Empagliflozin-Linagliptin/Metformin

Empagliflozin-Linagliptin/Metformin is a combination medication used to treat the symptoms of Type 2 Diabetes Mellitus. 

• Empagliflozin-Linagliptin/Metformin is available under the following different brand names: Trijardy XR

Common side effects of Empagliflozin-Linagliptin/Metformin include:

• Stomach pain,
• Diarrhea,
• Constipation,
• Bladder infection,
• Headache, and
• Cold symptoms (runny or stuffy nose, sneezing, sore throat)

Serious side effects of Empagliflozin-Linagliptin/Metformin include:

• Hives,
• Difficulty breathing,
• Swelling of the face, lips, tongue, or throat,
• Itching,
• Flaking or peeling skin,
• Trouble swallowing,
• Burning, itching, odor, discharge, pain, tenderness, redness, or swelling of the genital or rectal area,
• Feeling unwell,
• Lightheadedness,
• Severe or ongoing pain in the joints,
• Unusual muscle pain,
• Stomach pain,
• Vomiting,
• Irregular heart rate,
• Dizziness,
• Feeling cold,
• Weakness,
• Tiredness,
• Blisters,
• Breakdown of the outer layer of skin,
• Nausea,
• Confusion,
• Unusual drowsiness,
• Severe pain in the upper stomach spreading to the back,
• Confusion,
• Feeling very thirsty,
• Little or no urination,
• Pain or burning while urinating,
• Blood in your urine,
• Pain in the pelvis or back,
• Swelling in the legs or feet, and
• Rapid weight gain

Rare side effects of Empagliflozin-Linagliptin/Metformin include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

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

Adult dosage

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

Type 2 Diabetes Mellitus

Adult dosage

• Individualize starting dose based on the patient’s current regimen
• 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 Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Empagliflozin-Linagliptin/Metformin has severe interactions with no other drugs.
• Empagliflozin-Linagliptin/Metformin has serious interactions with at least 28 other drugs.
• Empagliflozin-Linagliptin/Metformin has moderate interactions with at least 257 other drugs.
• Empagliflozin-Linagliptin/Metformin has minor interactions with at least 75 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Severe renal impairment (eGFR below 30 mL/min/1.73 m2), ESRD, or dialysis
• Metabolic acidosis, including diabetic ketoacidosis
• Hypersensitivity to empagliflozin, linagliptin, metformin, or any of the excipients in the product

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Empagliflozin-Linagliptin/Metformin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Empagliflozin-Linagliptin/Metformin?”

Cautions

• Drug combination not indicated for the treatment of type 1 diabetes mellitus
• Post-marketing cases of metformin-associated lactic acidosis, including fatal cases, were reported (see Black Box Warnings)
• Post-marketing cases of serious urinary tract infections, including urosepsis, were reported; evaluate for signs and symptoms, and treat appropriately
• Serious hypersensitivity reactions, (. g, angioedema) in patients treated with empagliflozin reported post-marketing; discontinue therapy and treat promptly if it occurs per standard of care
• There have been reports of acute pancreatitis, including fatal pancreatitis; if pancreatitis is suspected, promptly discontinue
• Heart failure observed with 2 other DPP-4 inhibitors; consider risks and benefits in patients with known risk factors for heart failure; monitor for signs and symptoms
• Empagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after starting therapy; post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis; assess volume status and correct
• Necrotizing fasciitis of the perineum (Fournier gangrene) reported in post-marketing surveillance with SGLT2 inhibitors; it is a rare life-threatening necrotizing infection requiring urgent surgical intervention
• Hypersensitivity reactions reported with linagliptin; onset of reactions occurred within the first 3 months after initiating linagliptin; exercise caution with history of angioedema to another DPP-4 inhibitor
• In controlled clinical trials of metformin, a decrease to subnormal levels of serum vitamin B-12 levels, without clinical manifestations, was observed
• Empagliflozin increases the risks of genital mycotic infections; patients with a history of genital mycotic infections were more likely to develop genital mycotic infections; monitor and treat appropriately
• Increased LDL cholesterol may occur with empagliflozin; monitor LDL cholesterol and treat per standard of care
• Severe and disabling arthralgia in patients taking DPP-4 inhibitors have been reported; consider discontinuing the drug if the DPP-4 inhibitor is a cause of severe joint pain
• Post-marketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use
• Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; if suspected, discontinue Trijardy XR, evaluate, and treat promptly; before initiating treatment, consider risk factors for ketoacidosis; may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis
• Consider temporarily discontinuing therapy in any setting of reduced oral intake (.g, acute illness, fasting) or fluid losses (.g, gastrointestinal illness or excessive heat exposure); monitor for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
• Volume depletion
  • Therapy can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine; acute kidney injury, some requiring hospitalization, and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors reported post-marketing
  • Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension
  • Before initiating therapy in patients with one or more of these characteristics, assess volume status and renal function; in patients with volume depletion, correct this condition before initiating treatment; monitor for signs and symptoms of volume depletion, and renal function after initiating therapy
• Drug interaction overview
  • Empagliflozin or linagliptin in combination with an insulin secretagogue (. g, sulfonylurea) or insulin was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial; metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue
  • Topiramate or other carbonic anhydrase inhibitors (. g, zonisamide, acetazolamide, dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis
  • Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (. g, organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
  • Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion
  • Alcohol potentiates the effects of metformin on lactate metabolism
  • Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-GP or CYP3A4 inducer; use of alternatives is strongly recommended when linagliptin is to be administered with a strong P-GP or CYP3A4 inducer
  • Certain drugs (. g, thiazides, and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) tend to produce hyperglycemia and may lead to loss of glycemic control
  • SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests
  • Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors

Pregnancy and Lactation

• Based on animal data showing adverse renal effects from empagliflozin, use is not recommended during the second and third trimesters of pregnancy
• Limited data available with Trijardy XR, linagliptin, or empagliflozin in pregnant women are insufficient to determine a drug-associated risk for major birth defects and miscarriage
• Published studies with metformin use during pregnancy have not reported a clear association between metformin and major birth defect or miscarriage risk
• There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
• Clinical considerations
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications
• Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity
• Females and males of reproductive potential
• Advise the potential for unintended pregnancy with premenopausal women treated with metformin may result in ovulation in some anovulatory women
• Lactation
  • There is limited information regarding the presence of Trijardy XR or its components (empagliflozin, linagliptin, or metformin) 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
  • Empagliflozin and linagliptin are present in rat milk
  • Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be a risk to the developing human kidney
  • Owing to the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use is not recommended while breastfeeding