Dapagliflozin and Saxagliptin

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis : Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue dapagliflozin and saxagliptin if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Pancreatitis: If pancreatitis is suspected, promptly discontinue dapagliflozin and saxagliptin. ( 5.2 ) Heart Failure: Consider risks and benefits of dapagliflozin and saxagliptin in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 ) Volume Depletion: Before initiating dapagliflozin and saxagliptin, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.4 ) Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.5 ) Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating dapagliflozin and saxagliptin. ( 5.6 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. ( 5.7 ) Hypersensitivity Reactions : There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue dapagliflozin and saxagliptin, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.8 ) Genital Mycotic Infections: Monitor and treat if indicated. ( 5.9 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.10 ) Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue dapagliflozin and saxagliptin. ( 5.11 )

5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, dapagliflozin, a component of dapagliflozin and saxagliptin, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. Dapagliflozin and saxagliptin is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including dapagliflozin. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing dapagliflozin and saxagliptin [see CLINICAL PHARMACOLOGY (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue dapagliflozin and saxagliptin, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting dapagliflozin and saxagliptin. Withhold dapagliflozin and saxagliptin, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume dapagliflozin and saxagliptin when the patient is clinically stable and has resumed oral intake [see DOSAGE AND ADMINISTRATION (2.5) ]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue dapagliflozin and saxagliptin and seek medical attention immediately if signs and symptoms occur.

5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo. After initiation of dapagliflozin and saxagliptin, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue dapagliflozin and saxagliptin and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using dapagliflozin and saxagliptin.

5.3 Heart Failure In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of dapagliflozin and saxagliptin prior to initiating treatment in patients at a higher risk of heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of dapagliflozin and saxagliptin.

5.4 Volume Depletion Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR <60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating dapagliflozin and saxagliptin in patients with one or more of these characteristics, assess volume status and renal function. Dapagliflozin and saxagliptin is contraindicated in patients with an eGFR <45 mL/min/1.73 m 2 . Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.

5.5 Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections.Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [ see ADVERSE REACTIONS (6.2)].

5.6 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Both dapagliflozin and saxagliptin can individually increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia when these agents are used in combination with dapagliflozin and saxagliptin [ see ADVERSE REACTIONS (6.1)].

5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with dapagliflozin and saxagliptin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue dapagliflozin and saxagliptin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.8 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylactic reactions, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue dapagliflozin and saxagliptin, treat per standard of care, and monitor until signs and symptoms are resolved. Assess for other potential causes for the event. Institute alternative treatment for diabetes. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin.

5.9 Genital Mycotic Infections Dapagliflozin increases the risks of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [ see ADVERSE REACTIONS (6.1)]. Monitor and treat appropriately.

5.10 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate [ see ADVERSE REACTIONS (6)].

5.11 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving dapagliflozin and saxagliptin. If bullous pemphigoid is suspected, dapagliflozin and saxagliptin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

