TRIJARDY XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIJARDY XR (TRIJARDY XR).
TRIJARDY XR is a fixed-dose combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a biguanide. Empagliflozin reduces renal glucose reabsorption by inhibiting SGLT2 in the proximal tubule, increasing urinary glucose excretion. Metformin decreases hepatic gluconeogenesis, reduces intestinal glucose absorption, and improves insulin sensitivity.
| Metabolism | Empagliflozin is primarily metabolized via glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9; minor oxidation by CYP450 enzymes. Metformin is excreted unchanged in urine, does not undergo hepatic metabolism. |
| Excretion | Renal: empagliflozin ~54% unchanged, linagliptin ~5% unchanged, metformin ~90% unchanged; fecal: empagliflozin ~41% (mostly unchanged), linagliptin ~80% (mostly unchanged), metformin minimal. |
| Half-life | Empagliflozin: terminal t1/2 ~12.4 h; linagliptin: terminal t1/2 ~12-24 h (effective t1/2 due to long DPP-4 binding); metformin: terminal t1/2 ~6.2 h (prolonged in renal impairment, up to 18 h). |
| Protein binding | Empagliflozin: ~86% (primarily albumin); linagliptin: concentration-dependent (70-99%, saturable), primarily albumin; metformin: negligible (<5%). |
| Volume of Distribution | Empagliflozin: Vd/F ~179 L (2.6 L/kg for 70 kg); linagliptin: Vd ~111 L (1.6 L/kg); metformin: Vd ~654 L (9.3 L/kg). Vd of metformin indicates extensive tissue distribution. |
| Bioavailability | Empagliflozin: ~78% (oral); linagliptin: ~30% (oral); metformin ER: ~50-60% (oral, relative to immediate-release). |
| Onset of Action | Peak plasma concentrations at 1.5 h (empagliflozin), 1.5 h (linagliptin), and 2-4 h (metformin ER). Clinical glucose-lowering effects begin within 1-2 weeks, with maximal effect by 4-8 weeks. |
| Duration of Action | Dosing interval: once daily. Empagliflozin: >24 h (SGLT2 inhibition persists); linagliptin: >24 h (DPP-4 inhibition sustained); metformin ER: ~24 h. Antihyperglycemic effect duration is 24 h with regular dosing. |
| Molecular Weight | Empagliflozin: 450.91 Da; Linagliptin: 472.54 Da; Metformin: 165.62 Da |
Empagliflozin 5 mg / linagliptin 5 mg / metformin extended-release 1000 mg orally twice daily with meals; initial dose based on current regimen, titrate gradually.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR ≥ 60 mL/min/1.73 m²: no adjustment; eGFR 45-59: continue if tolerating, monitor renal function; eGFR < 45: contraindicated (risk of lactic acidosis with metformin). |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). Avoid use in patients with clinical or laboratory evidence of hepatic disease due to metformin component. |
| Pediatric use | Safety and efficacy not established in pediatric patients (age < 18 years). |
| Geriatric use | Use caution due to age-related renal impairment; assess renal function before initiation and periodically. Start at lowest effective dose and titrate slowly. Monitor for hypoglycemia, volume depletion, and lactic acidosis. |
| 1st trimester | Avoid use during first trimester; associated with fetal hypoglycemia and potential teratogenicity based on animal studies. Insulin is preferred. |
| 2nd trimester | Avoid use; insufficient human data, risk of fetal hypoglycemia and adverse effects. Insulin preferred. |
| 3rd trimester | Avoid use; risk of fetal hypoglycemia and neonatal hypoglycemia; closer to delivery may cause prolonged hypoglycemia. Insulin preferred. |
Clinical note
Comprehensive clinical and safety monograph for TRIJARDY XR (TRIJARDY XR).
| Placental transfer | Empagliflozin and linagliptin cross the placenta in animal studies; metformin is known to cross extensively. Human data limited but likely significant transfer. |
| Breastfeeding | Not recommended during breastfeeding. Drug is excreted in animal milk; unknown in humans. Potential for hypoglycemia in infant. Use insulin if needed. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis (MALA) is a rare but serious complication. Risk factors include renal impairment, hypoxia, sepsis, hepatic impairment, acute congestive heart failure, and excessive alcohol intake. Discontinue TRIJARDY XR if lactic acidosis is suspected.
| Serious Effects |
Hypersensitivity to any componentSevere renal impairment (eGFR <30 mL/min/1.73 m²)Metabolic acidosis (including diabetic ketoacidosis)History of pancreatitisUse during pregnancy and breastfeeding
| Precautions | Lactic acidosis, Increased risk of lower limb amputation (primarily toe), Ketoacidosis (including euglycemic ketoacidosis), Acute kidney injury and impairment in renal function, Volume depletion, Urosepsis and pyelonephritis, Hypoglycemia when used with insulin or sulfonylureas, Necrotizing fasciitis of the perineum (Fournier's gangrene), Vitamin B12 deficiency (metformin), Acute pancreatitis (postmarketing) |
| Food/Dietary | Avoid excessive alcohol intake due to increased risk of lactic acidosis and hypoglycemia. No specific food restrictions with empagliflozin. Metformin absorption may be reduced by high-fat meals; take with food to minimize GI side effects. |
Loading safety data…
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | TRIJARDY XR (empagliflozin, linagliptin, metformin) is contraindicated in the second and third trimesters due to the known fetal harm from metformin-associated lactic acidosis and empagliflozin's potential for renal injury. First trimester: Animal studies show empagliflozin causes renal pelvis dilatation; linagliptin shows no major malformations; metformin shows no consistent teratogenicity. Human data insufficient. Risk cannot be excluded. |
| Fetal Monitoring | Monitor maternal renal function (eGFR), blood glucose, and lactic acidosis symptoms. Fetal monitoring includes ultrasound for renal anomalies (empagliflozin-associated) and growth restriction. Neonatal monitoring for hypoglycemia and metabolic acidosis at delivery. |
| Fertility Effects | Empagliflozin: No adverse effects on fertility in animal studies. Linagliptin: No effect. Metformin: May improve ovulation in women with PCOS, but overall impact on fertility is neutral. |
| Clinical Pearls | Empagliflozin component reduces cardiovascular death and heart failure hospitalization. Metformin requires dose adjustment for eGFR <45 mL/min. Avoid in severe hepatic impairment. Assess volume status before initiation; consider diuretic dose reduction. Lactic acidosis risk with metformin; discontinue acutely ill patients or before iodinated contrast. Monitor for ketoacidosis even with normal glucose. |
| Patient Advice | Take exactly as prescribed, once daily with breakfast to reduce GI upset. · Do not crush or chew tablets; swallow whole. · Drink plenty of fluids to prevent dehydration and urinary tract infections. · Monitor for genital yeast infections and urinary tract infections; report symptoms. · Check blood sugar regularly as directed. · Seek immediate medical attention for symptoms of lactic acidosis (unusual tiredness, muscle pain, difficulty breathing, abdominal discomfort) or ketoacidosis (nausea, vomiting, abdominal pain, confusion, fruity breath). · Inform your doctor before any surgery or radiological procedure using contrast dye. · Do not use if you have severe kidney disease, dialysis, or metabolic acidosis. |