empagliflozin/linagliptin/metformin hydrochloride

Empagliflozin/linagliptin/metformin is a combination medication used to improve glycemic control in adults with type 2 diabetes mellitus, and to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. The medication is used as an adjunct to diet and exercise. Each of the three components of the combination drug works in different ways to reduce blood glucose levels.

• Empagliflozin: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor drug. SGLT2 is a protein molecule that is responsible for the majority of glucose reabsorption in the kidneys. Dapagliflozin inhibits SGLT2, reduces reabsorption of glucose and promotes its excretion in the urine.
• Linagliptin: The intestines release incretin hormones known as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), after a meal. Incretin hormones stimulate insulin release from the pancreas, reduce glucagon secretion, and glucose production in the liver. Dipeptidyl peptidase-4 (DPP-4) enzyme, present in many tissues, inactivates the incretin hormones within minutes. Linagliptin inhibits DPP-4 enzyme and slows down the inactivation of the incretin hormones.
• Metformin: Metformin belongs to a class of medications known as biguanides. Metformin improves the body’s response to natural insulin and increases peripheral glucose intake and utilization. Metformin also reduces glucose absorption from the intestines and decreases glucose production by the liver.

Empagliflozin/linagliptin/metformin is not recommended for the treatment of type I diabetes or diabetic ketoacidosis. The combination drug has not been studied in the treatment of patients with a history of pancreatitis and it is not known if such patients are at a higher risk for developing pancreatitis with empagliflozin/linagliptin/metformin treatment.

• Do not use empagliflozin/linagliptin/metformin in patients with hypersensitivity to empagliflozin, linagliptin, metformin or any other component of the medication. There have been reports of hypersensitivity reactions including hives (urticaria), bronchial reactions, exfoliative skin conditions, angioedema, and anaphylaxis following treatment with the combo drug.
• Do not use empagliflozin/linagliptin/metformin in patients with:
  • Severe impairment of kidney function, end-stage renal disease (ESRD) or dialysis
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Metformin use is associated with lactic acidosis, including fatal cases.
  • Symptoms may be nonspecific and include muscle pain, malaise, abdominal pain, respiratory distress, and drowsiness. Severe acidosis can cause abnormally low body temperature, heart rate, and blood pressure.
  • If the patient develops metformin associated lactic acidosis, discontinue the medication immediately, institute supportive measures and perform hemodialysis to correct acidosis and eliminate metformin.
  • Educate patients on the symptoms of lactic acidosis and advise them to report symptoms immediately.
  • Take appropriate measures to reduce the risk of metformin-associated lactic acidosis in patients with potential risk for acidosis. Risk factors include:
    • Impaired kidney function
    • Concomitant use of drugs that can increase lactic acidosis risk
    • Advanced age of 65 years or older
    • Radiological studies with contrast agent
    • Surgery and other procedures
    • Low oxygen levels
    • Impaired liver function
    • Excessive alcohol intake
• Linagliptin use is associated with pancreatitis, including fatal cases. Monitor the patient and discontinue empagliflozin/linagliptin/metformin if the patient develops signs and symptoms of pancreatitis and institute appropriate treatment. It is not known if patients with a history of pancreatitis are at a higher risk for developing pancreatitis.
• Treatment with the DPP-4 inhibitor class of medications has been associated with heart failure.
  • Consider risks and benefits before initiating empagliflozin/linagliptin/metformin treatment in patients at risk of heart failure and closely monitor them during therapy.
  • Apprise patients of heart failure symptoms and advise them to report such symptoms immediately.
  • If the patient develops heart failure symptoms, evaluate and manage appropriately and consider discontinuing empagliflozin/linagliptin/metformin.
• Empagliflozin reduces blood volume and can cause hypotension, particularly in patients with kidney impairment, patients on diuretics, elderly patients and patients with low systolic blood pressure. Check blood volume status and correct, if necessary, monitor for signs and symptoms of hypotension and continue monitoring during therapy.
• Treatment with SGLT-2 inhibitors, including empagliflozin, is associated with ketoacidosis, a life-threatening complication of type II diabetes mellitus.
  • Consider the patient’s risk for developing ketoacidosis before initiating empagliflozin/linagliptin/metformin.
  • Monitor patients for symptoms of ketoacidosis and discontinue treatment in patients who develop and treat appropriately.
  • In patients undergoing elective surgery, consider temporary discontinuation of empagliflozin/linagliptin/metformin at least 3 days before surgery.
  • Educate patients on symptoms of ketoacidosis and advise them to report such symptoms immediately.
• Empagliflozin can cause acute kidney injury, which may require dialysis and hospitalization in some cases.
  • Assess the patient’s risks before initiating empagliflozin/linagliptin/metformin.
  • Evaluate the patient’s kidney function before starting treatment and periodically thereafter.
  • If the patient develops signs and symptoms of kidney injury, discontinue empagliflozin/linagliptin/metformin and treat appropriately.
• Treatment with SGLT-2 inhibitors, including empagliflozin, is associated with urinary tract infections. Monitor patients for signs and symptoms of urinary tract infections and treat promptly.
• Empagliflozin/linagliptin/metformin treatment can cause hypoglycemia and the risk is higher when used in combination with insulin or insulin secretagogue medications such as sulfonylureas. Adjust the dosage of insulin or insulin secretagogue appropriately.
• There have been reports of a rare but life-threatening bacterial genital infection, necrotizing fasciitis of the perineum (Fournier’s gangrene), associated with empagliflozin, that have required surgical intervention.
  • Educate patients on symptoms of necrotizing fasciitis and advise them to report symptoms immediately.
  • If necrotizing fasciitis is suspected, institute appropriate treatment immediately, discontinue empagliflozin/linagliptin/metformin, monitor glucose levels closely and provide alternate treatment for glycemic control.
• Empagliflozin increases the risk for genital fungal (mycotic) infections, particularly in patients with a history. Monitor the patient and treat appropriately.
• There have been serious hypersensitivity reactions in some patients, including angioedema, anaphylaxis, and exfoliative skin conditions, generally within the first 3 months of treatment initiation with linagliptin.
  • Use empagliflozin/linagliptin/metformin with caution in patients with a history of hypersensitivity reaction to any other dipeptidyl peptidase-4 (DPP-4) inhibitor.
  • Advise patients to report hypersensitivity reactions immediately.
  • In case of hypersensitivity, discontinue empagliflozin/linagliptin/metformin immediately, provide appropriate treatment and monitor until symptoms resolve.
• Metformin treatment may decrease vitamin B12 levels, and the risk is higher in patients with inadequate vitamin B12 or calcium intake/absorption. Monitor the patient’s vitamin B12 levels and manage appropriately.
• DPP-4 inhibitors, including linagliptin can cause severe and disabling joint pain (arthralgia) that may occur immediately after initiation of therapy or even after years. Consider linagliptin as a possible cause if the patient develops arthralgia, and discontinue if appropriate.
• Some patients taking DPP-4 inhibitors have developed bullous pemphigoid, a rare skin disorder. Advise patients to report development of blisters, and lesions. If bullous pemphigoid is suspected, discontinue empagliflozin/linagliptin/metformin and refer to a dermatologist for appropriate treatment.

