with DPP-4 inhibitors.6 DPP4 inhibitors are associated with a low intrinsic
`risk of hypoglycemia.
`
`There are no data available on the use of SGLT2 inhibitors in conjunction with GLP-1 receptor
`agonists.
`
`1 Diabetes Care. Standards of Medical Care in Diabetes—2015, Position Statement. The J ofClinical and Applied
`Research and Education. Jan 2015;38(S1)1-93
`2 Inzucchi SE, Bergenstal RM, Buse JB, et al: Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-
`Centered Approach: Update to a Position Statement of the American Diabetes Association and the European
`Association for the Study of Diabetes. Diabetes Care 2015 Jan; 38(1): 140-149.
`3 Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2
`diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014;16:457–466
`4 Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with
`type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised,
`double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941–950
`5 Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2
`diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-
`controlled noninferiority trial. Diabetes Care 2011;34:2015–2022
`6 Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes
`and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-
`controlled, parallel-group study. Diabetes Obes Metab 2011;13:1088–1096
`
`Reference ID: 4057405
`
`Page 4 of 17
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`

`

`As noted in the original position statement by ADA and EASD in 20127, initial combination
`therapy with metformin plus a second agent may allow patients to achieve HbA1c targets more
`quickly than sequential therapy. SGLT2 and DPP4 are complementary to each other in reducing
`hyperglycemia.
`
`Disease Background
`Diabetes Mellitus and Pregnancy
`Adverse outcomes of diabetes during pregnancy relate to the onset of diabetes, its duration, and
`the degree of vasculopathy. Women with pregnancies complicated by diabetes mellitus may be
`separated into one of two groups:
` Gestational diabetes (GDM): women with carbohydrate intolerance of variable severity,
`with onset or first recognition during the present pregnancy. This means that the glucose
`intolerance may have antedated the pregnancy but was not recognized by the patient or
`the physician.
` Pregestational diabetes (PGD): women known to have diabetes before pregnancy.
`
`Ninety percent of all pregnant diabetic women have gestational diabetes mellitus (GDM),
`whereas type 1 (insulin-dependent diabetes) and type 2 (non-insulin dependent diabetes) account
`for the remaining 10%.8
`
`Gestational Diabetes
`The incidence of GDM varies in different study populations and is estimated to occur in 3–5% of
`all pregnant women in the United States. The likelihood of developing GDM is significantly
`increased among certain subgroups, and these include women with a family history of type 2
`diabetes, advancing maternal age, obesity, and nonwhite ethnicity. Infants born to women
`diagnosed with GDM do not have an increased risk of congenital anomalies when compared to
`infants born to women without GDM. GDM usually is diagnosed later in pregnancy when the
`risk of MCM has passed. PGD that is well under control is not associated with an increased risk
`either, however, infants of women with poorly controlled PGD have an increased risk of MCM.
`
`Pregestational Diabetes
`Poorly controlled PGD during pregnancy increases the risk for maternal complications, including
`diabetic ketoacidosis, preeclampsia, spontaneous abortions (SAB), preterm delivery,
`polyhydramnios, stillbirth and cesarean section due to fetal macrosomia. In addition, poorly
`controlled DM during pregnancy increases the risk for fetal malformations, including neural tube
`defects (anencephaly, open spina bifida, and holoprosencephaly), cardiovascular anomalies
`(ventricular septal defects and transposition of the great vessels), oral clefts, genitourinary
`abnormalities (absent kidneys, polycystic kidney, and double ureter), and sacral agenesis or
`caudal regression. Fetal complications include pyelonephritis, hypertensive disorders and
`macrosomia-related injuries (brachial plexus injury, hypoxia). Also directly related to metabolic
`control are fetal hyperglycemia and neonatal hypoglycemia, hypocalcemia, polycythemia, and
`hyperbilirubinemia.
`
`7 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach.
`Diabetes Care, Diabetologia. April 19, 2012
`8 Reece, EA, Hobbins, JC: Clinical Obstetrics, Third Edition, Chapter 38: Diabetes Mellitus in Pregnancy, pp: 292-
`305, Jan 14, 2008
`
`Reference ID: 4057405
`
`Page 5 of 17
`
`

