empagliflozin/metformin (Rx)

Brand and Other Names:Synjardy, Synjardy XR
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Dosing & Uses


Dosage Forms & Strengths


tablet, immediate-release

  • 5mg/500mg
  • 5mg/1000mg
  • 12.5mg/500mg
  • 12.5mg/1000mg

tablet, extended-release

  • 5mg/1000mg
  • 10mg/1000mg
  • 12.5mg/1000mg
  • 25mg/1000mg

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin is appropriate

Individualize starting dose based on the patient’s current drug regimen

Not to exceed 25 mg/2000 mg per day

Immediate-release tablet

  • Take twice daily with meals, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • Switching to Synjardy
    • Patients on metformin: Switch to tablet containing empagliflozin 5 mg with a similar total daily dose (TDD) of metformin
    • Patients on empagliflozin: Switch to tablet containing metformin 500 mg with a similar TDD of empagliflozin
    • Patients already treated with empagliflozin and metformin: Switch to tablet containing the same total daily doses of each component

Extended-release tablet

  • Take once daily with a meal in the morning, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • Switching to Synjardy XR
    • Patients on metformin: Switch to XR tablet containing a similar TDD of metformin and a total daily dose of empagliflozin 10 mg
    • Patients on empagliflozin: Switch to XR tablet containing the same TDD of empagliflozin and a TDD of metformin extended-release 1000 mg
    • Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same TDD of empagliflozin and a similar TDD of metformin

Dosage Modifications

Renal impairment

  • eGFR <45 mL/min/1.73 m2: Contraindicated

Iodinated contrast imaging procedures

  • Discontinue empagliflozin/metformin before or at the time of an iodinated contrast imaging procedure in the following:
    • Patients with an eGFR 45 to <60 mL/min/1.73 m2
    • Patients with a history of liver disease, alcoholism or heart failure
    • Patients who will be administered intra-arterial iodinated contrast
    • Re-evaluate eGFR 48 hr after the imaging procedure; restart dose if renal function is stable

Hepatic impairment

  • Avoid use in patients with clinical or laboratory evidence of hepatic disease
  • Use of metformin in patients with hepatic impairment has been associated with lactic acidosis

Dosing Considerations

Before initiation

  • Assess renal function and periodically, thereafter
  • Correct volume depletion before initiating if not previously treated with empagliflozin

Limitations of use

  • Not for patients with type 1 diabetes
  • Not for treatment of diabetic ketoacidosis

<18 years: Safety and efficacy not established

Monitor renal function more frequently after initiating drug in elderly patients, and then adjust dose based on renal function

Renal function abnormalities can occur after initiating empagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function



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            Adverse Effects


            Urinary tract infection (7.6-9.3%)

            Decreased vitamin B12 levels (7%)

            Increased LDL-C (4.6-6.5%)

            Female genital mycotic infections (5.4-6.4%)

            Dyslipidemia (2.9-3.9%)

            Increased urination (3.2-3.4%)

            Male genital mycotic infections (1.6-3.1%)

            Nausea (1.1-2.3%)

            Hypoglycemia, with monotherapy (1.4-1.8%)


            Volume depletion

            Impaired renal function

            Postmarketing Reports


            Urosepsis and pyelonephritis


            Skin reactions (e.g., rash, urticaria)

            Cholestatic, hepatocellular, and mixed hepatocellular liver injury



            Black Box Warnings

            Lactic acidosis

            • Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation
            • Risk increases with renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure
            • Onset is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress)
            • Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate
            • If acidosis is suspected, discontinue drug and hospitalize the patient immediately
            • Obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for development of renal impairment (e.g., the elderly), monitor renal function more frequently
            • Risk of metformin-associated lactic acidosis increases with age; elderly patients (>65 years) have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients; assess renal function more frequently in elderly patients


            Moderate-to-severe renal disease (eGFR <45 mL/min/1.73 m2), end-stage renal disease, or dialysis

