DAPAGLIFLOZIN AND SAXAGLIPTIN

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Assess renal function before initiation of therapy and periodically thereafter. ( 2.1 ) Take orally, once daily in the morning with or without food. ( 2.2 ) For patients not already taking dapagliflozin, the recommended starting dose of dapagliflozin and saxagliptin tablets is a 5 mg dapagliflozin/5 mg saxagliptin tablet once daily. ( 2.2 ) In patients tolerating 5 mg dapagliflozin and 5 mg saxagliptin once daily who require additional glycemic control, the dapagliflozin and saxagliptin tablets dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily. ( 2.2 ) Swallow tablet whole. Do not crush, cut or chew. ( 2.2 ) Withhold dapagliflozin and saxagliptin for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. ( 2.5 ) 2.1 Prior to Initiation of Dapagliflozin and Saxagliptin Tablets Assess renal function prior to initiation of dapagliflozin and saxagliptin tablets therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS (5.4) ] . Assess volume status. In patients with volume depletion, correct this condition before initiating of dapagliflozin and saxagliptin tablets [see WARNINGS AND PRECAUTIONS (5.4) and USE IN SPECIFIC POPULATIONS (8.5 , 8.6 )] . 2.2 Dosage For patients not already taking dapagliflozin, the recommended starting dose of dapagliflozin and saxagliptin tablets is a 5 mg dapagliflozin/5 mg saxagliptin tablet taken orally once daily in the morning with or without food. In patients tolerating 5 mg dapagliflozin and 5 mg saxagliptin once daily who require additional glycemic control, the dapagliflozin and saxagliptin tablets dose can be increased to 10 mg dapagliflozin/5 mg saxagliptin tablet once daily in the morning with or without food. Swallow whole. Do not crush, cut or chew dapagliflozin and saxagliptin tablets. 2.3 Patients with Renal Impairment No dose adjustment is needed in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m2. Dapagliflozin and saxagliptin tablets are contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see CONTRAINDICATIONS (4) and USE IN SPECIFIC POPULATIONS (8.6) ]. 2.4 Use with Strong CYP3A4/5 Inhibitors Do not coadminister dapagliflozin and saxagliptin tablets with strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [ see DRUG INTERACTIONS (7)]. 2.5 Temporary Interruption for Surgery Withhold dapagliflozin and saxagliptin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume dapagliflozin and saxagliptin tablets when the patient is clinically stable and has resumed oral intake [see WARNINGS AND PRECAUTIONS (5.1) and CLINICAL PHARMACOLOGY (12.2) ] .

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…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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 )

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 ob…

6 ADVERSE REACTIONS 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 ad…