The following important adverse reactions are described below or elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see WARNINGS AND PRECAUTIONS (5.1) ] Pancreatitis [see WARNINGS AND PRECAUTIONS (5.2) ] Heart Failure [see WARNINGS AND PRECAUTIONS (5.3) ] Volume Depletion [see WARNINGS AND PRECAUTIONS (5.4) ] Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS (5.5) ] Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see WARNINGS AND PRECAUTIONS (5.6) ] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see WARNINGS AND PRECAUTIONS (5.7) ] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.8) ] Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS (5.9) ] Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.10) ] Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS (5.11) ] Adverse reactions reported in ≥5% of subjects treated with dapagliflozin and saxagliptin were: upper respiratory tract infection, urinary tract infection, and dyslipidemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in adult subjects with type 2 diabetes mellitus in a pooled safety analysis of three phase 3 active/placebo-controlled clinical trials with a median exposure of 51 weeks. The pooled safety analysis included a total of 1169 adults: 492 patients in the combination of saxagliptin and dapagliflozin plus metformin group, 341 patients in the dapagliflozin plus metformin group, 336 patients in the saxagliptin plus metformin group.The mean age of these subjects was 54 years, 0.8% were 75 years or older and 53.7% were female. The population was 80.9% White, 8.3% Black or African American, 3.7% Asian, and 6.6% Other race. At baseline the population had diabetes for an average of 7.5 years and a mean HbA1c of 8.4%. The mean eGFR at baseline was 94.4 mL/min/1.73 m 2 . The common adverse reactions were based on the pooled analyses of these studies as shown in Table 2. Table 2: Adverse Reactions Reported in ≥2% of Subjects Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin plus Metformin (≥1,500 mg) Adverse Reaction Preferred Term* Frequency % Upper respiratory tract infection * 13.6 Urinary tract infection * 5.7 Dyslipidemia * 5.1 Headache 4.3 Diarrhea 3.7 Back pain 3.3 Genital infection * 3.0 Arthralgia 2.4 * Adverse reactions that are medically related were grouped to a single preferred term. Additionally, adverse reactions reported in <5% and ≥2% from the dapagliflozin development program and ≥1% more frequently compared to placebo included increased urination and discomfort with urination. Hypoglycemia In the pooled analysis, the incidences of hypoglycemia (defined as a blood glucose <54 mg/dL regardless of the presence or absence of symptoms) and severe hypoglycemia (event requiring assistance due to neuroglycopenia, characterized by altered mental and/or physical status) was 1% and 0.2%, respectively. Genital Mycotic Infections Genital mycotic infections were reported in 15 subjects (3%) treated with dapagliflozin and saxagliptin. Reported adverse reactions by frequency included vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis. The majority of subjects (84.2%) who experienced genital infection adverse reactions were females. Urinary Tract Infections Urinary tract infections were reported in 28 subjects (5.7%) treated with dapagliflozin and saxagliptin. Reported adverse reactions by frequency included urinary tract infection, Escherichia urinary tract infection, prostatitis, and pyelonephritis. The majority of subjects (80.6%) who experienced urinary tract infection adverse reactions were females. Volume Depletion Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in 2 subjects (0.4%) treated with dapagliflozin and saxagliptin plus metformin. Impairment of Renal Function Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with dapagliflozin and saxagliptin plus metformin. The reported adverse reactions included decreased glomerular filtration rate, renal impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of the adverse reactions were reported as serious and all but one was mild to moderate in intensity. Three subjects discontinued due to decreased eGFR. Subjects with AEs of renal impairment had lower mean eGFR values at baseline of 64.4 mL/min/1.73 m 2 compared to 94.4 mL/min/1.73 m2 in overall population treated with dapagliflozin and saxagliptin. Ketoacidosis Dapagliflozin In the cardiovascular outcome study with dapagliflozin in patients with type 2 diabetes mellitus, events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period. LaboratoryTests Increases in Serum Creatinine and Decreases in eGFR Dapagliflozin Initiation of SGLT2 inhibitors, including dapagliflozin causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury. In two studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin. Decrease in Lymphocyte Counts Saxagliptin A dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin. In a pool of 5 placebo-controlled studies, a mean decrease in absolute lymphocyte count of approximately 100 cells/microL relative to placebo was observed. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, and 0.4% in the 2.5 mg, 5 mg saxagliptin and placebo groups, respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. Increase in Hematocrit Dapagliflozin In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and 2.30% in the 10 mg dapagliflozin group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of 10 mg dapagliflozin-treated patients. Increase in Low-Density Lipoprotein Cholesterol Patients treated with dapagliflozin and saxagliptin demonstrated a mean percent increase from baseline LDL-cholesterol (ranging from 2.1 to 6.9%). Elevations in Creatine Kinase An imbalance in the number of subjects who experienced serum creatine kinase (CK) elevations >10x the upper limit of normal (a marker of muscle injury/necrosis) was observed in 5 subjects (1%) treated with dapagliflozin and saxagliptin. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which no obvious cause was identified. Decrease in Serum Bicarbonate In a study of concomitant therapy of 10 mg dapagliflozin with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups .

