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

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

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

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

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

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

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
• Prior to initiating therapy; 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 100.4 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

Ketoacidosis

• 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

Drug interactions overview

• Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion
• Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required
• SGLT2 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 glyce mic control in patients taking SGLT2 inhibitors

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 25°C (77°F); excursions permitted to 15-30°C (59-86°F)