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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRIJARDY XR (TRIJARDY XR).
| Breastfeeding | Metformin is excreted into human milk with an M/P ratio of approximately 0.35. Empagliflozin and linagliptin are not recommended during breastfeeding due to lack of human data and potential for adverse effects on infant kidney function (empagliflozin) or unknown effects (linagliptin). Breastfeeding is not recommended during therapy. |
| 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. |
■ 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 |
["Severe renal impairment (eGFR < 30 mL/min/1.73 m2)","End-stage renal disease or dialysis","Acute or chronic metabolic acidosis, including diabetic ketoacidosis","History of serious hypersensitivity reaction to empagliflozin or metformin"]
| 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)"] |
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| 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. |