6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of dapagliflozin and saxagliptin. Because the following reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dapagliflozin Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Rash Saxagliptin Gastrointestinal Disorders: Pancreatitis Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid

Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. ( 8.1 ) Lactation: Not recommended when breastfeeding. ( 8.2 ) Geriatrics: Higher incidence of adverse reactions related to hypotension. ( 8.5 ) Renal Impairment: Higher incidence of adverse reactions related to volume depletion. ( 8.6 )

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects from dapagliflozin, dapagliflozin and saxagliptin is not recommended during the second and third trimesters of pregnancy. The limited available data with dapagliflozin and saxagliptin or its components (dapagliflozin and saxagliptin) in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, adverse renal pelvic and tubular dilatations, that were not fully reversible, were observed in rats when dapagliflozin (a component of dapagliflozin and saxagliptin) was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data). No adverse developmental effects were observed when saxagliptin was administered to pregnant rats and rabbits ( see Data). The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Dapagliflozin Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose was 15-times the 10 mg clinical dose, (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats 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 21 day-old pup 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 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater than or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day, (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered to throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC). Saxagliptin In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC.

8.2 Lactation Risk Summary There is no information regarding the presence of dapagliflozin and saxagliptin or its components (dapagliflozin and saxagliptin) in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin and saxagliptin are present in the milk of lactating rats (see Data). However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of dapagliflozin and saxagliptin is not recommended while breastfeeding. Data Dapagliflozin Dapagliflozin was present at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Saxagliptin Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations.

8.4 Pediatric Use Safety and effectiveness of dapagliflozin and saxagliptin in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use Because elderly patients are more likely to have decreased renal function, care should be taken when using dapagliflozin and saxagliptin in the elderly based on renal function [see DOSAGE AND ADMINISTRATION (2.3) ] . Dapagliflozin A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level of renal function (eGFR), in clinical studies with dapagliflozin, efficacy was similar for patients under age 65 years and those 65 years and older. In patients 65 years and older, a higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see WARNINGS AND PRECAUTIONS (5.4)]. Saxagliptin In the seven double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11,301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects ≥65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Dapagliflozin and saxagliptin is contraindicated in patients with moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m 2 ), ESRD, or on dialysis [see DOSAGE AND ADMINISTRATION (2.3) , CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.4) ]. Dapagliflozin Dapagliflozin was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m 2 and an eGFR of 30 to less than 60 mL/min/1.73 m 2 ). Patients with diabetes and renal impairment using dapagliflozin for glycemic control may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m 2 , 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo.

8.7 Hepatic Impairment Dapagliflozin and saxagliptin may be used in patients with hepatic impairment. However, the benefit-risk for the use of dapagliflozin and saxagliptin in patients with severe hepatic impairment should be individually assessed since safety and efficacy have not been studied in this population [ see CLINICAL PHARMACOLOGY (12.3)].

12.1 Mechanism of Action Dapagliflozin 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. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Saxagliptin 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 DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP-4 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.

12.2 Pharmacodynamics Dapagliflozin Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin dose of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [ see ADVERSE REACTIONS (6.1) ]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days from discontinuation for the 10 mg dose. Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot) Saxagliptin In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Cardiac Electrophysiology Dapagliflozin Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50- times the recommended maximum daily dose) of dapagliflozin in healthy subjects. Saxagliptin In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the recommended maximum daily dose). fig-1 12.3 Pharmacokinetics Overall, the pharmacokinetics of dapagliflozin and saxagliptin were not affected in a clinically relevant manner when administered as dapagliflozin and saxagliptin. Saxagliptin The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, were similar in healthy subjects and in patients with type 2 diabetes mellitus. The C max and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng

