TRIJARDY XR is an extended-release formulation of empagliflozin, linagliptin, and metformin that is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. The FDA approved the Tripple combination therapy for the treatment of diabetes on the 28th of January, 2020. TRIJARDY XR is used to treat patients with diabetes type 2 as an adjunct to diet and exercise. It is not recommended for use in patients with diabetes mellitus type 1, diabetic ketoacidosis, and pancreatitis.

TRIJARDY XR is available in four different dosage strength and different colors as oval-shaped film-coated tablets:

• Grey tablet contains 5 mg empagliflozin, 2.5 mg linagliptin, and 1000 mg metformin extended-release.

• Tan tablet contains 10 mg empagliflozin, 5 mg linagliptin, and 1000 mg metformin extended-release.

• Red tablet contains 12.5 mg empagliflozin, 2.5 mg linagliptin, and 1000 mg metformin extended-release.

• Brown tablet contains 25 mg empagliflozin, 5 mg linagliptin, and 1000 mg metformin extended-release.

Trijardy XR Tablet Price in the US:

• Each 5-2.5-1000 mg tablet costs: $10.45
• Each 10-5-1000 mg tablet costs: $20.90
• Each 12.5-2.5-1000 mg tbalet costs: $10.45
• Each 25-5-1000 mg tablet costs: $20.90

TRIJARDY XR Dose in Adult patients with Type 2 Diabetes Mellitus:

Note:

• Correct volume depletion prior to initiating therapy
• Check Renal functions at baseline and periodically thereafter during the treatment.

• Patients on metformin with or without linagliptin:

  • Switch to TRIJARDY XR 10/5/1000 mg

• Patients on metformin and empagliflozin with or without linagliptin:

  • Switch to TRIJARDY XR that contains the same total dose of metformin, empagliflozin, and 5 mg of linagliptin
  • The dose should be adjusted if tolerated and adjustment in the dose is required to the maximum daily dose of empagliflozin 25 mg, linagliptin 5 mg, and metformin 2000 mg.

TRIJARDY XR 5/2.5/1000 mg and 12.5/2.5/1000 mg should be taken as a single tablet or two tablets together once a day. TRIJARDY XR 10/5/1000 mg and 25/5/1000 mg should be taken as a single tablet once a day. It should be taken as a whole, without splitting, crushing, or chewing early in the morning after breakfast.

TRIJARDY XR overdosage:

Linagliptin is unlikely to be removed from the body via hemodialysis or peritoneal dialysis. The removal of empagliflozin from the body via hemodialysis has not been studied. Metformin overdosage has been associated with lactic acidosis in 32% of the patients. Metformin is dialyzable and hemodialysis may be considered in patients in whom overdosage is suspected.

TRIJARDY XR Pregnancy Category: Undetermined

• Empagliflozin, linagliptin all cross the placental boundary. 
• In animal studies, Linagliptin was not associated to adverse fetal outcomes. 
• Empagliflozin was, however, associated with adverse fetal renal tube defects.
• Because of possible adverse effects on the development of the kidneys, the manufacturer suggests avoiding it during the second and third trimesters.
• Pregestational diabetic patients are at risk of major birth defects. The HbA1C level is higher than 7, 10%, and 6 to 10%, respectively.
• Uncontrolled diabetes can also increase the risk of preeclampsia and maternal diabetic ketoacidosis.
• Poorly controlled diabetes can also pose a risk for major birth defects, stillbirths, and macrosomia.

Use during lactation

• Metformin and empagliflozin can be excreted in breastmilk.
• In animal studies, adverse fetal outcomes were reported.
• It is not recommended for breastfeeding. Manufacturers recommend discontinuing breastfeeding or stopping the drug.

TRIJARDY XR dose adjustment in renal impairment:

• eGFR = 45 mL/min/1.73m2

  • There is no need to adjust the dosage.

• eGFR below 45 mL/min/1.73m2

  • It is not a good idea to start treatment.

• eGFR below 30 mL/min/1.73m2

  • Contraindicated

TRIJARDY XR for patients undergoing iodinated Contrast Image Procedures

Patients undergoing iodinated contrast image procedures at the same time or before the procedure should stop receiving treatment, especially patients with:

• eGFR below 60 mL/min/1.73m2
• History of liver disease
• Alcoholism
• Heart failure

After 48 hours, renal function should be checked again. Patients with stable renal function may be re-evaluated.

Dose in liver disease:

It should be avoided in patients with moderate and severe hepatic impairment.

Important Contraindications, warnings, and Precautions are covered in the "Contraindications & Warnings" tab.

Also see individual agents: metformin & empagliflozin

TRIJARDY XR Side effects:

• Acute Pancreatitis that may be fatal
• Ketoacidosis (Euglycemic ketoacidosis)
• Urosepsis and Pyelonephritis
• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
• Hypersensitivity Reactions including:
  • Anaphylaxis,
  • Angioedema, and
  • Exfoliative Skin Conditions
• Severe and Disabling Arthralgia
• Bullous Pemphigoid
• Skin reactions such as a rash or urticaria)
• Mouth Ulcerations and Stomatitis
• Cholestatic, hepatocellular, and mixed hepatocellular liver injury
• Rhabdomyolysis

TRIJARDY XR Contraindications:

• Severe renal impairment (eGFR lower than 30 mL/min/1.73m2)
• End-stage renal disease and patients on dialysis
• Metabolic acidosis includes diabetic ketoacidosis
• Allergy reactions (such as anaphylaxis or angioedema, exfoliative conditions, urticaria or bronchial hyperreactivity), to empagliflozin or linagliptin or any component in the formulation.

