empagliflozin (Rx)

1-10%

Urinary tract infection (7.6-9.3%)

Female genital mycotic infections (5.4-6.4%)

Upper respiratory tract infection (3.1-4%)

Increased urination (3.2-3.4%)

Dyslipidemia (2.9-3.9%)

Male genital mycotic infections (1.6-3.1%)

Arthralgia (2.3-2.4%)

Nausea (1.1-2.3%)

Polydipsia (1.5-1.7%)

<1%

Adverse reactions related to volume depletion (eg, blood pressure [ambulatory] decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope)

Increased urination (eg, nocturia)

Postmarketing reports

Ketoacidosis

Urosepsis and pyelonephritis

Necrotizing fasciitis of the perineum (Fournier’s gangrene)

Angioedema

Skin reactions

Contraindications

Serious hypersensitivity to empagliflozin (eg, anaphylaxis, angioedema)

Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Cautions

Serious hypersensitivity reactions, (eg, angioedema) in patients receiving treatment reported postmarketing; discontinue therapy and treat promptly if it occurs per standard of care

Increases serum creatinine and decreases eGFR; risk increased in elderly or those with moderate renal impairment

Increased incidence of bone fractures reported; American Diabetes Association recommends avoiding sodium glucose cotransporter-2 inhibitors in patients with fracture risk factors

Genital mycotic infections may occur; patients with history of genital mycotic infections and uncircumcised males are more susceptible

Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs

Dose-related increases in LDL-C reported

No conclusive evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent

Serious hypersensitivity reactions (eg, angioedema) reported; if a hypersensitivity reaction occurs, discontinue treatment; treat promptly per standard of care, and monitor until signs and symptoms resolve

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 postmarketing
• 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 function

• Acute kidney injury reported
• Consider risk factors, including hypovolemia, heart failure, and chronic renal insufficiency or use of medications, including diuretics, ACE inhibitors, NSAIDs, or angiotensin receptor blockers
• Correct volume status before initiating if needed and monitor renal function periodically thereafter

Necrotizing fasciitis

• 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

Ketoacidosis

• Drug not indicated for treatment of type 1 diabetes mellitus
• 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
• 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
• Restart once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis (blood acid buildup) are resolved

Drug interactions overview

• Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or insulin secretagogue may be required

Laboratory testing

• 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

Pregnancy

Based on animal data showing adverse renal effects, use not recommended during the second and third trimesters of pregnancy

Limited data available in pregnant women are insufficient to determine a drug-associated risk for major birth defects and miscarriage

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy

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

Because of 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

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

Absorption

Peak plasma time: 1.5 hr

Peak plasma concentration: 259 nmol/L (10 mg/day); 687 nmol/L (25 mg/day)

AUC: 1870 nmol•hr/L (10 mg/day); 4740 nmol•hr/L (25 mg/day)

Distribution

Protein bound: 86.2%

Red blood cell partitioning: 36.8%

Vd: 73.8 L

Metabolism

Primary route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9

No major metabolites were detected and the most abundant metabolites were 3 glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide)

Systemic exposure of each metabolite was <10%

Elimination

Half-life: 12.4 hr

Clearance: 10.6 L/hr

Excretion: 54.4% urine; 41.2% feces

Oral Administration

May take with or without food

Advise patient to have adequate fluid intake to decreased risk of hypotension

Storage

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)