Jardiance

JARDIANCE is indicated:

• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure.
• to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.
• to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.
• 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.

• Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. (
  2.1 Testing Prior to Initiation of JARDIANCE

  • Assess renal function before initiating JARDIANCE and as clinically indicated
    [see Warnings and Precautions (5.2)]
    .
    • Use for glycemic control is not recommended in patients with an eGFR less than 30 mL/min/1.73 m²
      [see Use in Specific Populations (8.6)].
  • Assess volume status. In patients with volume depletion, correct this condition before initiating JARDIANCE
    [see Warnings and Precautions (5.2)and Use in Specific Populations (8.5, 8.6)].
  )
• Recommended dosage is 10 mg orally once daily in the morning, taken with or without food. (
  2.2 Recommended Dosage

  Table 1 presents the recommended dosage of JARDIANCE in adult and pediatric patients aged 10 years and older.

  Table 1 Recommended Dosage of JARDIANCE

  Population	Indication	Recommended Dosage
  Adults	Reduce the risk of cardiovascular death and hospitalization in patients with heart failure	10 mg orally once daily in the morning, taken with or without food.
  	Reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.
  	Reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus with established cardiovascular disease
  	Glycemic control in type 2 diabetes mellitus	10 mg orally once daily in the morning, taken with or without food. For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily.
  Pediatric patients aged 10 years and older	Glycemic control in type 2 diabetes mellitus	10 mg orally once daily in the morning, taken with or without food. For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily.
  )
• For additional glycemic control, dosage may be increased to 25 mg orally once daily in patients tolerating JARDIANCE. (
  2.2 Recommended Dosage

  Table 1 presents the recommended dosage of JARDIANCE in adult and pediatric patients aged 10 years and older.

  Table 1 Recommended Dosage of JARDIANCE

  Population	Indication	Recommended Dosage
  Adults	Reduce the risk of cardiovascular death and hospitalization in patients with heart failure	10 mg orally once daily in the morning, taken with or without food.
  	Reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.
  	Reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus with established cardiovascular disease
  	Glycemic control in type 2 diabetes mellitus	10 mg orally once daily in the morning, taken with or without food. For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily.
  Pediatric patients aged 10 years and older	Glycemic control in type 2 diabetes mellitus	10 mg orally once daily in the morning, taken with or without food. For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily.
  )
• Withhold JARDIANCE for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
  2.3 Temporary Interruption for Surgery

  Withhold JARDIANCE for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume JARDIANCE when the patient is clinically stable and has resumed oral intake

  [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)].
  )

JARDIANCE tablets available as:

• 10 mg pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with "S 10" on one side and the Boehringer Ingelheim company symbol on the other side.
• 25 mg pale yellow, oval, biconvex, film-coated tablets debossed with "S 25" on one side and the Boehringer Ingelheim company symbol 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, JARDIANCE is not recommended during the second and third trimesters of pregnancy.

  The limited available data with JARDIANCE in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

  [see Clinical Considerations]

  .

  In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible

  [see Data]

  .

  The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >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 embryo/fetal risk

  Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, 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

  Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

  In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

  In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).
  )
• Lactation:
  Not recommended when breastfeeding. (
  8.2 Lactation

  Risk Summary

  There is limited information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production. Empagliflozin is present in the milk of lactating rats

  [see Data]

  . 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 a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of JARDIANCE is not recommended while breastfeeding.

  Data

  Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
  )
• Geriatric Patients:
  Higher incidence of adverse reactions related to volume depletion and reduced renal function. (
  8.5 Geriatric Use

  In glycemic control trials in patients with type 2 diabetes mellitus, a total of 2,721 (32%) patients treated with JARDIANCE were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment

  [see Use in Specific Populations (8.6)]

  . The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively

  [see Warnings and Precautions (5.2)and Adverse Reactions (6.1)]

  .

  In the EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials, no overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients. EMPEROR-Reduced included 1,188 (64%) patients treated with JARDIANCE 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,403 (80%) patients treated with JARDIANCE 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 1,803 (55%) patients treated with JARDIANCE 65 years of age and older, and 758 (23%) patients 75 years of age and older.
  )
• Renal Impairment:
  Higher incidence of adverse reactions related to reduced renal function. (
  8.6 Renal Impairment

  The efficacy and safety of JARDIANCE for glycemic control were evaluated in a trial of adult patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m²)

  [see Clinical Studies (14.1)]

  . In this trial, 195 adult patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m², 91 adult patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m², and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m². The glucose lowering benefit of JARDIANCE 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function

  [see Warnings and Precautions (5.2)]

  . Use of JARDIANCE for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors is not recommended when eGFR is less than 30 mL/min/1.73 m².

  JARDIANCE was evaluated in 7,020 adult patients with type 2 diabetes and established cardiovascular disease (eGFR greater than or equal to 30 mL/min/1.73 m²) in the EMPA-REG OUTCOME trial, in a total of 9,718 patients with heart failure (eGFR greater than or equal to 20 mL/min/1.73 m²) in the EMPEROR-Reduced and EMPEROR-Preserved trials, and in 6,609 adult patients with chronic kidney disease (eGFR 20 to 90 mL/min/1.73 m²) in the EMPA-KIDNEY study. The safety profile across eGFR subgroups in these trials was consistent with the known safety profile

  [see Adverse Reactions (6.1)and Clinical Studies (14.3, 14.4, 14.5)].

  Efficacy and safety trials with JARDIANCE did not enroll adult patients with an eGFR less than 20 mL/min/1.73 m²or on dialysis. Once enrolled, adult patients in the EMPA-REG OUTCOME, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials were not required to discontinue therapy for worsening of eGFR to less than 20 mL/min/1.73 m²or initiation of dialysis

  [see Clinical Studies (14.3, 14.4, 14.5)].
  )