Empagliflozin

Pharmacologic Category

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

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 to avoid hypoglycemia.

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. May be preferred in patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease given demonstrated cardiovascular and renal benefits (ADA 2020; DeSantis 2020; Zinman 2015).

Management of 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).

Use in patients with atherosclerotic cardiovascular disease: Oral: 10 or 25 mg once daily. Note: Risk reduction for major adverse cardiovascular events and for cardiovascular mortality has been demonstrated in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease (Zinman 2015).

Use in patients with 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).

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

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30 to <45 mL/minute/1.73 m2: The manufacturer recommends to not initiate therapy, or to discontinue therapy in patients already taking empagliflozin, when eGFR is persistently <45 mL/minute/1.73 m2. Some experts use empagliflozin off label at a dose of 10 mg once daily in patients with severely increased albuminuria (eg, urinary albumin excretion >300 mg/day). This regimen is also used off label in patients without severely increased albuminuria; benefits and harms may be more closely balanced due to smaller absolute renal benefit in this population (Perkovic 2020; Wanner 2016; Wanner 2018). In addition, data suggest that cardiovascular benefits may persist in patients with atherosclerotic cardiovascular disease and eGFR 30 to <45 mL/minute/1.73 m2 (Wanner 2018).

eGFR <30 mL/minute/1.73 m2: The manufacturer’s labeling states that use in contraindicated; 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 (Perkovic 2020).

End-stage renal disease, hemodialysis: Use is contraindicated.

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary. Systemic exposure is increased in hepatic impairment, but changes are not considered clinically significant (Macha 2014).

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.

* See Uses in AHFS Essentials for additional information.

Comparative Efficacy

• EMPAGLIFLOZIN

Clinical Practice Guidelines

AACE/ACE, “Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm - 2020 Executive Summary,” January 2020

ADA, “Standards of Medical Care in Diabetes - 2020,” January 2020

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Endocrine Society, “Treatment of Diabetes in Older Adults: An Endocrine Society Clinical Practice Guideline,” May 2019

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/Stability

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

Medication Patient Education with HCAHPS Considerations

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.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Jardiance: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204629s019lbl.pdf#page=34

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

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 renal function prior to initiation and periodically during treatment. According to the manufacturer, use is contraindicated in severe renal impairment (eGFR <30 mL/minute/1.73 m2), end-stage renal disease, and in dialysis patients; 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. However, data suggest that the cardiovascular and/or renal benefits may persist if used in patients with cardiovascular disease and eGFR <45 mL/minute/1.73 m2 (Wanner 2016; Wanner 2018).

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.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Per the manufacturer's labeling, 32% and 6% of clinical trial participants were ages >65 and >75 years old. Elderly patients may be more prone to adverse events due to volume depletion (eg, hypotension) and should be assessed for depleted volume prior to starting empagliflozin. Patients >75 years are at greater risk for volume depletion and urinary tract infections.

How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. In patients with advanced microvascular complications and/or a life expectancy <5 years, a target HbA1c of 8% to 9% is reasonable. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.

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).

Breast-Feeding Considerations

It is not known if empagliflozin is present in breast milk.

Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.

Lexicomp Pregnancy & Lactation, In-Depth

• Empagliflozin

Briggs' Drugs in Pregnancy & Lactation

• Empagliflozin

Adverse Reactions

>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 Ref

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

Endocrine & metabolic: Hypovolemia (less frequent: ≥1% to <4%; higher incidence in older patients) Ref, ketoacidosis (patients may be euglycemic; without concomitant insulin: rare: <1%, with concomitant insulin: less frequent: ≥1% to <4%) Ref

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

Hypersensitivity: Angioedema (rare: <1%) Ref

Infection: Necrotizing fasciitis (perineum) (rare: <1%) Ref

Renal: Acute kidney injury (rare: <1%) Ref, decreased estimated GFR (eGFR) (occurring early after initiation) Ref, increased serum creatinine Ref, pyelonephritis (rare: <1%) Ref

Respiratory: Asthma (rare: <1%) Ref

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, OAT1/3, OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor), UGT1A3, UGT1A8, UGT1A9, UGT2B7; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

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

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

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

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

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: 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. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

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

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk D: Consider therapy modification

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

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

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Avoid concomitant use of OAT1/3 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the OAT1/3 substrate would be expected to increase with combined use. Risk D: 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.

Monitoring Parameters

Blood glucose, HbA1c (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 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])

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2020):

HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics).

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Older adults (≥65 years of age) (ADA 2020):

Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (eg, sulfonylureas) (ES [LeRoith 2019]).

HbA1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment).

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).

