FARXIGA

1 INDICATIONS AND USAGE FARXIGA (dapagliflozin) is indicated: To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure. To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Limitations of Use FARXIGA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1) ]. FARXIGA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . FARXIGA is likely to be ineffective in this setting based upon its mechanism of action. FARXIGA is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. FARXIGA is not expected to be effective in these populations. FARXIGA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated: To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.. (1) To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure (1) To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. (1) As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older 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) Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . FARXIGA is likely to be ineffective in this setting based upon its mechanism of action. (1) Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. FARXIGA is not expected to be effective in these populations. (1)

2 DOSAGE AND ADMINISTRATION Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating. (2.1) To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dosage can be increased to 10 mg orally once daily for additional glycemic control. (2.2) For all other indications, the recommended dosage is 10 mg orally once daily. (2.2) See full prescribing information for dosage recommendations in patients with renal impairment. ( 2.2 , 2.3 ) Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.3) 2.1 Prior to Initiation of FARXIGA Assess renal function prior to initiation of FARXIGA therapy and then as clinically indicated [see Warnings and Precautions (5.2) ]. Assess volume status. In patients with volume depletion, correct this condition before initiating FARXIGA [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5 , 8.6) ] . 2.2 Recommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus In adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus, the recommended starting dosage of FARXIGA is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily. For Adult and Pediatric Patients with Type 2 Diabetes Mellitus and Renal Impairment: The recommended dosage for FARXIGA in patients with an eGFR greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. FARXIGA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . FARXIGA is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action. 2.3 Recommended Dosage for Other Indications in Adults The recommended dosage of FARXIGA is 10 mg orally once daily in adults for the following indications: To reduce the risk of sustained eGFR decline, end stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF) in patients with chronic kidney disease at risk of progression. To reduce the risk of CV death, hHF, and urgent heart failure visit in patients with heart failure. To reduce the risk of hHF in patients with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors. For Adults with Renal Impairment Receiving FARXIGA for Indications Other than Glycemic Control: The recommended dosage of FARXIGA in patients with an eGFR greater than or equal to 25 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. Initiation with FARXIGA is not recommended in patients with an eGFR less than 25 mL/min/1.73 m 2 . If the eGFR falls below 25 mL/min/1.73 m 2 while receiving treatment with FARXIGA, patients may continue FARXIGA 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF. 2.4 Temporary Interruption for Surgery Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume FARXIGA 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 with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue FARXIGA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.1) Volume depletion: Before initiating FARXIGA, 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. ( 5.2 ) Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.3) Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with FARXIGA. (5.4) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, 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. (5.5) Genital Mycotic Infections: Monitor and treat if indicated. (5.6) 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, FARXIGA 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. FARXIGA 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 FARXIGA. 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 FARXIGA [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 with type 1 diabetes mellitus and consider ketone monitoring in others 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 FARXIGA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting FARXIGA. Withhold FARXIGA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume FARXIGA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3) ] . Educate all patients on the signs …

4 CONTRAINDICATIONS FARXIGA is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in FARXIGA. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with FARXIGA [see Adverse Reactions (6.1) ] . History of serious hypersensitivity reaction to dapagliflozin or any of the excipients in FARXIGA. (4)

7 DRUG INTERACTIONS Table 4: Clinically Relevant Interactions with FARXIGA Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when FARXIGA is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.4) ] . 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 FARXIGA 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. See full prescribing information for information on drug interactions and interference of FARXIGA with laboratory tests. (7) Drug Interactions In Vitro Assessment of Drug Interactions 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 5 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin. Table 5: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Dapagliflozin Exposure (% Change [90% CI]) C max AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1000 mg) 20 mg ↔ ↔ Pioglitazone (45 mg) 50 mg ↔ ↔ Sitagliptin (100 mg) 20 mg ↔ ↔ Glimepiride (4 mg) 20 mg ↔ ↔ Voglibose (0.2 mg three times daily) 10 mg ↔ ↔ Other Medications Hydrochlorothiazide (25 mg) 50 mg ↔ ↔ Bumetanide (1 mg) 10 mg once daily for 7 days ↔ ↔ Valsartan (320 mg) 20 mg ↓12% [↓3%, ↓20%] ↔ Simvastatin (40 mg) 20 mg ↔ ↔ Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓7% [↓22%, ↑11%] ↓22% [↓27%, ↓17%] Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑13% [↑3%, ↑24%] ↑51% [↑44%, ↑58%] ↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25). Effects of Dapagliflozin on Other Drugs Table 6 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs. Table 6: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Coadministered Drug Exposu…

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, FARXIGA is not recommended during the second and third trimesters of pregnancy. Limited data with FARXIGA in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations ) . In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin 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 ). The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with 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 embryofetal 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 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 tested 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 pups 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 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 embryofetal development studies in rats and rabbits, dapagliflozin was administered 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).

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1) ] Volume Depletion [see Warnings and Precautions (5.2) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4) ] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.5) ] Genital Mycotic Infections [see Warnings and Precautions (5.6) ] Most common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 clinical practice. FARXIGA has been evaluated in clinical trials in adult and pediatric patients aged 10 years and older with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients with chronic kidney disease. The overall safety profile of FARXIGA was consistent across the studied indications. No new adverse reactions were identified in the DAPA-HF and DELIVER heart failure trials, or in the DAPA-CKD trial in patients with chronic kidney disease. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus. Clinical Trials for Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus Pool of 12 Placebo-Controlled Adult Trials for FARXIGA 5 and 10 mg for Glycemic Control The data in Table 1 is derived from 12 glycemic control placebo-controlled trials in adult patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 trials FARXIGA was used as monotherapy, and in 8 trials FARXIGA was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14.1) ] . These data reflect exposure of 2338 adult patients to FARXIGA with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), FARXIGA 5 mg (N=1145), or FARXIGA 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m 2 ). Table 1 shows common adverse reactions in adults associated with the use of FARXIGA. These adverse reactions were not present at baseline, occurred more commonly on FARXIGA than on placebo, and occurred in at least 2% of patients treated with either FARXIGA 5 mg or FARXIGA 10 mg. Table 1: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control Reported in ≥2% of Adults Treated with FARXIGA Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Trials Placebo N=1393 FARXIGA 5 mg N=1145 FARXIGA 10 mg N=1193 Female genital mycotic infections Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, FARXIG…