Reviewed on 5/18/2022

What Is Empagliflozin-Metformin and How Does It Work?

Empagliflozin-Metformin is a prescription medication used to treat the symptoms of Type 2 Diabetes Mellitus

  • Empagliflozin-Metformin is available under the following different brand names: Synjardy, Synjardy XR

What Are Dosages of Empagliflozin-Metformin?

Adult dosage

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

Adult dosage

  • 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 a tablet containing empagliflozin 5 mg with a similar total daily dose (three times daily) of metformin
  • Patients on empagliflozin: Switch to a tablet containing metformin 500 mg with a similar three times daily to empagliflozin
  • Patients already treated with empagliflozin and metformin: Switch to a 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 three times daily of metformin and a total daily dose of empagliflozin 10 mg
  • Patients on empagliflozin: Switch to XR tablet containing the same three times daily of empagliflozin and three times daily of metformin extended-release 1000 mg
  • Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same three times daily of empagliflozin and a similar three times daily of metformin

Dosage Considerations – Should be Given as Follows: 

  • See “Dosages”

What Are Side Effects Associated with Using Empagliflozin-Metformin?

Common side effects of Empagliflozin-Metformin include:

Serious side effects of the Empagliflozin-Metformin include:

  • hives,
  • difficulty breathing,
  • swelling of the face, lips, tongue, or throat,
  • burning or painful urination,
  • frequent or urgent urination,
  • pink or bloody urine,
  • little or no urination,
  • unusual vaginal discharge, burning, itching, or odor,
  • redness, itching, swelling of the penis,
  • unusual discharge from the penis,
  • pain, redness, or swelling in or around the genital or anal area,
  • fever,
  • feeling unwell,
  • sudden sweating,
  • shaking,
  • fast heartbeat,
  • hunger,
  • blurred vision,
  • dizziness,
  • tingling hands or feet,
  • thirst,
  • increased urination,
  • confusion,
  • drowsiness,
  • flushing,
  • rapid breathing,
  • fruity breath odor,
  • vomiting,
  • diarrhea,
  • heavy sweating,
  • dry mouth,
  • thirst,
  • light-headedness, and
  • fainting

Rare side effects of the Empagliflozin-Metformin include:

  • None 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

What Other Drugs Interact with Empagliflozin-Metformin?

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

  • Empagliflozin-Metformin has severe interactions with no other drugs.
  • Empagliflozin-Metformin has serious interactions with the following drugs:
  • Empagliflozin-Metformin has moderate interactions with at least 202 other drugs.
  • Empagliflozin-Metformin has minor interactions with at least 82 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

What Are Warnings and Precautions for Empagliflozin-Metformin?


Effects of drug abuse

  • None

Short-Term Effects

  • See “What Are Side Effects Associated with Using Empagliflozin-Metformin?”

Long-Term Effects

  • See “What Are Side Effects Associated with Using Empagliflozin-Metformin?”


  • Lactic acidosis is a metabolic complication that can occur due to metformin accumulation during treatment and is fatal in approximately 50% of cases 
  • Serious hypersensitivity reactions, (e.g., angioedema) in patients receiving treatment reported post-marketing; discontinue therapy and treat promptly if it occurs per standard of care
  • Necrotizing fasciitis of the perineum (Fournier gangrene) was 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; before initiating therapy, assess for volume contraction and correct volume status if indicated; monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected
  • Withholding of food and fluids during surgical or other procedures may increase the 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
  • Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and occurrence of lactic acidosis; stop treatment at the time of, or before, an iodinated contrast imaging procedure in patients with an eGFR between less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or patients who will be administered intra-arterial iodinated contrast; re-evaluate eGFR 48 hours after imaging procedure, and restart therapy if renal function is stable
  • There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin; if a hypersensitivity reaction occurs, discontinue therapy permanently; treat promptly per standard of care, and monitor until signs and symptoms resolve
  • Metformin is associated with decreased vitamin B12 levels without clinical manifestations; the decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation; measurement of hematologic parameters on an annual basis is advised in patients receiving therapy and any apparent abnormalities should be appropriately investigated and managed; certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful
  • Genital mycotic infections may occur with empagliflozin; patients with a history of genital mycotic infections and uncircumcised males are more susceptible; monitor and treat as appropriate
  • Empagliflozin increases the risk for urinary tract infections (.g, urosepsis, pyelonephritis)
  • Empagliflozin may increase LDL-C
  • No clinical studies were established for conclusive evidence of macrovascular risk reduction with Empagliflozin-Metformin
  • Volume depletion
    • Therapy can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine; acute kidney injury, some requiring hospitalization, and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors reported post-marketing
    • Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension
    • Before initiating therapy in patients with one or more of these characteristics, assess volume status and renal function; in patients with volume depletion, correct this condition before initiating treatment; monitor for signs and symptoms of volume depletion, and renal function after initiating therapy
  • Renal impairment
    • Empagliflozin causes intravascular volume contraction and can cause renal impairment; there have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors; some reports involved patients younger than 65 years of age
    • Before initiating therapy, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs).
    • Consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
    • Empagliflozin increases serum creatinine and decreases eGFR; patients with hypovolemia may be more susceptible to these changes; renal function abnormalities can occur after initiating therapy; renal function should be evaluated before initiation of treatment and monitored periodically thereafter; more frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2
  • Lactic acidosis
    • Metformin-associated lactic acidosis has been characterized by elevated blood lactate concentrations (above 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), increased lactate: pyruvate ratio; metformin plasma levels generally above5 mcg/mL; metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk
    • If metformin-associated lactic acidosis is suspected, institute general supportive measures promptly in a hospital setting, along with immediate discontinuation of therapy; in treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions); hemodialysis has often resulted in reversal of symptoms and recovery
    • Educate patients and their families about symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue therapy and report symptoms to their healthcare provider
  • Ketoacidosis
    • Drugs not indicated for the treatment of type 1 diabetes mellitus
    • Assess patients who present with signs and symptoms consistent with severe metabolic acidosis for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with therapy may be present even if blood glucose levels are below 250 mg/dl; if ketoacidosis is suspected, the drug should be discontinued, the patient should be evaluated, and prompt treatment should be instituted; treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement
    • Before initiating therapy, consider factors in the 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 discontinue therapy in other clinical situations known to predispose to ketoacidosis (.g, 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
      • A serious life-threatening condition requiring urgent hospitalization was identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors
      • 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 are 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
      • The 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 (e.g., 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 (e.g., zonisamide, acetazolamide, dichlorphenamide) frequently causes a decrease in serum bicarbonate and induces 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

Pregnancy and Lactation

  • Not recommended during the second and third trimesters of pregnancy based on animal data
  • Limited available data on 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
  • Clinical considerations
    • Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications; poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity
  • Lactation
    • There is no information regarding the presence of human milk, the effects on the breastfed infant, or milk production
    • Empagliflozin is present in the milk of lactating rats
    • Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be a risk of developing human kidney
    • Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that the use of drug combination is not recommended while breastfeeding

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