Steglujan (Ertugliflozin And Sitagliptin)

STEGLUJAN^® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• 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, STEGLUJAN 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 transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses. STEGLUJAN 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.

  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 4 days after discontinuing STEGLUJAN

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

  Withhold STEGLUJAN, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume STEGLUJAN 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 STEGLUJAN and seek medical attention immediately if signs and symptoms occur.

  ].
• Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN
  [see

  5.2 Pancreatitis

  There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin, a component of STEGLUJAN. After initiation of STEGLUJAN, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, STEGLUJAN should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using STEGLUJAN.

  ]
  .

• Assess renal function before initiating and as clinically indicated. (
  2.1 Prior to Initiation of STEGLUJAN

  • Assess renal function before initiating STEGLUJAN and as clinically indicated
    [see Warnings and Precautions (5.4)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLUJAN
    [see Warnings and Precautions (5.5)and Use in Specific Populations (8.5, 8.6)].
  )
• Correct volume depletion before initiating. (
  2.1 Prior to Initiation of STEGLUJAN

  • Assess renal function before initiating STEGLUJAN and as clinically indicated
    [see Warnings and Precautions (5.4)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating STEGLUJAN
    [see Warnings and Precautions (5.5)and Use in Specific Populations (8.5, 8.6)].
  )
• Recommended starting dosage is 5 mg ertugliflozin/100 mg sitagliptin orally once daily, taken in the morning, with or without food. (
  2.2 Recommended Dosage

  • The recommended starting dosage of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin orally once daily, taken in the morning, with or without food.
  • For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dosage of ertugliflozin can be maintained.
  • For additional glycemic control, the dosage may be increased to 15 mg ertugliflozin/100 mg sitagliptin orally once daily in patients tolerating STEGLUJAN.
  • Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD) or on dialysis
    [see Contraindications (4)]
    .
  )
• Increase dosage to 15 mg ertugliflozin/100 mg sitagliptin orally once daily in those tolerating STEGLUJAN and needing additional glycemic control. (
  2.2 Recommended Dosage

  • The recommended starting dosage of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin orally once daily, taken in the morning, with or without food.
  • For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dosage of ertugliflozin can be maintained.
  • For additional glycemic control, the dosage may be increased to 15 mg ertugliflozin/100 mg sitagliptin orally once daily in patients tolerating STEGLUJAN.
  • Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD) or on dialysis
    [see Contraindications (4)]
    .
  )
• Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m². (
  2.2 Recommended Dosage

  • The recommended starting dosage of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin orally once daily, taken in the morning, with or without food.
  • For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dosage of ertugliflozin can be maintained.
  • For additional glycemic control, the dosage may be increased to 15 mg ertugliflozin/100 mg sitagliptin orally once daily in patients tolerating STEGLUJAN.
  • Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD) or on dialysis
    [see Contraindications (4)]
    .
  )
• Withhold STEGLUJAN for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
  2.3 Temporary Interruption for Surgery

  Withhold STEGLUJAN for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume STEGLUJAN when the patient is clinically stable and has resumed oral intake

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

• STEGLUJAN 5 mg/100 mg tablets: contain ertugliflozin 5 mg and sitagliptin 100 mg and are beige, almond-shaped debossed with "554" on one side and plain on the other side.
• STEGLUJAN 15 mg/100 mg tablets: contain ertugliflozin 15 mg and sitagliptin 100 mg and are brown, almond-shaped debossed with "555" on one side and plain 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, from ertugliflozin, STEGLUJAN is not recommended during the second and third trimesters of pregnancy.

  The limited available data with ertugliflozin and sitagliptin use during pregnancy are not sufficient to determine a drug associated risk of adverse developmental outcomes. 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 ertugliflozin 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 and renal mineralization that were not fully reversible. There was no evidence of fetal harm in rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose of 15 mg/day when administered during organogenesis

  (see Data)

  .

  In rats and rabbits, sitagliptin doses of 250 and 125 mg/kg, respectively (approximately 30 and 20 times the human exposure at the maximum recommended human dose) did not adversely affect development outcomes of either species.

  The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% 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 2-4% and 15-20%, respectively.
  )
• Lactation:
  Breastfeeding not recommended. (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of STEGLUJAN, in human milk, the effects on the breastfed infant, or the effects on milk production. Ertugliflozin and sitagliptin are 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, based on data with ertugliflozin. Because of the potential for serious adverse reactions in a breastfed infant, advise women that the use of STEGLUJAN is not recommended while breastfeeding.
  )
• Geriatrics:
  Higher incidence of adverse reactions related to reduced intravascular volume. (
  8.5 Geriatric Use

  STEGLUJAN

  No dosage adjustment of STEGLUJAN is recommended based on age. Elderly patients are more likely to have decreased renal function. Because renal function abnormalities can occur after initiating ertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal function should be assessed more frequently in elderly patients

  [see Dosage and Administration (2.1)and Warnings and Precautions (5.4)]

  .

  Ertugliflozin

  In ertugliflozin clinical trials, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and older had a higher incidence of adverse reactions related to volume depletion compared to younger patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively

  [see Warnings and Precautions (5.5)and Adverse Reactions (6.1)]

  .

  In VERTIS CV, a total of 2780 (50.5%) patients treated with ertugliflozin were 65 years and older, and 595 (10.8%) patients treated with ertugliflozin were 75 years and older. Safety and efficacy were generally similar for patients age 65 years and older compared to patients younger than 65.

  Sitagliptin

  Of the total number of subjects (N=3,884) in pre-approval clinical safety and efficacy studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
  )
• Renal Impairment:
  Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (
  8.6 Renal Impairment

  A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30 to less than 60 mL/min/1.73 m²) treated with ertugliflozin did not demonstrate improvement in glycemic control. In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m², 2929 patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m², 879 patients (16%) with an eGFR of ≥45 to less than 60 mL/min/1.73 m²and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m²treated with ertugliflozin. Similar effects on glycemic control at Week 18 were observed in patients treated with ertugliflozin in each eGFR subgroup and also in the overall patient population.

  STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), ESRD, or on dialysis

  [see Contraindications (4)]

  .

  No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m².
  )