• h/mL and 214 ng
• h/mL, respectively. The corresponding plasma C max values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C max for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg. Absorption Dapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. Saxagliptin The median time to maximum concentration (T max ) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in T max of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Distribution Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. Saxagliptin The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metabolism Dapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [ 14 C]-dapagliflozin dose and is the predominant drug-related component in human plasma. Saxagliptin The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [ see DRUG INTERACTIONS (7) ]. Elimination Dapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ 14 C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. Saxagliptin Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of [ 14 C]-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/orunabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t 1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Effects of Age, Gender, Race and Body Weight on Pharmacokinetics Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of saxagliptin and dapagliflozin. Renal Impairment Dapagliflozin At steady state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see DOSAGE AND ADMINISTRATION (2.3) , WARNINGS AND PRECAUTIONS (5.4) and USE IN SPECIFIC POPULATIONS (8.6) ] . Saxagliptin A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment (eGFR 30 to less than 45 mL/min/1.73 m 2 ), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m 2 ) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.Dapagliflozina and saxagliptin is contraindicated in patients with an eGFR <45 mL/min/1.73 m 2 . Hepatic Impairment Dapagliflozin In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean C max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean C max and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [ see USE IN SPECIFIC POPULATIONS (8.7) ]. Saxagliptin In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean C max and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding C max and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful. Pediatric Pharmacokinetics of dapagliflozin and saxagliptin in the pediatric population has not been studied. Drug Interactions Saxagliptin and Dapagliflozin The lack of pharmacokinetic interaction between dapagliflozin and saxagliptin was demonstrated in a drug-drug interaction study between dapagliflozin and saxagliptin. Dapagliflozin In Vitro Assessment of Drug Interactions The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates. Effects of Other Drugs on Dapagliflozin Table 4 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. Table 4: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) * Dapagliflozin (Dose Regimen) * Dapagliflozin Change † in AUC ‡ Change † in C max Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg ↓1% ↓7% Pioglitazone (45 mg) 50 mg 0% ↑9% Sitagliptin (100 mg) 20 mg ↑8% ↓4% Glimepiride (4 mg) 20 mg ↓1% ↑1% Voglibose (0.2 mg three times daily) 10 mg ↑1% ↑4% Saxagliptin (5 mg single dose) 10 mg (single dose) ↓2% ↓6% Other Medications Hydrochlorothiazide (25 mg) 50 mg ↑7% ↓1% Bumetanide (1 mg) 10 mg once daily for 7 days ↑5% ↑8% Valsartan (320 mg) 20 mg ↑2% ↓12% Simvastatin (40 mg) 20 mg ↓1% ↓2% Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓22% ↓7% Non-Steroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑51% ↑13% * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. Effects of Dapagliflozin on Other Drugs Table 5 