Adult Dosing
Dosage Forms & Strengths
empagliflozin/metformin
tablet (twice daily dosing)
- 5mg/500mg
- 5mg/1000mg
- 12.5mg/500mg
- 12.5mg/1000mg
tablet, extended-release (once daily dosing)
- 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 the starting dose based on the patient’s current drug regimen
Not to exceed 25 mg/2000 mg per day
Tablet (twice daily)
- 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 of metformin
- Patients on empagliflozin: Switch to tablet containing metformin 500 mg with a similar total daily dose of empagliflozin
- Patients already treated with empagliflozin and metformin: Switch to tablet containing the same total daily doses of each component
Extended-release tablet (once daily)
- 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 total daily dose of metformin and a total daily dose of empagliflozin 10 mg
- Patients on empagliflozin: Switch to XR tablet containing the same total daily dose of empagliflozin and a total daily dose of metformin extended-release 1000 mg
- Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same total daily doses of empagliflozin and a similar total daily dose of metformin
Dosage Modifications
Hepatic impairment: No dosage change required
Renal impairment
- Obtain eGFR before starting metformin
- eGFR <45 mL/min/1.73 m²: Contraindicated
- Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
- If eGFR falls to <45 mL/min/1.73 m² during treatment: Discontinue
Dosing Considerations
Empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease; however, the effectiveness of empagliflozin/metformin on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established
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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
1-10%
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%)
<1%
Volume depletion
Impaired renal function
Postmarketing Reports
Ketoacidosis
Urosepsis and pyelonephritis
Angioedema
Skin reactions (e.g., rash, urticaria)
Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Warnings
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
Contraindications
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
Cautions
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 100.4 F 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
Fatal cases of ketoacidosis reported in patients taking empagliflozin
Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situation that may predispose to ketoacidosis
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
Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required
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
Metformin associated with decreased vitamin B12 levels
Alcohol is known to potentiate metformin’s effect on lactate metabolism; warn patients against excessive alcohol intake while in therapy
Cardiovascular collapse (shock) from whatever cause is associated with lactic acidosis and may also cause prerenal azotemia; discontinue drug immediately
Empagliflozin may increase LDL-C
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 45-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
Pregnancy
Pregnancy
There are no adequate and well-controlled studies in pregnant women with empagliflozin/metformin or its individual components
Animal studies
- Based on results from animal studies, empagliflozin may affect renal development and maturation
- In studies conducted in rats, empagliflozin crosses the placenta and reaches fetal tissues; during pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters
Lactation
Unknown if distributed in human breast milk As individual components, both empagliflozin and metformin were secreted in the milk of lactating rats
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
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.
Pharmacology
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
Pharmacokinetics
Empagliflozin
- Peak plasma time: 1.5 hr
- Peak plasma concentration: 259 nmol/L
- AUC: 1870 nmol·h/L
- Protein bound: 86.2%
- Vd: 73.8 L
- Red blood cell partitioning: 36.8%
- Metabolism: Primary route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyl transferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9
- Half-life: 12.4 hr
- Excretion: 54.4% urine; 41.2% feces
Metformin
- Bioavailability: 50-60% (fasting)
- Protein bound: Negligible
- Vd: 654 L
- Red blood cell partitioning: Partitions into erythrocytes, most likely as a function of time
- Metabolism: Does not undergo hepatic metabolism nor biliary excretion
- Half-life: 17.6 hr (blood); 6.2 hr (plasma)
- Excretion: 90% urine
Administration
Oral Administration
When initiating, gradually increase dose to avoid GI adverse effects from metformin
Take with meal(s)
Extended-release
- 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
Storage
Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)
Images
Patient Handout
Formulary
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