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 100.4ºF 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

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 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

Pregnancy

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

Lactation

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

Absorption

Empagliflozin

• 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)

Metformin

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

Distribution

Empagliflozin

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

Metformin

• Protein bound: >90%

Metabolism

Empagliflozin

• 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)

Metformin

• Does not undergo hepatic metabolism nor biliary excretion

Elimination

Empagliflozin

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

Metformin

• 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)

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)