Dapagliflozin

Indications and Usage

Dosage and Administration (

DAPAGLIFLOZIN TABLETS are 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.

• •DAPAGLIFLOZIN TABLETS are 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, dapagliflozin 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 TABLETS are 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 TABLETS

  [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 DAPAGLIFLOZIN TABLETS, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting DAPAGLIFLOZIN TABLETS.

  Withhold DAPAGLIFLOZIN TABLETS, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume DAPAGLIFLOZIN TABLETS when the patient is clinically stable and has resumed oral intake

  [see

  Dosage and Administration (2.4)

  ]

  .

  Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue DAPAGLIFLOZIN TABLETS and seek medical attention immediately if signs and symptoms occur.

  ]
  .
• •DAPAGLIFLOZIN TABLETS are 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 m². DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action.
• •DAPAGLIFLOZIN TABLETS are 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. DAPAGLIFLOZIN TABLETS are not expected to be effective in these

• •Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating.
  2.1 Testing Prior to Initiation of DAPAGLIFLOZIN TABLETS

  • •Assess renal function prior to initiation of DAPAGLIFLOZIN TABLETS and then as clinically indicated
    [see
    Warnings and Precautions (5.2)
    ].
  • •Assess volume status. In patients with volume depletion, correct this condition before initiating DAPAGLIFLOZIN TABLETS
    [see Warnings and Precautions (5.2)and Use in Specific Populations (8.5, 8.6)]
    .
• •To improve glycemic control, the recommended starting dosage is 5 mg orally once daily. Dosage can be increased to 10 mg orally once daily for additional glycemic control.
  2.000000000000000e+00

  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 DAPAGLIFLOZIN TABLETS 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 DAPAGLIFLOZIN TABLETS 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.
  • •DAPAGLIFLOZIN TABLETS 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. DAPAGLIFLOZIN TABLETS 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. (2.3)
• •See full prescribing information for dosage recommendations in patients with renal impairment.
• •Withhold DAPAGLIFLOZIN TABLETS for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.4)

Tablets:

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

• •
  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, DAPAGLIFLOZIN TABLETS are not recommended during the second and third trimesters of pregnancy.

  Limited data with dapagliflozin 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).
• •
  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

  (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 breastfed infants, advise women that use of DAPAGLIFLOZIN TABLETS 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 DAPAGLIFLOZIN TABLETS dosage change is recommended based on age.

  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 trials assessing the efficacy of dapagliflozin 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 dapagliflozin for glycemic control had adverse reactions of hypotension

  [see Warnings and Precautions (5.2)and Adverse 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

  Dapagliflozin was evaluated in 4304 adult patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m²) in the DAPA-CKD trial. Dapagliflozin 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 dapagliflozin across eGFR subgroups in these studies was consistent with the known safety profile

  [see Adverse Reactions (6.1)and Clinical Studies (14.4, 14.5)]

  .

  Dapagliflozin 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

  [see Clinical 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 dapagliflozin 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 dapagliflozin experienced bone fractures compared to none receiving placebo. Use of DAPAGLIFLOZIN TABLETS 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

  [see Dosage and Administration (2.1)]

  .

  Efficacy and safety trials with dapagliflozin 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

  [see Dosage and Administration (2.3)and Clinical Studies (14.4, 14.5)].
  )