empagliflozin/metformin (Rx)

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

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

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

Ketoacidosis

• 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 4 days for patients who undergo scheduled surgery
• Consider monitoring 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); ensure risk factors for ketoacidosis are resolved prior to restarting therapy
• Educate patients on signs and symptoms of ketoacidosis and instruct patients to discontinue therapy and seek medical attention immediately if signs and symptoms occur

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

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.

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

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)