Xigduo

Indications and Usage (

Dosage and Administration (

Dapagliflozin, when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

• •Sustained eGFR decline, end‑stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
• •
  Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure.
• •Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.

• •XIGDUO XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus
  [see

  5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

  In patients with type 1 diabetes mellitus, dapagliflozin, a component of XIGDUO XR, 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. XIGDUO XR 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 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 XIGDUO XR [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 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 XIGDUO XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting XIGDUO XR.

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

  [see Dosage and Administration (2.6)]

  .

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

  ]
  .
• •Because of the metformin HCl component, the use of XIGDUO XR is limited to patients with type 2 diabetes mellitus for all indications.
• •XIGDUO XR 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. XIGDUO XR is not expected to be effective in these populations.

XIGDUO XR (dapagliflozin and metformin HCl) extended-release tablets are available as follows:

• •
  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, XIGDUO XR is not recommended during the second and third trimesters of pregnancy.

  Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug‑associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk

  (see Data)

  . 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 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

  Human Data

  Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

  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 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).

  Metformin HCl

  Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m²) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
• •
  Lactation:
  Not recommended when breastfeeding.
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production.

  Limited published studies report that metformin is present in human milk

  (see Data)

  . However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin 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 XIGDUO XR is not recommended while breastfeeding.

  Data

  Dapagliflozin

  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.

  Metformin HCl

  Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
• •
  Females and Males of Reproductive Potential:
  Advise premenopausal females of the potential for an unintended pregnancy.
  8.3 Females and Males of Reproductive Potential

  Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
• •
  Geriatrics:
  Higher incidence of adverse reactions related to hypotension. Assess renal function more frequently. (
  8.5 Geriatric Use

  XIGDUO XR

  No XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients.

  Dapagliflozin

  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. 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 (5.3)and Adverse Reactions (6.1)]

  .

  In the DAPA-HF, DELIVER and DAPA-CKD trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65 in both the overall population and in the patients with type 2 diabetes mellitus. In the DAPA HF trial, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type 2 diabetes mellitus, 1211 (57%) were older than 65 years. In the DELIVER trial, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. Out of 2806 patients with LVEF >40% and type 2 diabetes mellitus, 2072 (74%) were older than 65 years. In the DAPA-CKD trial, 1818 (42%) out of 4304 patients with chronic kidney disease were older than 65 years. Out of 2906 patients with chronic kidney disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years.

  Metformin HCl

  Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients

  [see Warnings and Precautions (5.1)]

  .
  ,
  8.6 Renal Impairment

  Initiation of XIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m²and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or end‑stage renal disease

  [see Dosage and Administration (2.4), Contraindications (4)and Warnings and Precautions (5.1, 5.3)]

  .

  Dapagliflozin

  Dapagliflozin 10 mg 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 10 mg was also evaluated in 1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF trial. The safety profile of dapagliflozin across eGFR subgroups was consistent with the known safety profile

  [see Adverse Reactions (6.1)and

  Clinical Studies (14.4

  and

  14.5)

  ]

  .

  Dapagliflozin 10 mg was evaluated in two glycemic control trials that included adult patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m², and an eGFR of 30 to less than 60 mL/min/1.73 m²)

  [see Clinical Studies (14.1)]

  . Patients with diabetes and renal impairment using dapagliflozin 10 mg are 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 10 mg 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 (2.4)]

  .

  Metformin HCl

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. XIGDUO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m²

  [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology  (12.3)].
  )
• •
  Renal Impairment:
  Higher incidence of adverse reactions related to volume depletion. (
  8.6 Renal Impairment

  Initiation of XIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m²and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or end‑stage renal disease

  [see Dosage and Administration (2.4), Contraindications (4)and Warnings and Precautions (5.1, 5.3)]

  .

  Dapagliflozin

  Dapagliflozin 10 mg 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 10 mg was also evaluated in 1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF trial. The safety profile of dapagliflozin across eGFR subgroups was consistent with the known safety profile

  [see Adverse Reactions (6.1)and

  Clinical Studies (14.4

  and

  14.5)

  ]

  .

  Dapagliflozin 10 mg was evaluated in two glycemic control trials that included adult patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m², and an eGFR of 30 to less than 60 mL/min/1.73 m²)

  [see Clinical Studies (14.1)]

  . Patients with diabetes and renal impairment using dapagliflozin 10 mg are 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 10 mg 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 (2.4)]

  .

  Metformin HCl

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. XIGDUO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m²

  [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology  (12.3)].
  )
• •
  Hepatic Impairment:
  Avoid use in patients with hepatic impairment.
  8.7 Hepatic Impairment

  Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.1)]

  .