Dapagliflozin and Saxagliptin

Dapagliflozin and saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Dapagliflozin and saxagliptin tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [ see WARNINGS AND PRECAUTIONS (5.1) ]. Dapagliflozin and saxagliptin tablets is a combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor and saxagliptin a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 )

Dapagliflozin and saxagliptin tablets are available as follows: Table 1: Dosage Forms and Strengths for Dapagliflozin and saxagliptin Dapagliflozin Strength Saxagliptin Strength Color / Shape Tablet Markings 10 mg 5 mg Light brown to brown, biconvex, round, film-coated tablet Debossed with "MS" on one side and "4" on other side. Tablets: 10 mg dapagliflozin/5 mg saxagliptin ( 3 )

Dapagliflozin and saxagliptin is contraindicated in patients with: History of a serious hypersensitivity reactions to dapagliflozin or to saxagliptin, including anaphylactic reaction, angioedema or exfoliative skin conditions [ see WARNINGS AND PRECAUTIONS (5.8) and ADVERSE REACTIONS (6.2)]. Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m 2 ), end-stage renal disease (ESRD), or patients on dialysis [ see USE IN SPECIFIC POPULATIONS (8.6)]. History of a serious hypersensitivity reaction to dapagliflozin or to saxagliptin. ( 4 ) Moderate to severe renal impairment (eGFR <45 mL/min/1.73 m 2 ), end-stage renal disease, or patients on dialysis. ( 4 )

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. […]

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%). […]

Table 3 : Clinically Relevant Interactions with Dapagliflozin and Saxagliptin Strong Inhibitors of CYP3A4/5 Enzymes Clinical Impact Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). Intervention Do not coadminister dapagliflozin and saxagliptin with strong cytochrome P450 3A4/5 inhibitors [see DOSAGE AND ADMINISTRATION (2.4) and CLINICAL PHARMACOLOGY (12.3) ] . Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin and saxagliptin is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see WARNINGS AND PRECUATIONS (5.6) ] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin and saxagliptin initiation and dosage changes. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. Strong CYP3A4/5 Inhibitors (e.g., Ketoconazole): Do not coadminister dapagliflozin and saxagliptin with strong cytochrome P450 3A4/5 inhibitors. ( 7 ) See full prescribing information for additional drug interactions and information on interference of dapagliflozin and saxagliptin with laboratory tests. ( 7 )

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. […]

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.