            Acute or chronic metabolic acidosis, including diabetic ketoacidosis (treat ketoacidosis with insulin)

            History of serious hypersensitivity reaction to empagliflozin or metformin


            Lactic acidosis is a metabolic complication that can occur due to metformin accumulation during treatment and is fatal in ~50% of cases (see Black Box Warnings)

            Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors; signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4ºF or a general feeling of being unwell; if suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

            Empagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, elderly patients, patients with low systolic blood pressure, or patients taking diuretics

            Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake

            Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia; when such events occur, discontinue therapy

            Genital mycotic infections may occur with empagliflozin; patients with history of genital mycotic infections and uncircumcised males are more susceptible

            Empagliflozin increases the risk for urinary tract infections (eg, urosepsis, pyelonephritis)

            Empagliflozin may increase LDL-C

            No clinical studies were established for conclusive evidence of macrovascular risk reduction with empagliflozin/metformin

            Metformin associated with decreased vitamin B12 levels


            • Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
            • Consider temporarily discontinuing therapy for at least 3 days for patients who undergo scheduled surgery
            • Monitor for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery)
            • Restart once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis (blood acid buildup) are resolved

            Drug interaction overview

            • Empagliflozin
              • Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required
              • Urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors, increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
              • 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
            • Metformin
              • Alcohol is known to potentiate metformin’s effect on lactate metabolism; warn patients against excessive alcohol intake while in therapy
              • 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) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
              • Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis; coadministration with carbonic anhydrase inhibitors may increase the risk of lactic acidosis
              • Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control; these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid



            Not recommended during second and third trimester of pregnancy based on animal data

            Limited available data with use in pregnant women is not sufficient to determine a drug-associated risk for major birth defects and miscarriages

            Metformin may result in ovulation in some anovulatory women; discuss the potential for unintended pregnancy with premenopausal women

            Animal data

            • In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during 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 were reversible
            • Not teratogenic in rats and rabbits up to 300 mg/kg/day, which approximates 48-times and 128-times, respectively, the maximum clinical dose of 25 mg when administered during organogenesis

            Clinical considerations

            • Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity


            There is no information regarding presence in human milk, the effects on breastfed infant or on milk production

            Empagliflozin is present in the milk of lactating rats

            Owing to the potential for serious adverse reactions in a breastfed infant, advise women that it 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: Selective sodium-glucose transporter-2 (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

            Metformin: Decreases hepatic glucose production; decreases GI glucose absorption; increases target cell insulin sensitivity



            • Peak plasma concentration: 259 nmol/L (10-mg dose); 687 nmol/hr (25-mg dose)
            • AUC: 1870 nmol⋅hr/L (10-mg dose); 4740 nmol⋅hr/L (25-mg dose)


            • Absolute bioavailability: ~50-60% (fasting)



            • Vd (steady-state): 73.8 L
            • Protein bound: 86.2%


            • Protein bound: >90%



            • No major metabolites were detected in human plasma and the most abundant metabolites were 3 glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide)


            • Does not undergo hepatic metabolism nor biliary excretion



            • Half-life: 12.4 hr
            • Oral clearance: 10.6 L/hr
            • Excretion: 41.2% (feces); 54.4% (urine)


            • Following oral administration, ~90% of the absorbed drug is eliminated via the renal route within the first 24 hr, with a plasma elimination half-life of ~6.2 hr
            • Half-life:~ 17.6 hr


            Oral Administration

            When initiating, gradually increase dose to avoid GI adverse effects from metformin

            Take with meal(s)


            • Swallow extended-release tablets whole; do not split, crush, dissolve, or chew before swallowing
            • There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin extended-release; if a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control
            • 10 mg/1000 mg XR and 25 mg/1000 mg XR tablets should be taken as a single tablet once daily
            • 5 mg/1000 mg XR and 12.5 mg/1000 mg XR tablets should be taken as 2 tablets together once daily


            Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)





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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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