Warnings and precautions 

• Lactic Acidosis

  • Metformin-induced lactic acidosis can be life-threatening. It can cause death, hypothermia and hypotension, as well as cardiac bradyarrhythmias.
  • Non-specific symptoms of lactic acidosis include malaise, myalgias and somnolence.
  • It is characterised by high blood lactate levels (more that 5 mmol/L), anion gaps metabolic acidosis and increased lactate:pyruvate ratios. Plasma metformin levels are more than 5 mg/ml.
  • These patients are at high risk for developing lactic acidosis:
    • Patients with severe renal impairment
    • Use of other drugs, such as topiramate or Acetazolamide, in conjunction with certain drugs
    • Over 65
    • Radiocontrast study of patients
    • Major surgeries and diagnostic procedures are performed on patients undergoing major surgery.
    • Hypoxic states, such as heart failure, can be hypoxic.
    • Hepatic impairment
    • Alcohol intake that is excessive
  • Patients with lactic acidosis must stop treatment immediately. They may need hemodialysis.

• Pancreatitis

  • DPP IV inhibitors have been shown to be effective in treating acute pancreatitis, including necrotizing and hemorhagic pancreatitis. These cases can prove fatal.
  • Patients who have had a history of pancreatitis in the past should not take this drug.

• Heart Failure 

  • Heart failure has been linked to DPP IV inhibitors. It can exacerbate myocardial damage.
  • Before you decide to start the treatment, it is important to weigh the benefits and risks.
  • Patients should report any symptoms such as chest pain, new-onset dyspnea or palpitations.
  • The patient should be treated as soon as possible and evaluated.

• Hypotension 

  • Because SGLT2 inhibitors prevent glucose absorption from your kidneys.
  • They can also cause fluid loss and osmotic dilution. If patients are taking diuretics or ACE inhibitors concurrently, hypotension may occur.
  • Patients should be instructed to drink adequate fluids.

• Ketoacidosis

  • SGLT2 inhibitors have been linked to serious and potentially fatal cases of diabetic ketoacidosis.
  • Patients with rapid breathing, shortness of breath or abdominal pain should have their serum ketones measured, even if plasma glucose is below 250 mg/dl.
  • Diabetic ketoacidosis is more common in patients with DKA history, alcoholics, or those who are insulin-dependent.
  • It is important to stop all treatment and get insulin infusions and hydration immediately.
  • Surgery patients should temporarily stop using TRIJARDY XR at least three days before to the procedure.

• Acute Kidney Injury

  • Like other SGLT2 inhibitors empagliflozin causes intravascular volume loss.
    • Patients at high risk for kidney injury such as:
      • Hypovolemia patients
      • Chronic renal failure
      • Heart failure
      • The concomitant intake of diuretics, ACE inhibitors and ARBs as well as NSAIDs.
    • Patients with acute illnesses and patients who have experienced fluid loss (diarrhea or vomiting) should temporarily stop TRIJARDY XR.
    • Renal function needs to be closely monitored if the eGFR at baseline is less than 60 ml/min/m2.

• Pyelonephritis and Urosepsis

  • Recurrent infections of the urinary tract, including pyelonephritis, may occur in patients taking empagliflozin.
  • It is important that patients report UTI symptoms.
  • It is important to evaluate patients promptly and treat them accordingly.

• Hypoglycemia 

  • Hypoglycemia can occur when metformin, empagliflozin and linagliptin are given to patients who are insulin-secretagogues or insulin-secretagogues.
  • When initiating TRIJARDY XR, the insulin dose and secretagogues should both be decreased.

• Necrotizing Fasciitis in the Perineum (Fournier’s Gangrene).

  • Patients receiving empagliflozin may develop serious and sometimes fatal necrotizing fasciitis (Fournier's Gangrene).
  • Patients should stop taking the medicine.
  • Sometimes, hospitalization and multiple surgical debridements are required.
  • Ask patients to describe any pain, tenderness or redness in the genital or perineal areas.
  • Necrotizing fasciitis patients should immediately be treated with broad-spectrum antibiotics and surgical care.
  • To avoid hyperglycemia, you can take alternative anti-diabetic medications.

• Genital Mycotic Infections 

  • SGLT2 inhibitors can cause genital infections, especially fungi.
  • Patients must be properly treated and monitored.

• Hypersensitivity Reactions

  • Liningriptin has been linked to allergic reactions.
  • Patients might experience angioedema or angioedema.
  • These reactions are common in patients who begin treatment within three months.
  • Patients who have had angioedema to DPP IV inhibitor therapy in the past are at particular risk.
  • Emagliflozin, including angioedema, has also been linked to hypersensitivity reactions.
  • The treatment must be stopped and the condition properly managed.
  • Patients who have had severe allergic reactions in the past should not use TRIJARDY XR.

