Empagliflozin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Jardiance: 10 mg, 25 mg

Pharmacology

Mechanism of Action

By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, empagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RT_G). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RT_G result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 73.8 L

Metabolism

Primarily through glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9 to minor metabolites

Excretion

Urine (54.4%; 50% as unchanged drug); feces (41.2%; majority as unchanged drug)

Time to Peak

1.5 hours

Half-Life Elimination

12.4 hours

Protein Binding

86.2%

Use in Specific Populations

Special Populations: Renal Function Impairment

Clearance is decreased and AUC is increased in patients with impaired renal function. In mild, moderate, and severe renal impairment and in end-stage renal disease (ESRD), AUC increased approximately 18%, 20%, 66%, and 48% respectively.

Special Populations: Hepatic Function Impairment

In patients with mild, moderate, and severe hepatic impairment, AUC increased by approximately 23%, 47%, and 75%, and C_max increased by approximately 4%, 23%, and 48%, respectively.

Use: Labeled Indications

Diabetes mellitus, type 2: Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control; risk reduction of cardiovascular mortality in adults with type 2 diabetes mellitus and established cardiovascular disease.

Guideline recommendation: In patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD) and on metformin, empagliflozin is a preferred add-on agent to reduce major adverse cardiovascular events and/or slow progression of HF/CKD, provided baseline renal function is sufficient to initiate therapy (ADA 2019).

Contraindications

History of serious hypersensitivity to empagliflozin or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m²), end-stage renal disease (ESRD), or dialysis

Dosage and Administration

Dosing: Adult

Note: Hypovolemia, if present, should be corrected prior to initiating treatment.

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for patients who fail initial therapy with lifestyle intervention and metformin or cannot take metformin. Empagliflozin may be preferred as an additional antidiabetic agent or alternative first-line agent in patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease given empagliflozin's demonstrated cardiovascular and renal benefits (ACC [Das 2018]; ADA 2019; DeSantis 2019; Zelniker 2019; Zinman 2015).

Oral: Initial: 10 mg once daily; may increase to 25 mg once daily if needed to achieve glycemic goals.

Use in patients with diabetic nephropathy (off-label use): Although the manufacturer recommends against routine use in patients with eGFR <45 mL/minute/1.73 m², in the setting of prevalent kidney disease, SGLT2 inhibitors have established renal and cardiovascular benefits when eGFR is >30 mL/minute/1.73 m² (Bakris 2019; Wanner 2016; Wanner 2018; Zelniker 2019). Because SGLT2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Wexler 2019).

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylurea): Reduced dose of insulin and/or insulin secretagogues may be needed.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer once daily in the morning, with or without food.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Monitor therapy

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Patients being treated with the Jynarque brand of tolvaptan should avoid concomitant use of OAT1/3 substrates. Concentrations and effects of the OAT1/3 substrate would be expected to increase with any combined use. Consider therapy modification

Test Interactions

Positive test for glucosuria; may interfere with 1,5-anhydroglucitol (1,5-AG) assay; use alternative methods to monitor glycemic control.

Adverse Reactions

>10%: Genitourinary: Urinary tract infection (9%; females: 18%; males: 4%)

1% to 10%:

Endocrine & metabolic: Dyslipidemia (4%), increased thirst (2%)

Gastrointestinal: Nausea (2%)

Genitourinary: Increased urine output (3%)

Hematologic & oncologic: Increased hematocrit (3% to 4%)

Infection: Genitourinary fungal infection (2% to 6%)

Frequency not defined: Endocrine & metabolic: Increased LDL cholesterol

<1%, postmarketing, and/or case reports: Acute renal failure, angioedema, decreased estimated GFR (eGFR), hypersensitivity reaction, hypovolemia, increased serum creatinine, ketoacidosis, necrotizing fasciitis (perineum), phimosis, pyelonephritis, skin rash, urinary tract infection with sepsis, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: An increased incidence of bone fractures has been observed with other SGLT-2 inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• Genital mycotic infections: May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, skin, urticaria) have been observed; discontinue promptly if hypersensitivity occurs and treat as indicated. Use is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin.
• Hypotension: May cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m²), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT-2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL) (Bobart 2016; FDA 2015; Handelsman 2016). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or discontinuation of insulin, caloric restriction, alcohol abuse, extensive exercise, MI, stroke, severe infection, surgery, any other extreme stress event) (Handelsman 2016). The American Association of Clinical Endocrinologists and American College of Endocrinology recommend considering withholding of SGLT-2 inhibitors for at least 24 hours prior to events that may precipitate diabetic ketoacidosis (Handelsman 2016), while others have suggested withholding for 3 to 5 days (Bobart 2016). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• Lipid abnormality: May cause low-density lipoprotein cholesterol (LDL-C) elevation; monitor LDL-C and treat as needed.
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Renal effects: Acute kidney injury has been reported. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT-2 inhibitors increases the risk for urinary tract infection (UTI); monitor for signs and symptoms of UTI and treat as needed.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).

– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).

– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT-2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.

• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Use is contraindicated in severe renal impairment (eGFR <30 mL/minute/1.73 m²), ESRD, and in dialysis patients. According to the manufacturer, empagliflozin should not be initiated in patients with eGFR <45 mL/minute/1.73 m² and should be discontinued when eGFR is persistently <45 mL/minute/1.73 m². In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end-point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m² and high cardiovascular risk receiving standard care. Post-hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m²) (Wanner 2016). An additional post-hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45, 45 to <60, and ≥60 mL/minute/1.73 m² (Wanner 2018). However, additional trials may be necessary to definitively establish whether empagliflozin improves these outcomes in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Risk of intravascular volume depletion, renal impairment, and UTI may be increased in elderly patients.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.

Monitoring Parameters

Blood glucose, HbA_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2019); renal function (baseline and periodically during treatment); volume status (eg, blood pressure, hematocrit, electrolytes); LDL-C; monitor for genital mycotic infections and UTI; blood pressure; if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016])

Pregnancy

Pregnancy Considerations

Information related to the use of empagliflozin in pregnancy is limited (Formoso 2018). Due to adverse effects on renal development observed in animal studies, the manufacturer does not recommend use of empagliflozin during the second and third trimesters of pregnancy.

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Agents other than empagliflozin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2020).

Patient Education

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).
• It is used to lower the chance of death from heart disease in certain people.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.
• Vaginal yeast infection
• Penile yeast infection or pain
• Edema
• infection in the genitals or rectum
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.