Get your patient on Farxiga (Dapagliflozin)

Indications and Usage (

Dosage and Administration (

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

  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

  [seeClinical 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 and symptoms of ketoacidosis and instruct patients to discontinue FARXIGA and seek medical attention immediately if signs and symptoms occur.

  ].
• •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 m². 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.

• •Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating.
  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
    [seeWarnings and Precautions (5.2)andUse in Specific Populations (8.5,8.6)]
    .
• •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 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 m²is 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 m². FARXIGA is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action.
• •For all other indications, the recommended dosage is 10 mg orally once daily.
  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 m²is 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 m². FARXIGA is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action.
• •See full prescribing information for dosage recommendations in patients with renal impairment. (
  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 m²is 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 m². FARXIGA is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action.
  ,
  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 [seeWarnings and Precautions (5.1)andClinical Pharmacology (12.2)].
  )
• •Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.
  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 [seeWarnings and Precautions (5.1)andClinical Pharmacology (12.2)].

Tablets: 5 mg and 10 mg

• •
  Pregnancy:
  Advise females of the potential risk to a fetus especially during the second and third trimesters.
  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

  (seeClinical 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 (

  seeData).

  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).
• •
  Lactation:
  Not recommended when breastfeeding.
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin is present in the milk of lactating rats

  (seeData)

  . 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 breastfed infants, advise women that use of FARXIGA is not recommended while breastfeeding.

  Data

  Dapagliflozin was present in rat milk 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 risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
• •
  Geriatrics:
  Higher incidence of adverse reactions related to hypotension. (
  8.5 Geriatric Use

  No FARXIGA dosage change is recommended based on age.

  A total of 1424 (24%) of the 5936 FARXIGA-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 trials assessing the efficacy of FARXIGA in improving glycemic control in type 2 diabetes mellitus. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with FARXIGA for glycemic control had adverse reactions of hypotension

  [seeWarnings and Precautions (5.2)andAdverse Reactions (6.1)]

  .

  In the DAPA-CKD, DAPA-HF and DELIVER trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.
  )
• •
  Renal Impairment:
  Higher incidence of adverse reactions related to volume depletion. (
  8.6 Renal Impairment

  FARXIGA was evaluated in 4304 adult patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m²) in the DAPA-CKD trial. FARXIGA was also evaluated in 1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m²in the DAPA-HF trial. The safety profile of FARXIGA across eGFR subgroups in these studies was consistent with the known safety profile

  [seeAdverse Reactions (6.1)andClinical Studies (14.4,14.5)].

  FARXIGA was evaluated in two glycemic control adult trials that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m²

  [seeClinical Studies (14.1)]

  , and an eGFR of 30 to less than 60 mL/min/1.73 m², respectively). Patients with diabetes and renal impairment using FARXIGA may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the trial of adult patients with an eGFR 30 to less than 60 mL/min/1.73 m², 13 patients receiving FARXIGA experienced bone fractures compared to none receiving placebo. Use of FARXIGA for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m²

  [seeDosage and Administration (2.1)]

  .

  Efficacy and safety trials with FARXIGA did not enroll patients with an eGFR less than 25 mL/min/1.73 m²or on dialysis. Once enrolled in the DAPA-CKD and DELIVER trials, adult patients were not required to discontinue therapy if eGFR fell below 25 mL/min/1.73 m²or if dialysis was initiated. Once enrolled in the DAPA-HF trial, adult patients were not required to discontinue therapy if eGFR fell below 30 mL/min/1.73 m²or if dialysis was initiated

  [seeDosage and Administration (2.3)andClinical Studies (14.4,14.5)]

  .
  )

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

• •
  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 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

  [seeClinical 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 and symptoms of ketoacidosis and instruct patients to discontinue FARXIGA and seek medical attention immediately if signs and symptoms occur.
• •
  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 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 m²), 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:
  Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated.
  5.3 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

  [see

  Adverse Reactions (6)

  ]

  .
• •
  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 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

  Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. FARXIGA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue

  [seeAdverse Reactions (6.1)]

  . 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

  [seeDrug Interactions (7)]

  .
• •
  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 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:
  Monitor and treat if indicated.
  5.6 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

  [seeAdverse Reactions (6.1)]

  . Monitor and treat appropriately.

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

  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

  [seeClinical 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 and symptoms of ketoacidosis and instruct patients to discontinue FARXIGA and seek medical attention immediately if signs and symptoms occur.

  ]
• •Volume Depletion
  [see

  5.2 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 m²), 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
  [see

  5.3 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

  [see

  Adverse Reactions (6)

  ]

  .

  ]
• •Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
  [see

  5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

  Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. FARXIGA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue

  [seeAdverse Reactions (6.1)]

  . 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

  [seeDrug Interactions (7)]

  .

  ]
• •Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
  [see

  5.5 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
  [see

  5.6 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

  [seeAdverse Reactions (6.1)]

  . Monitor and treat appropriately.

  ]

In

Dapagliflozin, an inhibitor of SGLT2, is described chemically as D-glucitol, 1,5-anhydro-1-

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: anhydrous lactose, crospovidone, magnesium stearate, microcrystalline cellulose, and silicon dioxide. In addition, the film coating contains the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

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.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72‑times (males) and 105‑times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131‑times (males) and 186‑times (females) the clinical dose of 10 mg per day, based on AUC exposure.

Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of

There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.

Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708‑times and 998‑times the maximum recommended human dose in males and females, respectively.

FARXIGA has been studied in adult patients as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist (exenatide extended release) added on to metformin. FARXIGA has also been studied in adult patients with type 2 diabetes mellitus and moderate renal impairment.

Treatment with FARXIGA as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).

FARXIGA (dapagliflozin) tablets have markings on both sides and are available in the strengths and packages listed in Table 19.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

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.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.