Common side effects of empagliflozin/linagliptin/metformin hydrochloride include:

• Upper respiratory infection
• Urinary tract infection
• Asymptomatic bacteriuria
• Bladder inflammation (cystitis)
• Nose and throat inflammation (nasopharyngitis)
• Diarrhea
• Constipation
• Headache
• Gastroenteritis
• Low blood glucose levels (hypoglycemia)

Common side effects of empagliflozin include:

• Urinary tract infection
• Genital mycotic infections
• Upper respiratory tract infection
• Increased urination
• Imbalance of blood fats (dyslipidemia)
• Joint pain (arthralgia)
• Nausea
• Thirst
• Volume depletion
• Low blood pressure (hypotension)
• Fainting (syncope)

Common side effects of linagliptin include:

• Nose and throat inflammation (nasopharyngitis)
• Diarrhea
• Cough
• Hypersensitivity reactions including:
  • Hives (urticaria)
  • Swelling beneath the skin and in mucous tissue (angioedema)
  • Localized skin exfoliation
  • Bronchial hyperreactivity

Common side effects of metformin include:

• Diarrhea
• Nausea
• Vomiting
• Gas (flatulence)
• Abdominal discomfort
• Indigestion
• Headache
• Weakness (asthenia)
• Hypoglycemia

Lab test abnormalities of empagliflozin/linagliptin/metformin include:

• Increase in serum creatinine
• Decrease in eGFR
• Increase in LDL cholesterol
• Increase in hematocrit
• Increase in uric acid
• Increase in pancreatic enzyme lipase
• Decrease in vitamin B12

Less common side effects of empagliflozin/linagliptin/metformin include:

• Pancreas inflammation (pancreatitis)
• Ketoacidosis
• Kidney infections including:
  • Urosepsis
  • Pyelonephritis
• Necrotizing fasciitis of the perineum (Fournier’s gangrene)
• Hypersensitivity reactions including:
  • Angioedema
  • Exfoliative skin conditions
  • Severe allergic reactions (anaphylaxis)
• Severe and disabling arthralgia
• Bullous pemphigoid
• Skin reactions
• Mouth ulceration and inflammation
• Liver injury
• Muscle breakdown (rhabdomyolysis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 5 mg/2.5 mg/1000 mg
• 12.5 mg/2.5 mg/1000 mg
• 10 mg/5 mg/1000 mg
• 25 mg/5 mg/1000 mg

Adult:

Type 2 Diabetes Mellitus

• Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)
• Empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with T2DM and established cardiovascular disease
• Individualize starting dose based on the patient’s current regimen
• Monitor effectiveness and tolerability, and adjust dosing as appropriate
• Maximum recommended daily dose of empagliflozin 25 mg/linagliptin 5 mg/metformin 2000 mg

