empagliflozin/linagliptin/metformin (Rx)

Brand and Other Names:Trijardy XR
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

empagliflozin/linagliptin/metformin

tablet

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

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 PO 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 PO as 2 tablets together once daily

Dosage Modifications

Renal impairment

  • Mild (eGFR ≥45 mL/min/1.73 m2): No dosage adjustment necessary
  • Moderate-to-severe (eGFR <45 mL/min/1.73 m2): Should not be initiated or continued
  • Severe renal impairment (eGFR <30 mL/min/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 <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
  • Reevaluate eGFR 48 hr 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

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and empagliflozin/linagliptin/metformin

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    Contraindicated

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            Adverse Effects

            >10%

            Upper respiratory tract infection (8-10.3%)

            Urinary tract infection (9.6-10.2%)

            Metformin

            • Hypoglycemia (13.7%)
            • Diarrhea (12.5%)

            1-10%

            Nasopharyngitis (5.8-8.1%)

            Diarrhea (2.2-6.6%)

            Constipation (5.1-5.8%)

            Gastroenteritis (2.9-5.8%)

            Headache (5.1%)

            Empagliflozin

            • Urinary tract infection (7.6-9.3%)
            • Increased LDL cholesterol (4.6-6.5%)
            • Female genital mycotic infections (5.4-6.4%)
            • Dyslipidemia (2.9-3.9%)
            • Male genital mycotic infections (1.6-3.1%)
            • Increased hematocrit (2.8%)
            • Arthralgia (2.3-2.4%)
            • Nausea (1.1-2.3%)
            • Thirst (1.5-1.7%)

            Linagliptin

            • Nasopharyngitis (6.1-7%)
            • Diarrhea (3-3.3%)
            • Increased uric acid (2.7%)
            • Cough (1.4-2.1%)

            Metformin

            • Decreased vitamin B-12 (~7%)
            • Nausea (6.7%)
            • Diarrhea (>5%)
            • Nausea/vomiting (>5%)
            • Flatulence (>5%)
            • Abdominal discomfort (>5%)
            • Indigestion (>5%)
            • Asthenia (>5%)
            • Headache (>5%)

            <1%

            Hypoglycemia (0.7%)

            Postmarketing Reports

            Acute pancreatitis, including fatal pancreatitis

            Ketoacidosis

            Urosepsis and pyelonephritis

            Necrotizing fasciitis of the perineum (Fournier gangrene)

            Hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions)

            Severe and disabling arthralgia

            Bullous pemphigoid

            Skin reactions (eg, rash, urticaria)

            Mouth ulceration, stomatitis

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            Warnings

            Black Box Warnings

            Lactic Acidosis

            • Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
            • Onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain)
            • Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL
            • Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment
            • Steps to reduce the risk of and to manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information
            • If lactic acidosis is suspected, discontinue treatment and institute general supportive measures in a hospital setting
            • Prompt hemodialysis is recommended

            Contraindications

            Severe renal impairment (eGFR <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

            Cautions

            Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported (see Black Box Warnings)

            Postmarketing cases of serious urinary tract infections, including urosepsis, were reported; evaluate for signs and symptoms and treat appropriately

            There have been reports of acute pancreatitis, including fatal pancreatitis; if pancreatitis 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; postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis; assess volume status and correct

            Necrotizing fasciitis of the perineum (Fournier gangrene) reported in postmarketing 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 has been reported; consider discontinuing drug if DPP-4 inhibitor is a cause for severe joint pain

            Postmarketing 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 (eg, acute illness, fasting) or fluid losses (eg, 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

            Drug interaction overview

            • Empagliflozin or linagliptin in combination with an insulin secretagogue (eg, 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 (eg, zonisamide, acetazolamide, dichlorphenamide) frequently decrease serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis
            • Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (eg, 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 (eg, 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
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            Pregnancy & Lactation

            Pregnancy

            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 with metformin and major birth defect or miscarriage risk

            There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

            Animal data

            • In animal studies, empagliflozin 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 ~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 were administered to pregnant rats or rabbits

            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 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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Empagliflozin: SGLT2 inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

            Linagliptin: DPP-4 inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and reducing glucagon secretion from pancreatic alpha cells

            Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and use; improves glucose tolerance and lowers both basal and postprandial plasma glucose

            Absorption

            Empagliflozin

            • Peak plasma time: 1.5 hr
            • Peak plasma concentration (steady-state): 259 nmol/L (10-mg dose); 687 nmol/L (25-mg dose)
            • AUC (steady-state): 1870 nmol·hr/L (10-mg dose); 4740 nmol·hr/L (25-mg dose)

            Linagliptin

            • Absolute bioavailability: ~30%
            • May be administered with or without food

            Metformin

            • Peak plasma time: ~7-8 hr
            • Low- and high-fat meals prolonged metformin peak plasma time by ~3 hr, but peak plasma concentration was not affected

            Distribution

            Empagliflozin

            • Vd (steady-state): 73.8 L
            • Protein bound: 86.2%

            Linagliptin

            • Vd: 1110 L (single 5-mg IV dose)
            • Protein bound: 70-80%

            Metformin

            • Vd: 654 L
            • Negligibly bound to plasma proteins

            Metabolism

            Empagliflozin

            • Studies suggest that the primary route of metabolism in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9

            Elimination

            Empagliflozin

            • Half-life: 12.4 hr
            • Oral clearance: 10.6 L/hr
            • Excretion: Feces (41.2%); urine (54.4%)

            Linagliptin

            • Half-life (steady-state): ~200 hr (terminal): 11 hr (accumulation)
            • Renal clearance (steady-state); ~70 mL/min
            • Excretion: Enterohepatic system (80%); urine (5%)

            Metformin

            • Half-life: ~6.2 hr (plasma); 17.6 hr (blood)

            Excretion: ~90% (renal)

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            Administration

            Oral Administration

            Take qDay with morning meal

            Swallow whole; do not split, crush, dissolve, or chew

            Storage

            Tablet: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Protect from exposure to high humidity

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.