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Empagliflozin

Medically reviewed by Drugs.com. Last updated on Oct 12, 2020.

Pronunciation

(em pa gli FLOE zin)

Index Terms

  • BI10773

Dosage Forms

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

Tablet, Oral:

Jardiance: 10 mg, 25 mg

Brand Names: U.S.

  • Jardiance

Pharmacologic Category

  • Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
  • Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Pharmacology

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 (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

Distribution

Vd: 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.

Duration of Action

Following discontinuation, urinary glucose excretion returns to baseline within ~3 days for the 10 mg and 25 mg doses.

Half-Life Elimination

12.4 hours.

Protein Binding

86.2%.

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 Cmax increased by approximately 4%, 23%, and 48%, respectively.

Use: Labeled Indications

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

Off Label Uses

Heart failure with reduced ejection fraction

Data from a large, double-blind, randomized, placebo-controlled trial support the use of empagliflozin in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes mellitus, to reduce the risk of hospitalization for heart failure and cardiovascular death. Empagliflozin should not be used for patients with type 1 diabetes mellitus. To be considered candidates, patients should have symptomatic HFrEF (ejection fraction [EF] ≤40%) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) despite optimal initial pharmacologic therapy (eg, beta-blocker, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker or angiotensin II receptor blocker-neprilysin inhibitor, and a mineralocorticoid receptor antagonist [if indicated]) and device therapy (eg, an implantable cardioverter-defibrillator, cardiac resynchronization therapy, or both) (if indicated). Patients with an EF of >30% to 40% should also have been hospitalized for heart failure within the prior 12 months or have a very elevated NT-proBNP level (>1,000 pg/mL for EF of 31% to 35%, >2,500 mg/mL for EF of 36% to 40%) [Packer 2020].

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

Dosing: Adult

Note: Hypovolemia, if present, should be corrected prior to initiating treatment. May require a gradual dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (AACE/ACE [Garber 2020]).

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or those who cannot take metformin. May be preferred in patients with atherosclerotic cardiovascular disease (ASCVD), heart failure, or diabetic kidney disease given demonstrated cardiovascular and renal benefits (ADA 2020; DeSantis 2020; Zinman 2015).

Hyperglycemia: Oral: Initial: 10 mg once daily; may increase to 25 mg once daily after 4 to 12 weeks if needed to achieve glycemic goals (DeSantis 2020; manufacturer's labeling).

Atherosclerotic cardiovascular disease: Note: In patients with type 2 diabetes mellitus and established ASCVD, empagliflozin has been shown to reduce the risk of major adverse cardiovascular events and cardiovascular death.

Oral: 10 or 25 mg once daily (Zelniker 2019; Zinman 2015).

Diabetic kidney disease (off-label use): Oral: 10 mg once daily in patients with urinary albumin excretion >300 mg/day; it is unknown if higher doses result in better kidney protection.

Note: Some experts also use this regimen in patients without severely increased albuminuria (eg, urinary albumin excretion ≤300 mg/day); benefits and harms may be more closely balanced due to smaller absolute benefit (Neuen 2019; Perkovic 2020; Wanner 2016; Wanner 2018). Because SGLT2 inhibitors have less glycemic benefit as eGFR declines, another agent may be needed to achieve glycemic goals (Wexler 2020).

Heart failure (off-label use): Note: In patients with type 2 diabetes mellitus and established ASCVD, multiple cardiovascular risk factors or established HF with reduced ejection fraction, empagliflozin has been shown to reduce the risk of heart failure hospitalization.

Oral: 10 mg once daily (Packer 2020; Zelniker 2019; Zinman 2015).

Heart failure with reduced ejection fraction (adjunct) (off-label use):

Note: May be used in persistently symptomatic patients who are already optimized on other therapies (including evidence-based drug and device therapies, as indicated). Benefits were consistently demonstrated in patients with or without type 2 diabetes (Packer 2020).

Oral: 10 mg once daily (Packer 2020).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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 Agents with Blood Glucose Lowering Effects. 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 Agents with Blood Glucose Lowering Effects. Monitor therapy

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

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

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

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

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

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. 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 Agents with Blood Glucose Lowering Effects. Monitor therapy

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

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

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Genitourinary: Urinary tract infection (9% [placebo: 8%]; females: 18% [placebo: 17%]; males: 4% [placebo: 3%])

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% [placebo: ≤2%])

<1%: Genitourinary: Phimosis (placebo: 0%)

Postmarketing:

Cardiovascular: Hypersensitivity angiitis To 2018

Dermatologic: Skin rash (rare: <1%) EMA 2017, urticaria (rare: <1%) EMA 2017

Endocrine & metabolic: Hypovolemia (less frequent: ≥1% to <4%; higher incidence in older patients) Kohler 2017, ketoacidosis (patients may be euglycemic; without concomitant insulin: rare: <1%, with concomitant insulin: less frequent: ≥1% to <4%) FDA 2015, Handelsman [AACE/ADA 2016], Rosenstock 2018, Zinman 2015

Genitourinary: Urinary tract infection with sepsis (rare: <1%) Fisher 2020

Hypersensitivity: Angioedema (rare: <1%) EMA 2017

Infection: Necrotizing fasciitis (perineum) (rare: <1%) Bersoff-Match 2019, FDA 2018

Renal: Acute kidney injury (rare: <1%) Wanner 2016, Zinman 2015, decreased estimated GFR (eGFR) (occurring early after initiation) Wanner 2016, increased serum creatinine Wanner 2016, pyelonephritis (rare: <1%) Kohler 2016, Kufel 2017

Respiratory: Asthma (rare: <1%) DeFronzo 2018

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: An increased incidence of bone fractures has been observed with other SGLT2 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 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior to surgery or any event which may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. 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.

• Lower limb amputation: There is conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Inzucchi 2018; Khouri 2018). The following FDA guidance (developed specifically for canagliflozin) may reasonably apply to use of other SGLT2 inhibitors: Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care. Discontinue therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA 2017).

• 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 SGLT2 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 SGLT2 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 kidney function prior to initiation and periodically during treatment. The manufacturer’s labeling states that use is contraindicated in eGFR <30 mL/minute/1.73 m2; however, in patients previously established on empagliflozin, some experts continue use off label at a dose of 10 mg once daily as a treatment for diabetic kidney disease (Packer 2020; Perkovic 2020).

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.

• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).

• Surgical procedures: Consider temporary discontinuation of therapy at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.

Monitoring Parameters

Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients in whom treatment goals have not been met or with therapy change (ADA 2020); renal function (baseline and periodically during treatment); volume status (eg, blood pressure, hematocrit, electrolytes); 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 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 HbA1c 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.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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

• Swelling

• infection in the genitals or rectum

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.