Patients on metformin with or without linagliptin

• Switch to Trijardy XR containing a similar total daily dose (TDD) of metformin, a TDD of empagliflozin 10 mg, and linagliptin 5 mg
• Patients on metformin and any regimen containing empagliflozin, with or without linagliptin H4
• Switch to Trijardy XR containing a similar TDD of metformin, the same TDD of empagliflozin, and linagliptin 5 mg

Dosage regimen with morning meal

• For metformin TDD 1000 mg: Take Trijardy XR 10 mg/5 mg/1000 mg OR 25 mg/5 mg/1000 mg orally as a single tablet once daily
• For metformin TDD 2000 mg: Take Trijardy XR 5 mg/2.5 mg/1000 mg OR 12.5 mg/2.5 mg/1000 mg orally as 2 tablets together once daily

Dosage Modifications

Renal impairment

• Mild (eGFR 45 mL/minute/1.73 m2 or above): No dosage adjustment necessary
• Moderate-to-severe (eGFR below 45 mL/minute/1.73 m2): Should not be initiated or continued
• Severe renal impairment (eGFR below 30 mL/minute/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis: Contraindicated

Hepatic impairment

• Not recommended; use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis

Discontinuation for iodinated contrast imaging procedures

• Discontinue treatment at the time of, or before, an iodinated contrast imaging procedure in patients with an eGFR below 60 mL/minute/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
• Reevaluate eGFR 48 hours after the imaging procedure; restart Trijardy XR if renal function is stable

Dosing Considerations

Prior to initiating treatment

• Assess renal function and periodically thereafter
• In patients with volume depletion, correct this condition

Limitations of use

• Not recommended for patients with type 1 diabetes or for treatment of diabetic ketoacidosis
• Not studied in patients with a history of pancreatitis; it is unknown whether patients with a history of pancreatitis are at an increased risk for developing pancreatitis while using Trijardy XR

Pediatric:

Safety and efficacy not established

Overdose

• Metformin overdose can cause lactic acid buildup (lactic acidosis) with symptoms including muscle pain, malaise, abdominal pain, respiratory distress and drowsiness.
• There is no information available on overdose of empagliflozin and linagliptin.
• Empagliflozin/linagliptin/metformin overdose is treated with symptomatic and supportive care, including gastric lavage to eliminate undigested drug, if appropriate.
• Hemodialysis may be useful in removing metformin, removal of empagliflozin through hemodialysis has not been studied and removal of linagliptin through hemodialysis or peritoneal dialysis is unlikely.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Empagliflozin/linagliptin/metformin has no listed severe interactions with other drugs.
• Empagliflozin/linagliptin/metformin has serious interactions with at least 27 different drugs.
• Empagliflozin/linagliptin/metformin has moderate interactions with at least 259 different drugs.
• Empagliflozin/linagliptin/metformin has mild interactions with at least 67 different drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• The limited available data with the use of empagliflozin/linagliptin/metformin, linagliptin or empagliflozin are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use in pregnant women have not revealed a clear drug-associated risk for major birth defects or miscarriage.
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications, and fetal risks of birth defects and abnormally large growth (macrosomia).
• Based on animal studies that show adverse kidney effects from empagliflozin, use of empagliflozin/linagliptin/metformin is not recommended during the second and third trimesters of pregnancy.
• There is limited information on the presence of empagliflozin/linagliptin/metformin and its components in breastmilk, and their effects on milk production or the breastfed infant. Limited studies show metformin is present in breastmilk. Empagliflozin and linagliptin are present in animal milk and likely present in human milk as well.
• Human kidney matures in the uterus and in the first 2 years of life and exposure to empagliflozin can adversely affect the kidneys. Use of empagliflozin/linagliptin/metformin is not recommended in nursing mothers because of the potential for serious adverse reactions, including kidney adverse effects, in the breastfed infant.

• Take empagliflozin/linagliptin/metformin exactly as prescribed.
• You will need regular tests while on treatment with empagliflozin/linagliptin/metformin. Follow up with your physician and keep up with your appointments.
• Report to your treating physician immediately if you experience:
  • Symptoms of lactic acidosis such as unexplained hyperventilation, feeling unwell, muscular pains and unusual drowsiness
  • Persistent severe abdominal pain with or without vomiting
  • Heart failure symptoms such as shortness of breath, rapid increase in weight and swelling of feet
  • Symptoms of low blood pressure
  • Severe joint pain
  • Hypersensitivity systemic or skin reactions
  • Blisters or lesions in the skin
• Drink adequate fluids while on empagliflozin/linagliptin/metformin therapy and report any kidney-related symptoms and urinary infections to your physician immediately.
• Seek immediate medical care if you develop any signs of genital infection.
• If you experience symptoms of ketoacidosis, a life-threatening condition, with symptoms that include nausea, vomiting, abdominal pain, tiredness, and labored breathing, discontinue empagliflozin/linagliptin/metformin immediately and seek medical care.
• Store empagliflozin/linagliptin/metformin safely out of reach of children.
• In case of overdose, seek medical care or call the Poison Center.