`

`Infants of diabetic mothers in unsatisfactory glycemic control often develop hypoglycemia
`during the first few hours of life. The reported incidence ranges from 25% to 40% of infants of
`diabetic mothers. Poor glycemic control during pregnancy and high maternal plasma glucose
`levels at the time of delivery increase the risk of hypoglycemia in the infant. Clinical studies
`suggest that euglycemia during organogenesis in pregestational pregnant diabetics is critical in
`the prevention of congenital anomalies.3 Achieving and maintaining maternal euglycemia prior
`to conception and throughout pregnancy decreases the risk of adverse outcomes for both the
`mother and the infant.9,10,11
`
`Poorly controlled pre-gestational Diabetes Mellitus (PGD) (before conception) and in the first
`trimester is associated with Major Congenital Malformation (MCM) (5-10%) and spontaneous
`abortion (15-20%).12 The higher the fasting serum glucose level is at diagnosis, the higher the
`incidence of MCM.13
`
`The Micromedex database states that pregestational diabetes mellitus in pregnant women with
`poor control during organogenesis is associated with a 3-fold increase in congenital anomalies
`that include cardiac malformations, lumbosacral agenesis, hyperbilirubinemia, polycythemia, and
`renal vein thrombosis. Offspring of mothers with poorly controlled PGD during pregnancy have
`a mortality rate that is 5 times greater than that of non-diabetic mothers; the mortality rate is
`higher at all gestational ages.14
`
`The American College of Obstetricians and Gynecologists (ACOG) in a statement issued in 2005
`and reaffirmed in 2012 for PGD, states that HbA1c of 5-6% is associated with a fetal
`malformation rate close to what is seen in normal pregnancies. An HbA1c near 10% is
`associated with a fetal malformation rate of 20-25%.15 Major malformations include:
`Hydrocephalus, meningomyelocele (lumbar), anencephaly, cleft palate, atresia of pulmonary
`valve, caudal regression syndrome, agenesis of a kidney, supernumerary toe, anomalous lumbar
`spine, aplasia of left diaphragm with hypoplasia of left lung, and omphalocele.16
`
`PLLR
`On June 30, 2015, the “Content and Format of Labeling for Human Prescription Drug and
`Biological Products; Requirements for Pregnancy and Lactation Labeling,” also known as the
`Pregnancy and Lactation Labeling Rule (PLLR), went into effect. 17 The PLLR requirements
`
`9 Mills JL. Malformations in infants of diabetic mothers. Teratology.1982:25;385-94
`10 Persson, M. and Fadi, H. Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational
`and gestational diabetes- a population-based study. Diabetes Med. 2014; 31(9): 1047-54.
`11 www.cdc.gov. Problems of Diabetes in Pregnancy. Accessed 12/30/2015.
`12 Ornoy, et al. Effect of Maternal Diabetes on the Embryo, Fetus, and Children: Congenital Anomalies, Genetic and
`Epigenetic Changes and Developmental Outcomes. Birth Defects Research, Part C: Embryo Today: Reviews. 2015;
`105(1): 53-72.
`13 Schaefer UM, Songster G, Xiang A, Berkowitz K, Buchanan TA, Kjos SL. Congenital malformations in offspring
`of women with hyperglycemia first detected during pregnancy. Am J Obstet Gynecol. 1997;177:1165–1171.
`14 The Behrman RE, Kleigman RM, Nelson WE, et al: Nelson Textbook of Pediatrics, 14th. WB Saunders
`Company, Philadelphia, PA, 1992.
`15 ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists. 2005; 60:675-685.
`16 Ylinen K, Aula P, Stenman UH, et. al. Risk of minor and major fetal malformations in diabetics with high
`haemoglobin A1c values in early pregnancy. British Med. J.1984;289:345-6
`
`Reference ID: 4057405
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`

