SYNJARDY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYNJARDY (SYNJARDY).
SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Empagliflozin reduces renal glucose reabsorption, increasing urinary glucose excretion. Linagliptin inhibits DPP-4, increasing incretin hormone levels (GLP-1, GIP), which stimulate insulin release and decrease glucagon secretion.
| Metabolism | Empagliflozin: Primarily via glucuronidation (UGT2B7, UGT1A3, UGT1A8, UGT1A9); minimal CYP metabolism. Linagliptin: Primarily via enterohepatic circulation; minimal CYP metabolism (CYP3A4 is a minor pathway). |
| Excretion | Renal: ~95% of empagliflozin as unchanged drug; ~20% of metformin as unchanged drug via glomerular filtration and tubular secretion. Fecal: <1% for empagliflozin; ~30% of metformin as unchanged drug. Biliary: negligible. |
| Half-life | Empagliflozin: terminal half-life ~12.4 hours (supports once-daily dosing). Metformin: terminal half-life ~6.2 hours in plasma, but prolonged to ~17.6 hours in whole blood due to RBC binding; clinical effect duration aligns with daily dosing. |
| Protein binding | Empagliflozin: ~86.2% bound (primarily to albumin). Metformin: negligible protein binding (<5% bound). |
| Volume of Distribution | Empagliflozin: Vd/F ~118 L (approx 1.5 L/kg in adult); indicates extensive tissue distribution. Metformin: Vd 654±358 L (approx 9 L/kg); large Vd due to extensive tissue distribution, especially to erythrocytes. |
| Bioavailability | Empagliflozin: absolute oral bioavailability ~78% (fasting). Metformin: absolute oral bioavailability ~50–60% for immediate-release; reduced to ~30–40% with extended-release under fed conditions. |
| Onset of Action | Empagliflozin: onset of urinary glucose excretion within 1 hour (oral). Metformin: onset of glucose-lowering effect begins within 2–3 hours (oral); full effect may take several days to weeks. |
| Duration of Action | Empagliflozin: glucose-lowering effect persists for ≥24 hours (once-daily dosing). Metformin: glucose-lowering effect lasts 8–12 hours with immediate-release; extended-release formulation provides up to 24-hour effect. |
Initial: 5 mg empagliflozin/1000 mg metformin hydrochloride extended-release orally twice daily with meals. Titrate based on glycemic control, up to maximum of 25 mg/2000 mg per day (given as 12.5 mg/1000 mg twice daily).
| Dosage form | TABLET |
| Renal impairment | Contraindicated if eGFR < 30 mL/min/1.73 m². Not recommended if eGFR 30-45 mL/min/1.73 m². If eGFR falls below 45 mL/min/1.73 m² during therapy, assess risks vs benefits and consider discontinuation if eGFR persists <45 mL/min/1.73 m². |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh class C). Avoid use in patients with clinical or laboratory evidence of hepatic disease. In mild to moderate impairment, use metformin components with caution; empagliflozin has not been studied. |
| Pediatric use | Not recommended for pediatric patients under 18 years of age due to lack of safety and efficacy data. |
| Geriatric use | No specific dose adjustment based on age alone. Assess renal function before initiation and monitor periodically. Avoid initiation if eGFR <45 mL/min/1.73 m². Consider lower starting doses due to potential age-related decline in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYNJARDY (SYNJARDY).
| Breastfeeding | Metformin is excreted into human breast milk; low infant plasma levels reported (M/P ratio 0.35-0.66). Empagliflozin not studied; animal data indicate excretion. Not recommended during breastfeeding due to potential adverse effects on infant kidney development. |
| Teratogenic Risk | SYNJARDY (empagliflozin/metformin) is contraindicated in second and third trimesters due to metformin-associated risk of lactic acidosis in neonates and empagliflozin's potential for oligohydramnios and renal toxicity. In first trimester, limited data; animal studies show fetal harm. Avoid in all trimesters. |
■ FDA Black Box Warning
None
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73m2) or end-stage renal disease on dialysis","History of serious hypersensitivity reaction to empagliflozin, linagliptin, or any excipient","Type 1 diabetes","Diabetic ketoacidosis"]
| Precautions | ["Pancreatitis","Hypoglycemia with concomitant sulfonylurea or insulin","Ketoacidosis in patients with type 1 diabetes or other conditions","Renal impairment: Acute kidney injury, monitoring of renal function","Volume depletion: Hypotension, especially in patients with impaired renal function, elderly, or on diuretics","Urosepsis and pyelonephritis","Lower limb amputation: Consider risk factors","Genital mycotic infections","Hypersensitivity reactions","Arthralgia with DPP-4 inhibitors","Bullous pemphigoid","Heart failure with DPP-4 inhibitors? (linagliptin not associated, but class warning)"] |
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| Fetal Monitoring | Monitor maternal renal function (serum creatinine, eGFR), blood glucose, and lactate levels. In second/third trimester, fetal ultrasound for oligohydramnios and kidney development. Monitor newborn for hypoglycemia, lactic acidosis, and renal function. |
| Fertility Effects | Empagliflozin: no clinical data on human fertility; animal studies show no impairment. Metformin may improve fertility in women with PCOS by restoring ovulation. No negative impact on male fertility documented. |