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs Table 5: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) * Dapagliflozin (Dose Regimen) * Coadministered Drug Change † in AUC ‡ Change † in C max Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg 0% ↓5% Pioglitazone (45 mg) 50 mg 0% ↓7% Sitagliptin (100 mg) 20 mg ↑1% ↓11% Glimepiride (4 mg) 20 mg ↑13% ↑4% Other Medictaions Hydrochlorothiazide (25 mg) 50 mg ↓1% ↓5% Bumetanide (1 mg) 10 mg once daily for 7 days ↑13% ↑13% Valsartan (320 mg) 20 mg ↑5% ↓6% Simvastatin (40 mg) 20 mg ↑19% ↓6% Digoxin (0.25 mg) 20 mg loading dose then 10 mg once daily for 7 days 0% ↓1% Warfarin (25 mg) S-warfarin R-warfarin 20 mg loading dose then 10 mg once daily for 7 days ↑3% ↑6% ↑7% ↑8% * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. Saxagliptin In Vitro Assessment of Drug Interactions The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. Effects of Other Drugs on Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Table 6: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Saxagliptin Co­-administered Drug Dosage of Coadministered Drug * Dosage of Saxagliptin * Change † in AUC Change † in C max Metformin 1,000 mg 100 mg saxagliptin 5-hydroxy saxagliptin ↓2% ↓1% ↓21% ↓12% Glyburide 5 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↓2% ND ↑8% ND Pioglitazone § 45 mg QD for 10 days 10 mg QD for 5 days saxagliptin 5-hydroxy saxagliptin ↑11% ND ↑11% ND Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin 5-hydroxy saxagliptin ↓1% ↑9% ↓7% ↑6% Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days saxagliptin 5-hydroxy saxagliptin ↑5% ↑6% ↓1% ↑2% Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days saxagliptin 5-hydroxy saxagliptin ↑12% ↑2% ↑21% ↑8% Diltiazem 360 mg LA QD for 9 days 10 mg saxagliptin 5-hydroxy saxagliptin ↑109% ↓34% ↑63% ↓43% Rifampin ¶ 600 mg QD for 6 days 5 mg saxagliptin 5-hydroxy saxagliptin ↓76% ↑3% ↓53% ↑39% Omeprazole 40 mg QD for 5 days 10 mg saxagliptin 5-hydroxy saxagliptin ↑13% ND ↓2% ND Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2,400 mg magnesium hydroxide: 2,400 mg simethicone: 240 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↓3% ND ↓26% ND Famotidine 40 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↑3% ND ↑14% ND Saxagliptin coadministered with strong CYP3A4/5 inhibitors [ see DRUG INTERACTIONS (7) and DOSAGE AND ADMINISTRATION (2.4) ] : Ketoconazole 200 mg BID for 9 days 100 mg saxagliptin 5-hydroxy saxagliptin ↑145% ↓88% ↑62% ↓95% Ketoconazole 200 mg BID for 7 days 20 mg saxagliptin 5-hydroxy saxagliptin ↑267% ND ↑144% ND ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. § Results exclude one subject. ¶ The plasma dipeptidyl peptidase-4 (DPP-4) activity inhibition over a 24-hour dose interval was not affected by rifampin. Effects of Saxagliptin on Other Drugs Table 7: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs Coadministered Drug Dosage of Coadministered Drug* Dosage of Saxagliptin* Coadministered Drug Change in † AUC ‡ Change † in C max Metformin 1,000 mg 100 mg metformin ↑20% ↑9% Glyburide 5 mg 10 mg glyburide ↑6% ↑16% Pioglitazone § 45 mg QD for 10 days 10 mg QD for 5 days pioglitazone hydroxy-pioglitazone ↑8% ND ↑14% ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days digoxin ↑6% ↑9% Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days simvastatin simvastatin acid ↑4% ↑16% ↓12% 0% Diltiazem 360 mg LA QD for 9 days 10 mg diltiazem ↑10% ↑16% Ketoconazole 200 mg BID for 9 days 100 mg ketoconazole ↓13% ↓16% Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days 5 mg QD for 21 days ethinyl estradiol norelgestromin norgestrel ↑7% ↑10% ↑13% ↓2% ↑9% ↑17% ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. § Results include all subjects.