`

`include a change to the structure and content of labeling for human prescription drug and
`biologic products with regard to pregnancy and lactation, and creates a new subsection for
`information with regard to females and males of reproductive potential. Specifically, the
`pregnancy categories (A, B, C, D and X) will be removed from all prescription drug and
`biological product labeling and a new format will be required for all products that are subject to
`the 2006 Physicians Labeling Rule format to include information about the risks and benefits of
`using these products during pregnancy and lactation.
`
`Current Labeling
`The current labeling for Onglyza (saxagliptin) states18:
`8.1 Pregnancy
`Pregnancy Category B
`
`There are no adequate and well-controlled studies in pregnant women. Because animal
`reproduction studies are not always predictive of human response, ONGLYZA, like other
`antidiabetic medications, should be used during pregnancy only if clearly needed.
`
`Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits
`during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental
`delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human
`exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended
`human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed
`at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active
`metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose
`of 200 mg/kg, or approximately 1432 and 992 times the MRHD.
`
`Co-administration of saxagliptin and metformin, to pregnant rats and rabbits during the period of
`organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses
`yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin 5 mg and
`metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats,
`minor developmental toxicity was limited to an increased incidence of wavy ribs; associated
`maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study,
`and related reductions in maternal food consumption. In rabbits, co-administration was poorly
`tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion.
`However, among surviving mothers with evaluable litters, maternal toxicity was limited to
`marginal reductions in body weight over the course of gestation days 21 to 29; and associated
`developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and a
`low incidence of delayed ossification of the fetal hyoid.
`
`Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in
`decreased body weights in male and female offspring only at maternally toxic doses (exposures
`≥1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or
`behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.
`
`17 Content and Format of Labeling for Human Prescription Drug and Biological Products, Requirements for
`Pregnancy and Lactation Labeling (79 FR 72063, December 4, 2014).
`18 Onglyza labeling, updated January 18, 2017
`
`Reference ID: 4057405
`
`Page 7 of 17
`
`

`

`Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
`
`The current labeling for Farxiga (dapagliflozin) states19:
`8.1 Pregnancy
`Pregnancy Category C
`
`There are no adequate and well-controlled studies of Farxiga in pregnant women. Based on
`results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect
`renal development and maturation. In a juvenile rat study, increased incidence and/or severity of
`renal pelvic and tubular dilatations were evident at the lowest tested dose which was
`approximately 15 times clinical exposure from a 10 mg dose.
`
`These outcomes occurred with drug exposures during periods of animal development that
`correlate with the late second and third trimesters of human pregnancy. During pregnancy,
`consider appropriate alternative therapies, especially during the second and third trimesters.
`Farxiga should be used during pregnancy only if the potential benefit justifies the potential risk
`to the fetus.
`
`In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal
`day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and
`renal pelvic and tubular dilatations were reported at all levels. Exposure at the lowest tested dose
`was 15 times the maximum clinical dose, based on AUC. The renal pelvic and tubular dilatations
`observed in juvenile animals did not fully reverse within the approximate 1-month recovery
`period.
`
`In a prenatal and postnatal development study, maternal rats were dosed from gestation day 6
`through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in
`utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was
`observed in adult offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin
`exposures were 1415 times and 137 times, respectively, the human values at the clinical dose).
`Dose-related reductions in pup body weights were observed at doses ≥1 mg/kg/day
`(approximately ≥19 times the clinical dose). No adverse effects on developmental endpoints
`were noted at 1 mg/kg/day, or approximately 19 times the clinical dose.
`
`In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered for
`intervals coinciding with the first trimester period of organogenesis in humans. No
`developmental toxicities were observed in rabbits at any dose tested. In rats, dapagliflozin was
`neither embryolethal nor teratogenic at doses up to 75 mg/kg/day or 1441 times the maximum
`clinical dose of 10 mg. At higher doses in rats, malformations of blood vessels, ribs, vertebra,
`manubria, and skeletal variations in fetuses at ≥150 mg/kg or 2344 times the 10 mg clinical dose
`were observed.
`
`PREGNANCY
`Animal Data
`
`19 Farxiga labeling, updated August 12, 2016
`
`Reference ID: 4057405
`
`Page 8 of 17
`
`

