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 (2.3-2.4%)

Male genital mycotic infections (1.6-3.1%)

Nausea (1.1-2.3%)

Polydipsia (1.5-1.7%)

Postmarketing reports

Severe and disabling arthralgia

Hypersensitivity reactions

Angioedema

Skin reactions (e.g., rash, urticaria)

Contraindications

History of serious hypersensitivity reaction to drug or any of excipients formulation

Severe renal impairment, end-stage renal disease, or dialysis

Cautions

Causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, low systolic blood pressure, on diuretics, or in the elderly

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, prior to initiating therapy; correct volume status before initiating if needed and monitor renal function periodically thereafter

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

May increase low density lipoprotein levels; monitor and treat as necessary

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

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

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

Dose-related increases in LDL-C reported

GLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests; use alternative methods to monitor glycemic control

Monitoring glycemic control with 1,5-AG assay is not recommended; this test is unreliable in assessing glycemic control in patients taking SGLT2 inhibitors

Fatal cases of ketoacidosis associated with SGLT2 inhibitors reported; monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness); 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

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

Pregnancy

Limited data available in pregnant women not sufficient to determine a drug-associated risk for major birth defects and miscarriage; there are risks to mother and fetus associated with poorly controlled diabetes in pregnancy; based on animal data showing adverse renal effects, not recommended during second and third trimesters of pregnancy

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; because of potential for serious adverse reactions in a breastfed infant, advise women that it is not recommended while breastfeeding

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•h/L (10 mg/day); 4740 nmol•h/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