Synjardy (empagliflozin)
Metformin Hydrochloride, Empagliflozin
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WHAT IS SYNJARDY (empagliflozin)?

Synjardy is an oral medication that includes a combination of two antidiabetic medications, metformin and empagliflozin. Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Metformin is a biguanide. Synjardy is indicated in adults with type 2 diabetes mellitus (T2DM) to improve glycemic control in addition to diet and exercise. Controlling hyperglycemia prevents downstream complications such as kidney damage, loss of limbs, blindness, heart attack, stroke, or nerve problems. It is important that diabetes remains controlled to lessen the chance of related complications. Synjardy is not indicated for the treatment of type 1 diabetes mellitus (T1DM) because it can increase a patient’s risk for diabetic ketoacidosis.


Metformin, a biguanide, and empagliflozin, an SGLT2 inhibitor, work together through a complementary mechanism to improve glycemic control. The individual components of Synjardy work in the following ways:


The SGLT2 is the primary transporter involved in the reabsorption of glucose from the glomerular filtrate. Empagliflozin inhibits SGLT2, decreasing the amount of glucose that is reabsorbed and reducing the renal threshold for glucose. This causes increased excretion of glucose in the urine.


Metformin is a biguanide that lowers the production of hepatic glucose, lowers absorption of glucose in the intestine, and improves insulin sensitivity through increasing peripheral glucose. Insulin release does not change with metformin, however, fasting levels of insulin and day-long plasma insulin response can be lowered.


Common side effects of Synjardy include:

  • Nausea and vomiting
  • Diarrhea
  • Gas
  • Stomach pain
  • Indigestion
  • Urinary tract infections
  • Female genital infections
  • Headache
  • Sore throat
  • Stuffy or runny nose
  • Weakness


Lactic acidosis

There have been multiple reports of lactic acidosis with metformin use, with some being fatal cases. Onset was typically gradual with symptoms including muscle pain, abdominal pain, drowsiness, and respiratory distress. More severe cases of acidosis included symptoms such as hypothermia, hypotension, and bradyarrhythmia. The signs and symptoms were accompanied by increased blood lactate concentrations, anion gap acidosis, and an elevated lactate/pyruvate ratio. There are multiple risk factors that increase an individual’s chance of developing lactic acidosis while on metformin. Risk factors and subsequent risk reduction measures include:

  • Renal impairment – Do not use in patients with an eGFR of less than 45 mL/min/1.73 m2
  • Age 65 or greater – Assess renal function more often
  • Radiological studies with contrast – Discontinue Synjardy prior to an iodinated contrast imaging procedure in certain patients
  • Surgery – Hold Synjardy while patients have restricted food and fluid intake
  • Hypoxic states – Stop Synjardy when hypoxic states occur, such as in acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, and sepsis
  • Alcohol – Avoid excessive alcohol intake
  • Hepatic impairment – Do not use Synjardy if the patient exhibits signs of hepatic disease

Volume Depletion

Empagliflozin and other SGLT2 inhibitors have been known to cause intravascular volume contraction which presents as hypotension or short-term changes to creatinine. Volume depletion has been shown to cause acute kidney injury (AKI) resulting in hospitalization and sometimes dialysis. Synjardy should be used with caution in patients with eGFR of less than 60 mL/min/1.73 m2, elderly patients, or patients taking loop diuretics. These patients could have an elevated risk of developing hypotension and volume depletion. Providers should monitor patients for signs of volume depletion throughout treatment with Synjardy.

Urosepsis and Pyelonephritis

Empagliflozin has caused cases of severe urinary tract infections involving urosepsis and pyelonephritis. Occurrences have sometimes required hospitalization. If a patient presents with signs of a urinary tract infection, they should be treated appropriately.

Hypoglycemia with Concomitant Use of Insulin Products

Synjardy can cause hypoglycemia when used in combination with other products that lower blood glucose, such as insulin. Dose adjustments to insulin may be required to prevent development of hypoglycemia. Patients should be counseled on common signs and symptoms of hypoglycemia.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Necrotizing fasciitis of the perineum, also known as Fournier’s gangrene, is a rare but potentially fatal infection that requires immediate intervention with surgery. Occurrences can result in hospitalization, surgeries, and death. Patients should be aware of the signs and symptoms associated with necrotizing fasciitis such as pain, erythema, tenderness, or swelling of the genital or perineal area. Symptoms can also include malaise or fever.

If necrotizing fasciitis is suspected, providers should treat with broad-spectrum antibiotics and possibly surgical debridement. Synjardy should be stopped, and blood glucose levels should be monitored.