`

`The applicant states that no new animal data for the use of mono-components dapagliflozin and
`saxagliptin are available. No animal studies were performed with the combined use of
`dapagliflozin and saxagliptin. In animal studies, adverse renal pelvic and tubular dilatations, that
`were not fully reversible, were observed in juvenile rats when dapagliflozin (a component of
`Qtern) was administered at an exposure 15-times the exposure at the 10 mg clinical dose, during
`a period of renal development and corresponding to the late second and third trimesters of human
`pregnancy. No adverse developmental effects were observed when saxagliptin was administered
`to pregnant rats and rabbits.
`For nonclinical experience of the mono-components dapagliflozin and saxagliptin, the reader is
`referred to the corresponding updated labelings.
`
`Summary
`The nonclinical data on dapagliflozin /saxagliptin (Qtern) have been previously reviewed and
`remain unchanged. Based on animal reproduction studies, there may be risks to the fetus from
`exposure to dapagliflozin during pregnancy.
`
`Review of Literature
`Applicant’s Review
`Onglyza
`A literature search of Embase, Medline and
` database up to September 16,
`2015, was performed by the applicant. The following search parameters were used “(saxagliptin
`or KOMBIGLYZE XR)” and (pregnancy* OR lactation* OR “breast milk”). The following
`criteria were used for the
` search: (SAXAGLIPTIN OR "BMS 477118" OR
`"BMS 512148" OR "BMS477118" OR "BMS-477118" OR "Onglyza" ) AND (PREGNANT OR
`"maternal" OR "pregnancy" OR LACTATATE OR LACTATION OR "breast feeding" OR
`LACTATING OR "BREAST MILK" OR "BREAST FEEDING"). No new and/or relevant
`studies of saxagliptin exposure and pregnancy were found upon review of the literature. No
`adequate and well-controlled studies of saxagliptin in pregnant women have been conducted.
`Overall, this search did not reveal any relevant literature articles regarding potential use of
`saxagliptin in pregnancy.
`
`Farxiga
`Similarly, a literature search of Embase, Medline and
` database up to May 19,
`2016, was performed with search parameters: “(dapagliflozin or 'bms 512148' or Edistride or
`FARXIGA or FORXIGA)” and (pregnancy* OR lactation* OR 'breast milk’). The following
`criteria was used for the
` search: (dapagliflozin or "bms 512148" or "Farxiga"
`or "Forxiga") AND (“pregnant” OR "maternal" OR "pregnancy" OR “lactate” OR “lactation”
`OR "breast feeding" OR lactating OR "breast milk" OR "breast feeding”). No new and/or
`relevant studies of dapagliflozin exposure and pregnancy were found upon review of the
`literature. No adequate and well-controlled trials of dapagliflozin in pregnant women have been
`conducted. This search did not reveal any relevant literature articles regarding potential use of
`dapagliflozin in pregnancy and lactation.
`
`DPMH Review
`In addition to the search of published literature performed by the applicant, DPMH also
`conducted a literature search in PubMed, Embase and the TERIS and ReproTox databases20 for
`
`Reference ID: 4057405
`
`Page 9 of 17
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`dapagliflozin/saxagliptin and use in pregnancy. No publications were identified discussing use
`of dapagliflozin/saxagliptin in pregnancy or lactation.
`
`Experience with other drugs in the class include Glyxambi (empagliflozin and linagliptin) tablets
`FDC of a SGLT2 and a DPP4 inhibitor approved on January 30, 2015. As per Dr. M. Dinatale
`review of August 4, 2016, there was no relevant information that discussed the use of linagliptin
`or empagliflozin or the combination of the two in the literature in pregnancy. Empagliflozin, a
`SGLT2 inhibitor, use during pregnancy raises concerns for the developing kidney in the fetus
`based on juvenile animal studies similar to dapagliflozin.
`
`Review of Pharmacovigilance
`The applicant’s Global Patient Safety database (SAPPHIRE) search included any report of
`pregnancy using dapagliflozin/ saxagliptin FDC, or combined use of the mono-components
`dapagliflozin and saxagliptin through May 18, 2016.
`
`Dapagliflozin
`From the clinical trials, a 39-year—old White female randomized to the dapagliflozin + metformin
`group, received study medication from
`(I'm until the positive pregnancy test on
`(I'm The baby was born on
`(hm The infant was seen by a cardiac
`M0 for a congenital cardiac anomaly. The birth defect was deemed not
`specialist in
`related to study treatment.
`
`A cumulative review of the Global Patient Safety database (SAPPHIRE) through May 20, 2016
`of all reports for Farxiga (dapagliflozin) associated with pregnancy yielded 24 reports. See Table
`1 below.
`
`2° TERIS and ReproTox databases. Truven Health Analytics, Micromedex Solutions, 2016.
`
`Reference ID: 4057405
`
`Page 10 of 17
`
`