Overall, the pharmacokinetics of dapagliflozin and saxagliptin were not affected in a clinically relevant manner when administered as dapagliflozin and saxagliptin. Saxagliptin The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, were similar in healthy subjects and in patients with type 2 diabetes mellitus. The C max and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng

• h/mL and 214 ng
• h/mL, respectively. The corresponding plasma C max values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C max for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg. Absorption Dapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. Saxagliptin The median time to maximum concentration (T max ) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in T max of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Distribution Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. Saxagliptin The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metabolism Dapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [ 14 C]-dapagliflozin dose and is the predominant drug-related component in human plasma. Saxagliptin The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [ see DRUG INTERACTIONS (7) ]. Elimination Dapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ 14 C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. Saxagliptin Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of [ 14 C]-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/orunabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t 1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Effects of Age, Gender, Race and Body Weight on Pharmacokinetics Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of saxagliptin and dapagliflozin. Renal Impairment Dapagliflozin At steady state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see DOSAGE AND ADMINISTRATION (2.3) , WARNINGS AND PRECAUTIONS (5.4) and USE IN SPECIFIC POPULATIONS (8.6) ] . Saxagliptin A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment (eGFR 30 to less than 45 mL/min/1.73 m 2 ), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m 2 ) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.Dapagliflozina and saxagliptin is contraindicated in patients with an eGFR <45 mL/min/1.73 m 2 . Hepatic Impairment Dapagliflozin In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean C max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean C max and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [ see USE IN SPECIFIC POPULATIONS (8.7) ]. Saxagliptin In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean C max and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding C max and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful. Pediatric Pharmacokinetics of dapagliflozin and saxagliptin in the pediatric population has not been studied. Drug Interactions Saxagliptin and Dapagliflozin The lack of pharmacokinetic interaction between dapagliflozin and saxagliptin was demonstrated in a drug-drug interaction study between dapagliflozin and saxagliptin. Dapagliflozin In Vitro Assessment of Drug Interactions The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates. Effects of Other Drugs on Dapagliflozin Table 4 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. Table 4: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) * Dapagliflozin (Dose Regimen) * Dapagliflozin Change † in AUC ‡ Change † in C max Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg ↓1% ↓7% Pioglitazone (45 mg) 50 mg 0% ↑9% Sitagliptin (100 mg) 20 mg ↑8% ↓4% Glimepiride (4 mg) 20 mg ↓1% ↑1% Voglibose (0.2 mg three times daily) 10 mg ↑1% ↑4% Saxagliptin (5 mg single dose) 10 mg (single dose) ↓2% ↓6% Other Medications Hydrochlorothiazide (25 mg) 50 mg ↑7% ↓1% Bumetanide (1 mg) 10 mg once daily for 7 days ↑5% ↑8% Valsartan (320 mg) 20 mg ↑2% ↓12% Simvastatin (40 mg) 20 mg ↓1% ↓2% Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓22% ↓7% Non-Steroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑51% ↑13% * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. Effects of Dapagliflozin on Other Drugs Table 5 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs Table 5: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) * Dapagliflozin (Dose Regimen) * Coadministered Drug Change † in AUC ‡ Change † in C max Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg 0% ↓5% Pioglitazone (45 mg) 50 mg 0% ↓7% Sitagliptin (100 mg) 20 mg ↑1% ↓11% Glimepiride (4 mg) 20 mg ↑13% ↑4% Other Medictaions Hydrochlorothiazide (25 mg) 50 mg ↓1% ↓5% Bumetanide (1 mg) 10 mg once daily for 7 days ↑13% ↑13% Valsartan (320 mg) 20 mg ↑5% ↓6% Simvastatin (40 mg) 20 mg ↑19% ↓6% Digoxin (0.25 mg) 20 mg loading dose then 10 mg once daily for 7 days 0% ↓1% Warfarin (25 mg) S-warfarin R-warfarin 20 mg loading dose then 10 mg once daily for 7 days ↑3% ↑6% ↑7% ↑8% * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. Saxagliptin In Vitro Assessment of Drug Interactions The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. Effects of Other Drugs on Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Table 6: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Saxagliptin Co­-administered Drug Dosage of Coadministered Drug * Dosage of Saxagliptin * Change † in AUC Change † in C max Metformin 1,000 mg 100 mg saxagliptin 5-hydroxy saxagliptin ↓2% ↓1% ↓21% ↓12% Glyburide 5 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↓2% ND ↑8% ND Pioglitazone § 45 mg QD for 10 days 10 mg QD for 5 days saxagliptin 5-hydroxy saxagliptin ↑11% ND ↑11% ND Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin 5-hydroxy saxagliptin ↓1% ↑9% ↓7% ↑6% Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days saxagliptin 5-hydroxy saxagliptin ↑5% ↑6% ↓1% ↑2% Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days saxagliptin 5-hydroxy saxagliptin ↑12% ↑2% ↑21% ↑8% Diltiazem 