Dapagliflozin, an inhibitor of SGLT2, is described chemically as D-glucitol, 1,5-anhydro-1- C -[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1 S )-, compounded with (2 S )-1,2-propanediol, hydrate (1:1:1). The empirical formula is C 21 H 25 ClO 6 •C 3 H 8 O 2 •H 2 O and the molecular weight is 502.98. The structural formula is: FARXIGA is available as a film-coated tablet for oral administration containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide. Dapagliflozin Chemical Structure

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 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 . • FARXIGA is not recommended for use to improve glycemic control in adults 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. • 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 with type 2 diabetes mellitus. Limitations of use: • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. • Not recommended for use to improve glycemic control in adults 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. • 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.

• FARXIGA 5 mg tablets are yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side. • FARXIGA 10 mg tablets are yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side. • Tablets: 5 mg and 10 mg

• Assess volume status and correct volume depletion before initiating. eGFR (mL/min/1.73 m 2 ) Recommended Dose eGFR 45 or greater To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control. For all other indications, the recommended starting dose is 10 mg orally once daily. eGFR 25 to less than 45 10 mg orally once daily eGFR less than 25 Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF. • Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting

Prior to Initiation of FARXIGA Assess renal function prior to initiation of FARXIGA therapy and then as clinically indicated . Assess volume status. In patients with volume depletion, correct this condition before initiating FARXIGA

Recommended Dosage See Table 1 for dosage recommendations based on estimated glomerular filtration rate (eGFR). Table 1: Recommended Dosage eGFR (mL/min/1.73 m 2 ) Recommended Dose eGFR 45 or greater To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control FARXIGA is not recommended for use to improve glycemic control in adults 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. . For all other indications, the recommended starting dose is 10 mg orally once daily. eGFR 25 to less than 45 10 mg orally once daily . eGFR less than 25 Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF. hHF: hospitalization for heart failure, CV: Cardiovascular, ESKD: End Stage Kidney Disease 2.3 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 .

• 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. • 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. • Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. • Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with FARXIGA. • 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. • Genital Mycotic Infections: Monitor and treat if indicated. 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 ; 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 . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue FARXIGA and seek medical attention immediately if signs and symptoms occur

Volume Depletion FARXIGA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 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 FARXIGA in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy

Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including FARXIGA. 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

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA may 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 minimize the risk of hypoglycemia when these agents are used in combination with FARXIGA

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 FARXIGA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with FARXIGA 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 FARXIGA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control

Genital Mycotic Infections FARXIGA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections . Monitor and treat appropriately.

Table 5: 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) . 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.