`

`Table 1: Cumulative Pregnancy Outcomes Reported for Farxiga maternal use
`
`Pre_nanc Outcome
`
`Premature delivery
`
`Baby with serious diabetic
`fetopathy, hypoglycemia and
`h p rbilirubinemia.
`
`Male baby born with birth
`defect of right aortic arch
`con enital aortic anomal
`
`Ex » osure time
`
`Infant Outcome
`
`For 5 weeks in 1St
`trimester
`
`For 4 weeks in lSt
`trimester
`
`Healthy baby
`
`At 9 months child
`reported no problems
`
`For 46 days prior and 18 Baby in good health
`days after conception (lSt
`trimester
`
`Fetal encephalocele
`Up to diagnosis of
`Infant died
`
`regnancy
`
`Severe congenital
`h drocehalus
`
`Unknown/Dapagliflozin Unknown
`was discontinued
`
`trimester
`
`
`
`Miscarriage - For 2 weeks in 1St
`Electiveabortion - For 107 days (pregnancy N0anomaly
`
`date confirmation not
`
`re u orted
`
`Ectopic pregnancies
`
`Unknown
`For 173 days, of which
`44 days after last
`menstrual eriod
`
`Not reported
`Unknown AEs or outcomes
`
`9
`
`Unknown
`Unknown
`
`
`
`
`
`Normal deliveries
`
`Unknown
`
`Normal infants
`
`Applicant’s response to IR. June 2. 2016
`
`Saxagliptin
`From the clinical trials, a 36-year-old female partner of a 36-year-old White male randomized to
`the saxagliptin + metformin group, had a positive pregnancy test on
`(I'm (paternal drug
`exposure). She had a miscarriage/spontaneous abortion on
`
`M6)
`
`Dapagliflozin /Saxagliptin FDC
`Qtem (dapagliflozin Isaxagliptin FDC) is not currently marketed anywhere in the world. No
`reports of pregnancy associated with use of Qtern (dapagliflozin /saxagliptin FDC) were
`identified. However, 1 pregnancy report was identified with the combined use of the mono-
`components dapagliflozin and saxagliptin in the integrated phase 3 trial evaluating the safety and
`efficacy of the combined use of saxagliptin 5 mg and dapagliflozin 10 mg in the first trimester.
`When the pregnancy was identified, the subject discontinued from the study and declined follow-
`up. The subject, a 41-year-old White female, randomized to the saxagliptin + dapagliflozin +
`metforrnin group, received study medication on
`M6) The subject reported the
`pregna