EMPAGLIFLOZIN;METFORMIN HYDROCHLORIDE
Clinical safety rating: safe
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption, increasing urinary glucose excretion. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Empagliflozin: Primarily metabolized via glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9, with minor CYP metabolism (CYP3A4). Metformin: Not metabolized; excreted unchanged in urine (90% via renal tubular secretion). |
| Excretion | Empagliflozin: ~54% renal (unchanged), ~41% fecal (unchanged and metabolites). Metformin: ~90% renal (unchanged); fecal elimination negligible. |
| Half-life | Empagliflozin: terminal t1/2 ~12.4 h, supports once-daily dosing. Metformin: terminal t1/2 ~6.2 h (plasma), prolonged to ~17.6 h in blood (accumulation in RBCs); requires dose adjustment in renal impairment. |
| Protein binding | Empagliflozin: ~86% bound (primarily to albumin). Metformin: negligible (<5% bound to plasma proteins). |
| Volume of Distribution | Empagliflozin: Vd ~0.5 L/kg (moderate tissue distribution). Metformin: Vd 1-5 L/kg (large distribution, with accumulation in GI tract, liver, and renal tissue; clinical significance: dose loading not required). |
| Bioavailability | Empagliflozin: absolute oral bioavailability ~78% (fasted); high-fat meal slightly reduces peak concentration but not AUC. Metformin: immediate-release oral bioavailability ~50-60% (fasted), decreased by food; extended-release bioavailability ~50%. |
| Onset of Action | Empagliflozin: glycemic effect onset 24 h (steady state); SGLT2 inhibition maximal by 2 h post-dose. Metformin: immediate-release, onset 2-3 h; extended-release, onset ~7 h. |
| Duration of Action | Empagliflozin: duration ~24 h (once-daily dosing). Metformin: immediate-release, duration 8-12 h; extended-release, duration ~24 h. |
Oral: one tablet twice daily. Starting dose: empagliflozin 5 mg/metformin hydrochloride 500 mg or empagliflozin 5 mg/metformin hydrochloride 1000 mg. Titrate based on glycemic response; maximum dose: empagliflozin 25 mg/metformin hydrochloride 2000 mg per day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR ≥60 mL/min/1.73 m²: no adjustment. eGFR 45-59 mL/min/1.73 m²: limit to empagliflozin 5 mg/metformin hydrochloride 1000 mg twice daily. eGFR 30-44 mL/min/1.73 m²: do not initiate; if already on, reduce to empagliflozin 5 mg/metformin hydrochloride 500 mg twice daily. eGFR <30 mL/min/1.73 m²: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: avoid metformin due to increased risk of lactic acidosis. Child-Pugh Class C: contraindicated. |
| Pediatric use | Not approved for pediatric patients under 18 years of age. |
| Geriatric use | No specific dose adjustment recommended based on age alone. Assess renal function before initiation and periodically; eGFR should be ≥45 mL/min/1.73 m². Use cautiously due to potential for volume depletion and renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
| FDA category | Human |
| Breastfeeding | Metformin is excreted into breast milk in low amounts (M/P ratio ~0.35); empagliflozin is likely excreted but data absent. Caution advised; monitor infant for hypoglycemia and diarrhea. |
| Teratogenic Risk | First trimester: Metformin is not associated with major malformations; empagliflozin has limited human data, but animal studies show renal toxicity at high doses. Second and third trimesters: Metformin may increase risk of preterm birth and neonatal hypoglycemia; empagliflozin may cause fetal renal impairment and oligohydramnios. Avoid in second and third trimesters. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication. Risk factors include renal impairment, use of iodinated contrast media, surgery, hypoxic states, excessive alcohol intake, and hepatic impairment. Discontinue metformin if lactic acidosis is suspected.
| Common Effects | Diarrhea |
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73 m²)","Acute or chronic metabolic acidosis, including diabetic ketoacidosis","History of lactic acidosis","Hypersensitivity to empagliflozin, metformin, or any component"]
| Precautions | ["Lactic acidosis (metformin-associated)","Pancreatitis (empagliflozin)","Ketoacidosis (empagliflozin, including euglycemic DKA)","Acute kidney injury (empagliflozin)","Hypoglycemia when used with insulin or sulfonylureas","Urinary tract infections and urosepsis (empagliflozin)","Necrotizing fasciitis of the perineum (Fournier gangrene, empagliflozin)","Vitamin B12 deficiency (metformin, long-term use)","Hypersensitivity reactions"] |
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| Fetal Monitoring | Monitor maternal renal function, blood glucose, HbA1c, and fetal growth via ultrasound. Assess for oligohydramnios if empagliflozin used. |
| Fertility Effects | Metformin may improve ovulation in women with PCOS; empagliflozin effects unknown. No adverse effect on male fertility reported. |