empagliflozin/linagliptin/metformin (Rx)

>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

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

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.

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)

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