Trijardy Xr (Empagliflozin, Linagliptin, Metformin Hydrochloride)

TRIJARDY XR is a combination of empagliflozin, linagliptin, and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease

[see

14.2 Empagliflozin Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic CV disease. Concomitant antidiabetic medications were kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7,020 patients were treated (empagliflozin 10 mg = 2,345; empagliflozin 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years. Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black or African American. The mean age was 63 years and approximately 72% were male.

All patients in the trial had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes mellitus for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators, respectively and the mean eGFR was 74 mL/min/1.73 m². At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin HCl (74%), insulin (48%), sulfonylurea (43%) and dipeptidyl peptidase-4 inhibitor (11%).

All patients had established atherosclerotic CV disease at baseline including one (82%) or more (18%) of the following: a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a CV death or a non-fatal myocardial infarction (MI) or a non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of CV death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 8and Figures 4and 5). Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dose groups.

Table 8 Treatment Effect for the Primary Composite Endpoint and its Components^a

	Placebo N=2,333	Empagliflozin N=4,687	Hazard ratio vs placebo (95% CI)
aTreated set (patients who had received at least one dose of trial drug)
bp−value for superiority (2−sided) 0.04
cTotal number of events
Composite of CV death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b	282 (12.1%)	490 (10.5%)	0.86 (0.74, 0.99)
Non-fatal myocardial infarctionc	121 (5.2%)	213 (4.5%)	0.87 (0.70, 1.09)
Non-fatal strokec	60 (2.6%)	150 (3.2%)	1.24 (0.92, 1.67)
CV deathc	137 (5.9%)	172 (3.7%)	0.62 (0.49, 0.77)

Figure 4 Estimated Cumulative Incidence of First MACE

Figure 5 Estimated Cumulative Incidence of CV Death

The efficacy of empagliflozin on CV death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as CV deaths. The non-CV deaths were only a small proportion of deaths and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).

]

• 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 TRIJARDY XR

  • Assess renal function before initiating TRIJARDY XR and as clinically indicated
    [see Warnings and Precautions (5.1, 5.4)]
    .
  • Assess volume status. In patients with volume depletion, correct this condition before initiating TRIJARDY XR
    [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 and renal function. (
  2.2 Recommended Dosage and Administration

  • Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
    • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
    • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
  • Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg
    .
  • Take TRIJARDY XR orally, once daily with a meal in the morning.
    • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
    • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
  • Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.
  ,
  2.3 Dosage Recommendations in Patients with Renal Impairment

  • Initiation of TRIJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component.
  • TRIJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
    [see Contraindications (4), Warnings and Precautions (5.1, 5.4), and Use in Specific Populations (8.6)]
    .
  )
• Initiation is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component. (
  2.3 Dosage Recommendations in Patients with Renal Impairment

  • Initiation of TRIJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin HCl component.
  • TRIJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
    [see Contraindications (4), Warnings and Precautions (5.1, 5.4), and Use in Specific Populations (8.6)]
    .
  )
• The maximum recommended dosage of TRIJARDY XR is 25 mg empagliflozin, 5 mg linagliptin and 2,000 mg metformin HCl. (
  2.2 Recommended Dosage and Administration

  • Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
    • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
    • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
  • Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg
    .
  • Take TRIJARDY XR orally, once daily with a meal in the morning.
    • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
    • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
  • Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.
  )
• Take once daily with a meal in the morning. (
  2.2 Recommended Dosage and Administration

  • Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
    • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
    • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
  • Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg
    .
  • Take TRIJARDY XR orally, once daily with a meal in the morning.
    • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
    • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
  • Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.
  )
• Swallow whole; do not split, crush, dissolve, or chew. (
  2.2 Recommended Dosage and Administration

  • Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen:
    • In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg;
    • In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg.
  • Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg
    .
  • Take TRIJARDY XR orally, once daily with a meal in the morning.
    • Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily.
    • Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily.
  • Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew.
  )
• TRIJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (
  2.4 Discontinuation for Iodinated Contrast Imaging Procedures

  Discontinue TRIJARDY XR 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 TRIJARDY XR if renal function is stable

  [see Warnings and Precautions (5.1)]

  .
  )
• Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. (
  2.5 Temporary Interruption for Surgery

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

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

TRIJARDY XR Tablets:

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

  The limited available data with TRIJARDY XR, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl 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, empagliflozin, a component of TRIJARDY XR, resulted in adverse renal changes in rats when 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. No adverse developmental effects were observed when linagliptin or metformin HCl were administered to pregnant rats or rabbits

  (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

  Human Data

  Published data from postmarketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl 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

  Empagliflozin:

  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).

  Linagliptin:

  No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure.

  Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.

  Metformin HCl:

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

  Risk Summary

  There is limited information regarding the presence of TRIJARDY XR, or its components (empagliflozin, linagliptin, or metformin HCl) 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)

  . Empagliflozin and linagliptin are present in rat milk

  (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 TRIJARDY XR is not recommended while breastfeeding

  .

  Data

  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 HCl during lactation because of small sample size and limited adverse event data collected in infants.

  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.
  )
• 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 HCl may result in ovulation in some anovulatory women.
  )
• Geriatric Patients:
  Higher incidence of adverse reactions related to volume depletion and reduced renal function. (
  8.5 Geriatric Use

  Assess renal function more frequently in TRIJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients

  [see Warnings and Precautions (5.1, 5.4)].

  The recommended dosage for the metformin HCl component of TRIJARDY XR in geriatric patients should usually start at the lower end of the dosage range.

  Of the 273 patients treated with the combination of empagliflozin, linagliptin, and metformin HCl to improve glycemic control in adults with type 2 diabetes mellitus, 58 were 65 years of age and older, while 8 were 75 years of age and older. Clinical trials of TRIJARDY XR did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adult patients.

  Empagliflozin

  In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.

  Linagliptin

  In linagliptin trials, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin trials, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.

  Metformin HCl

  Clinical trials of metformin HCl did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
  )
• Renal Impairment:
  Higher incidence of adverse reactions related to reduced renal function. (
  8.6 Renal Impairment

  TRIJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m²due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).

  Empagliflozin

  The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment

  [see Warnings and Precautions (5.4)]

  , volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.

  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

  [see Warnings and Precautions (5.1)]

  .
  )
• Hepatic Impairment:
  Avoid use in patients with hepatic impairment. (
  8.7 Hepatic Impairment

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

  [see Warnings and Precautions (5.1)].
  )