Segluromet (Ertugliflozin And Metformin Hydrochloride)

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

• Assess renal function prior to initiation and as clinically indicated. (
  2.1 Prior to Initiation of SEGLUROMET

  • Assess renal function before initiating SEGLUROMET and as clinically indicated
    [see Warnings and Precautions (5.2)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating SEGLUROMET
    [see Warnings and Precautions (5.4)and Use in Specific Populations (8.5, 8.6)].
  )
• Correct volume depletion before initiation. (
  2.1 Prior to Initiation of SEGLUROMET

  • Assess renal function before initiating SEGLUROMET and as clinically indicated
    [see Warnings and Precautions (5.2)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating SEGLUROMET
    [see Warnings and Precautions (5.4)and Use in Specific Populations (8.5, 8.6)].
  )
• Individualize the starting dosage based on the patient's current regimen. (
  2.2 Recommended Dosage

  • Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
    • In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total oral daily dosage of metformin HCl.
    • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total oral daily dosage of ertugliflozin.
    • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage of metformin HCI.
  • Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin
    [see Adverse Reactions (6.1)].
  • Dosing may be adjusted based on effectiveness and tolerability.
  • Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of SEGLUROMET 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)]
    .
  )
• Maximum recommended dosage is 7.5 mg ertugliflozin/1,000 mg metformin orally twice daily. (
  2.2 Recommended Dosage

  • Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
    • In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total oral daily dosage of metformin HCl.
    • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total oral daily dosage of ertugliflozin.
    • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage of metformin HCI.
  • Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin
    [see Adverse Reactions (6.1)].
  • Dosing may be adjusted based on effectiveness and tolerability.
  • Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of SEGLUROMET 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)]
    .
  )
• Take orally twice daily with meals, with gradual dose escalation. (
  2.2 Recommended Dosage

  • Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
    • In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total oral daily dosage of metformin HCl.
    • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total oral daily dosage of ertugliflozin.
    • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage of metformin HCI.
  • Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin
    [see Adverse Reactions (6.1)].
  • Dosing may be adjusted based on effectiveness and tolerability.
  • Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
  • Use of SEGLUROMET 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)]
    .
  )
  
  • Do not use in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m².
  • Use is not recommended in patients with an eGFR less than 45 mL/min/1.73 m². (
    2.2 Recommended Dosage

    • Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
      • In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total oral daily dosage of metformin HCl.
      • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total oral daily dosage of ertugliflozin.
      • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage of metformin HCI.
    • Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin
      [see Adverse Reactions (6.1)].
    • Dosing may be adjusted based on effectiveness and tolerability.
    • Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
    • Use of SEGLUROMET 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 contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage-renal disease (ESRD), or on dialysis. (
    2.2 Recommended Dosage

    • Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride (HCI), based on the patient’s current regimen, while not exceeding the maximum recommended oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
      • In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin, with a similar total oral daily dosage of metformin HCl.
      • In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin HCl, with a similar total oral daily dosage of ertugliflozin.
      • In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage of metformin HCI.
    • Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those initiating metformin HCl to reduce the gastrointestinal side effects due to metformin
      [see Adverse Reactions (6.1)].
    • Dosing may be adjusted based on effectiveness and tolerability.
    • Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/min/1.73 m².
    • Use of SEGLUROMET 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)]
      .
    )
• SEGLUROMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (
  2.3 Discontinuation for Iodinated Contrast Imaging Procedures

  Discontinue SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart SEGLUROMET if renal function is stable

  [see Warnings and Precautions (5.1)]

  .
  )
• Withhold SEGLUROMET for at least 4 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
  2.4 Temporary Interruption for Surgery

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

  [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)].
  )

• Tablets: ertugliflozin 2.5 mg and metformin HCl 500 mg, pink, oval, debossed with "2.5/500" on one side and plain on the other side.
• Tablets: ertugliflozin 2.5 mg and metformin HCl 1,000 mg, pink, oval, debossed with "2.5/1000" on one side and plain on the other side.
• Tablets: ertugliflozin 7.5 mg and metformin HCl 500 mg, red, oval, debossed with "7.5/500" on one side and plain on the other side.
• Tablets: ertugliflozin 7.5 mg and metformin HCl 1,000 mg, red, oval, debossed with "7.5/1000" 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, SEGLUROMET is not recommended during the second and third trimesters of pregnancy. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk

  (see Data)

  .

  The limited available data with SEGLUROMET in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or 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 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)

  .

  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.

  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

  Human Data

  Published data from postmarketing 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

  Ertugliflozin

  When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development, and did not fully reverse within a 1-month recovery period.

  In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately 300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally toxic dose (250 mg/kg/day) in rats (707 times the clinical dose) was associated with reduced fetal viability and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC).

  Metformin HCl

  Metformin did not adversely affect development outcomes when administered to rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
  )
• Lactation:
  Breastfeeding not recommended. (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of SEGLUROMET or ertugliflozin 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. Ertugliflozin

  (see Data)

  and metformin are present in the milk of lactating rats. 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 SEGLUROMET is not recommended while breastfeeding.

  Data

  The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).

  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 reduced intravascular volume. (
  8.5 Geriatric Use

  SEGLUROMET

  No dosage adjustment of SEGLUROMET 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 metformin is known to be substantially excreted by the kidneys, care should be taken in dose selection in the elderly. Assess renal function in elderly patients prior to initiating dosing and periodically thereafter

  [see Dosage and Administration (2.1)and Warnings and Precautions (5.1, 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 (5.4)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.

  Metformin HCl

  Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose 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 Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]

  .
  )
• 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 have 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 m², and 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.

  SEGLUROMET 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.

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.
  )
• 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. SEGLUROMET is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.1)]

  .
  )