Genital Mycotic Infections

Empagliflozin has been shown to elevate the risk of genital mycotic infections. Patients who have had genital mycotic infections in the past or who are uncircumcised males have a higher likelihood of developing genital mycotic infections. If suspected, providers should monitor and treat the patient appropriately.

Hypersensitivity Reactions

Empagliflozin has been shown to cause severe hypersensitivity reactions, including anaphylaxis and angioedema, within hours or days of starting therapy. If anaphylaxis or angioedema should occur, Synjardy should be stopped and the patient should seek medical attention.

Vitamin B12 Deficiency

Studies have shown a decrease in vitamin B12 levels with the use of metformin. Monitor hematologic measures annually and vitamin B12 parameters every 2 to 3 years for patients taking Synjardy. If abnormalities are present, manage appropriately with Synjardy discontinuation or vitamin B12 supplementation.


Carbonic Anhydrase Inhibitors (CAI)

Carbonic anhydrase inhibitors can lower serum bicarbonate and cause non-anion gap metabolic acidosis. When used concomitantly with Synjardy, this combination can elevate an individual’s risk for developing lactic acidosis. Patients that are taking these drugs in combination should be frequently monitored. Examples of CAIs include topiramate and acetazolamide.

Drugs that Decrease Clearance of Metformin

Medications that interfere with the renal elimination of metformin should be avoided. Drugs like ranolazine, dolutegravir, and cimetidine can increase a patient’s systemic exposure to metformin and elevate the risk of lactic acidosis.


Patients should avoid excessive alcohol intake. Alcohol has been shown to increase metformin’s effect on lactate metabolism, causing increased risk for lactic acidosis.

Other Drugs Affecting Glycemic Control

When used in combination with other drugs that can cause hypoglycemia, the risk for developing hypoglycemia with Synjardy is increased. Patients should be monitored for signs of hypoglycemia when on concomitant glucose-altering agents such as steroids, diuretics, and phenytoin.

Positive Urine Glucose Test

SGLT2 inhibitors such as empagliflozin can elevate glucose excretion in the urine. This phenomenon will cause positive urine glucose tests if administered. Therefore, do not use urine glucose tests to monitor glycemic control in patients taking Synjardy.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

The 1,5-AG assay is not a reliable form of glycemic control monitoring in patients taking Synjardy. Other methods should be implemented to monitor glucose control in patients taking SGLT2 inhibitors.


Take Synjardy exactly as your doctor directs. Typically, Synjardy is taken by mouth twice a day.

If you miss a dose of Synjardy, take the dose as soon as you remember. If it is time for the next dose at the time that you remember, skip the missed dose and return to your normal dosing schedule. Do not take more than one dose of Synjardy at the same time.

Synjardy can be taken long term to control type II diabetes mellitus.

Synjardy can be taken with meals. Taking Synjardy with meals may reduce your chances of having an upset stomach.

If you overdose with Synjardy, you should immediately go to the emergency room or contact the Poison Control Center. Overdosing on Synjardy increases an individual’s chance of developing hypoglycemia or lactic acidosis.

Avoid excessive alcohol intake, as this increases one’s risk of developing lactic acidosis while on Synjardy.

Common side effects of Synjardy include:

  • Nausea and vomiting
  • Diarrhea
  • Gas
  • Stomach pain
  • Indigestion
  • Urinary tract infections
  • Female genital infections
  • Headache
  • Sore throat
  • Stuffy or runny nose
  • Weakness

It is important that you tell your doctor all of the medications, vitamins, and supplements that you take. Tell your doctor especially if you take:

  • Insulin or other antidiabetic agents
  • Diuretics (water pills)

Additionally, tell your doctor if you:

  • Have inflammation of your pancreas (pancreatitis)
  • Have kidney problems
  • Have liver problems
  • Have heart problems or heart failure
  • Are 65 years of age or older
  • Drink alcohol frequently or drink large amounts of alcohol at once (“binge” drinking)
  • Have a history of genital infections
  • Are eating less or are planning to alter your diet
  • Plan to have surgery
  • Will be receiving injection of dye or contrast agents for an x-ray procedure
  • Have low vitamin B12 levels in your blood
  • Have type 1 diabetes
  • Are pregnant or plan to become pregnant
  • Are breastfeeding or plan to breastfeed
  • Are a premenopausal woman

Synjardy should be stored at room temperature between 68°F and 77°F (20°C and 25°C). Synjardy should be kept out of reach from children.