360 mg LA QD for 9 days 10 mg saxagliptin 5-hydroxy saxagliptin ↑109% ↓34% ↑63% ↓43% Rifampin ¶ 600 mg QD for 6 days 5 mg saxagliptin 5-hydroxy saxagliptin ↓76% ↑3% ↓53% ↑39% Omeprazole 40 mg QD for 5 days 10 mg saxagliptin 5-hydroxy saxagliptin ↑13% ND ↓2% ND Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2,400 mg magnesium hydroxide: 2,400 mg simethicone: 240 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↓3% ND ↓26% ND Famotidine 40 mg 10 mg saxagliptin 5-hydroxy saxagliptin ↑3% ND ↑14% ND Saxagliptin coadministered with strong CYP3A4/5 inhibitors [ see DRUG INTERACTIONS (7) and DOSAGE AND ADMINISTRATION (2.4) ] : Ketoconazole 200 mg BID for 9 days 100 mg saxagliptin 5-hydroxy saxagliptin ↑145% ↓88% ↑62% ↓95% Ketoconazole 200 mg BID for 7 days 20 mg saxagliptin 5-hydroxy saxagliptin ↑267% ND ↑144% ND ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. § Results exclude one subject. ¶ The plasma dipeptidyl peptidase-4 (DPP-4) activity inhibition over a 24-hour dose interval was not affected by rifampin. Effects of Saxagliptin on Other Drugs Table 7: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs Coadministered Drug Dosage of Coadministered Drug* Dosage of Saxagliptin* Coadministered Drug Change in † AUC ‡ Change † in C max Metformin 1,000 mg 100 mg metformin ↑20% ↑9% Glyburide 5 mg 10 mg glyburide ↑6% ↑16% Pioglitazone § 45 mg QD for 10 days 10 mg QD for 5 days pioglitazone hydroxy-pioglitazone ↑8% ND ↑14% ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days digoxin ↑6% ↑9% Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days simvastatin simvastatin acid ↑4% ↑16% ↓12% 0% Diltiazem 360 mg LA QD for 9 days 10 mg diltiazem ↑10% ↑16% Ketoconazole 200 mg BID for 9 days 100 mg ketoconazole ↓13% ↓16% Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days 5 mg QD for 21 days ethinyl estradiol norelgestromin norgestrel ↑7% ↑10% ↑13% ↓2% ↑9% ↑17% ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting. * Single dose unless otherwise noted. † Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. ‡ AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses. § Results include all subjects.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that dapagliflozin and saxagliptin can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis. Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue dapagliflozin and saxagliptin and seek medical attention immediately [see WARNINGS AND PRECAUTIONS (5.1) ] . Pancreatitis Inform patients that acute pancreatitis has been reported during postmarketing use of saxagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue dapagliflozin and saxagliptin and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS (5.2) ]. Heart Failure Inform patients of the signs and symptoms of heart failure. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see WARNINGS AND PRECAUTIONS (5.3) ]. Volume Depletion Inform patients that symptomatic hypotension may occur with dapagliflozin and saxagliptin and advise them to contact their healthcare provider if they experience such symptoms. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake [see WARNINGS AND PRECAUTIONS (5.4) ]. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Inform them of the symptoms of urinary tract infections and advise them to seek medical advice if such symptoms occur [ see WARNINGS AND PRECAUTIONS (5.5) ]. Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Inform patients that the incidence of hypoglycemia may increase when dapagliflozin and saxagliptin is added to an insulin secretagogue (e.g., sulfonylurea) and/or insulin. Educate patients on the signs and symptoms of hypoglycemia [see WARNINGS AND PRECAUTIONS (5.6) ]. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with dapagliflozin, a component of dapagliflozin and saxagliptin . Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see WARNINGS AND PRECAUTIONS (5.7) ]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, and exfoliative skin conditions) have been reported with dapagliflozin and saxagliptin, components of dapagliflozin and saxagliptin. Symptoms of these allergic reactions include: rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. Advise patients to immediately report any signs or symptoms suggesting allergic reaction, angioedema or exfoliative skin conditions, and stop taking dapagliflozin and saxagliptin and seek medical advice promptly [see WARNINGS AND PRECAUTIONS (5.8) ]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [ see WARNINGS AND PRECAUTIONS (5.9) ]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [ see WARNINGS AND PRECAUTIONS (5.9) ]. Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [ see WARNINGS AND PRECAUTIONS (5.10)]. Bullous Pemphigoid Inform patients that bullous pemphigoid may occur with dapagliflozin and saxagliptin. Instruct patients to seek medical advice if blisters or erosions occur [ see WARNINGS AND PRECAUTIONS (5.11)]. Pregnancy Advise pregnant patients of the potential risk to a fetus with treatment with dapagliflozin and saxagliptin. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [ see USE IN SPECIFIC POPULATIONS (8.1)]. Lactating Mothers Advise patients that use of dapagliflozin and saxagliptin is not recommended while breastfeeding [ see USE IN SPECIFIC POPULATIONS (8.2)]. Laboratory Tests Inform patients that due to its mechanism of action, patients taking dapagliflozin and saxagliptin will test positive for glucose in their urine. Administration Instruct patients that dapagliflozin and saxagliptin must be swallowed whole and not crushed or chewed. Missed Dose If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of dapagliflozin and saxagliptin at the same time. Manufactured by: MSN Laboratories Private Limited Telangana - 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 Issued on: April 2026