• Vitamin B12 Deficiency

  • Metformin can impair vitamin B 12 absorption
  • Vitamin B12 levels should be checked at least every 2 to 3 years. Supplementation may also be recommended.
  • To rule out anemia or macrocytosis, it is important to evaluate your hemoglobin levels annually.

• Arthralgia severe and disabling

  • DPP IV inhibitors, such as Liningriptin, may cause severe arthralgias.
  • Some patients may experience symptoms as soon as a drug is started.
  • The treatment should be stopped and symptomatic treatment may be offered.
  • You can try reinitiation at a lower dosage.

• Bullous Pemphigoid

  • Patients may develop bullous pemphigoid.
  • It can be caused by the use of DPP IV inhibitors, such as linagliptin.
  • Patients should be told to stop taking the medicine and consult their treating physician.

Monitor:

• Monitoring plasma sugars and HbA1C to determine drug efficacy (every 3 – 6 months)
• Examine patients for genital and urinary tract infections.
• Status of blood pressure and volume
• Renal functions
• Ketones
• Patients suspected of having DKA may have an atrial PH or bicarbonate.
• If indicated, levels of lactate
• Serum amylase
• If indicated, pregnancy test

How to administer TRIJARDY XR?

• TRIJARDY XRTake 5/2.5/1000mg and 12.5/2.5/1000mg as one tablet, or two tablets at a time.
• TRIJARDY XR 10/5/1000mg and 25/5/1000mg should be taken in one tablet daily. It should be taken whole.

TRIJARDY XR Mechanism of Action [Ref]:

• TRIJARDY XR includes:

  • Empagliflozin is an SGLT2 inhibitor (sodiumglucose cotransporter 2 inhibitor).
  • Linagliptin is a dipeptidylpeptidase-4 inhibitor (DPP-4)
  • Metformin is a biguanide.

• Empagliflozin

  • Empagliflozin, an SGLT2 inhibitor, inhibits the reabsorption and use of filtered glucose via renal tubules.
  • It also lowers the renal threshold for glucose, causing excess glucose loss in urine.
  • The urine loses glucose. With a dose of between 10 and 25 mg, the urine loses an average of 64 gms to 78 gms glucose.
  • TheTime to reach plasma peak concentrationEmagliflozin takes 1.5 hours
  • TheTerminal elimination half-lifeIt takes 12.4 hours to complete oral administration.
  • 41.2% of this drug isExcreted54.4% excreted through feces, and 54.4% via urine.
  • In severe renal impairment, the peak plasma levels for empagliflozin can be 20% higher.
  • The urine level of empagliflozin remains constant. With a decrease in the eGFR, urinary glucose excretion falls.

• Linagliptin

  • Linagliptin blocks the enzyme DPP-4, which is responsible for the breakdown of incretin hormones GIP (glucose dependent insulinotropic polypeptide), and GLP (glucagon -like peptide-1).
  • This causes an increase in incretin levels, which stimulate insulin release in a glucose-dependent fashion and decreases glucagon levels.
  • Although Incretin levels can be released throughout the day (in the presence elevated blood glucose), they increase after meals.
  • The liver produces less glucose when glucagon is present.
  • Lininguilin's bioavailability is 30%. This is lower if taken with high-fat meals.
  • It is widely distributed to tissues.
  • 70% - 80% of drug is bound to plasma protein.
  • It has an accumulation half life of approximately 11 hours and a terminal 1/2-life of around 200 hours.
  • 90% of the drug can be thrown away unchanged.
  • Patients with kidney impairment may be exposed to more drugs, but the accumulation half-life, terminal life, or an elevated accumulation factor are all higher.
  • Lininguilin excretion in the kidney is lower than 5% of the dose administered and is not affected if there is a decrease in renal function.

• Metformin HCl

  • Metformin lowers glucose output from the liver and inhibits intestinal absorption. It also increases glucose uptake in tissues through insulin sensitivity.
  • It doesn't affect insulin secretion.
  • Metformin may be more easily absorbed if taken with high-fat meals.
  • After a single oral dose of extended-release metformin, the time it takes to reach plasma peak concentration is approximately 7 - 8 hours.
  • It doesn't bind to plasma proteins.
  • The plasma's half-life is 6.2 hours and the blood's 17.6 hours.
  • Within 24 hours, approximately 90% of the drug is eliminated via the kidneys.
  • Patients with impaired renal clearance have a longer plasma and blood half-life for metformin.

Empagliflozin, linagliptin, and metformin extended-release brands available:

• TRIJARDY XR

Trijardy XR Tablet Price in the US:

• Each 5-2.5-1000 mg tablet costs: $10.45
• Each 10-5-1000 mg tablet costs: $20.90
• Each 12.5-2.5-1000 mg tbalet costs: $10.45
• Each 25-5-1000 mg tablet costs: $20.90

Empagliflozin, linagliptin, and metformin extended-release brands in Pakistan:

TRIJARDY XR is not available in Pakistan.