Classification of hypoglycemia (ADA 2020):

Level 1: ≥54 to ≤70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.

Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.

Advanced Practitioners Physical Assessment/Monitoring

Assess renal function; dosage adjustments may be needed. Obtain blood glucose, HbA1c, LDL-C, electrolytes, hematocrit, and renal function. Monitor blood pressure. Observe for signs of UTI or genital infection. Refer patient to diabetes educator for instruction if needed.

Nursing Physical Assessment/Monitoring

Check ordered labs and report any abnormalities. Monitor blood pressure. Watch for signs of hypoglycemia and educate patient to report. Refer patient to diabetes educator for instruction if needed. Educate patient about increased risk of urinary tract or genital infection and to report any signs or symptoms.

Dosage Forms: US

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

Tablet, Oral:

Jardiance: 10 mg, 25 mg

Dosage Forms: Canada

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

Tablet, Oral:

Jardiance: 10 mg, 25 mg

Anatomic Therapeutic Chemical (ATC) Classification

• A10BK03

Generic Available (US)

No

Pricing: US

Tablets (Jardiance Oral)

10 mg (per each): $20.90

25 mg (per each): $20.90

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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 (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.

Pharmacodynamics/Kinetics

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

Distribution: Vd: 73.8 L.

Protein binding: 86.2%.

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

Half-life Elimination: 12.4 hours.

Time to Peak: 1.5 hours.

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

Pharmacodynamics/Kinetics: Additional Considerations

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.

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.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Dizziness and syncope have been reported; patients may experience orthostatic hypotension as they stand up after treatment; especially if lying in dental chair for extended periods of time. Use caution with sudden changes in position during and after dental treatment.

Empagliflozin-dependent patients with diabetes (noninsulin dependent, type 2) should be questioned by the dental professional at each dental visit to assess their risk for stress-induced hypoglycemia. The dental professional should inquire about the patient’s routine (ie, work, sleep schedule, eating patterns), history of hypoglycemia, time of last medication dose, last meal, and most recent blood sugar assessment. Keep a supply of glucose tablets and other carbohydrates in the office to prepare for a hypoglycemic event. Seek medical attention when necessary (American Diabetes Association 2016).

Effects on Bleeding

No information available to require special precautions

Related Information

• Oral Antidiabetic Agents Comparison Table

Index Terms

BI10773

FDA Approval Date

August 01, 2014

References

American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 201: Pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi: 10.1097/AOG.0000000000002960.[PubMed 30461693]

American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: Gestational diabetes mellitus. Obstet Gynecol. 2018;131(2):e49-e64.[PubMed 29370047]

American Diabetes Association (ADA). Standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S1-S212. https://care.diabetesjournals.org/content/43/Supplement_1. Accessed January 22, 2020.

Arakaki RF. Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes. Postgrad Med. 2016;128(4):409-417. doi:10.1080/00325481.2016.1167570[PubMed 26982554]

Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann Intern Med. 2019;170(11):764-769. doi:10.7326/M19-0085[PubMed 31060053]

Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9[PubMed 30558872]

Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249.[PubMed 24194617 ]

Bobart SA, Gleason B, Martinez N, Norris K, Williams SF. Euglycemic ketoacidosis caused by sodium-glucose cotransporter 2 inhibitors: a case report. Ann Intern Med. 2016;165(7):530-532.[PubMed 27699391]

Chu C, Lu YP, Yin L, Hocher B. The SGLT2 inhibitor empagliflozin might be a new approach for the prevention of acute kidney injury. Kidney Blood Press Res. 2019;44(2):149-157. doi:10.1159/000498963[PubMed 30939483]

Danne T, Garg S, Peters AL, et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care. 2019;42(6):1147-1154. doi:10.2337/dc18-2316[PubMed 30728224]

Dave CV, Schneeweiss S, Patorno E. Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2019;21(2):434-438. doi:10.1111/dom.13531[PubMed 30207042]

DeFronzo RA, Lee C, Kohler S. Safety and tolerability of combinations of empagliflozin and linagliptin in patients with type 2 diabetes: pooled data from two randomized controlled trials. Adv Ther. 2018;35(7):1009-1022. doi:10.1007/s12325-018-0724-y[PubMed 29949041]

DeSantis A. Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 8, 2020.

Dizon S, Keely EJ, Malcolm J, Arnaout A. Insights into the recognition and management of SGLT2-inhibitor-associated ketoacidosis: it's not just euglycemic diabetic ketoacidosis. Can J Diabetes. 2017;41(5):499-503. doi:10.1016/j.jcjd.2017.05.004[PubMed 28797889]

European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisations(s). https://www.ema.europa.eu/en/documents/scientific-conclusion/jardiance-h-c-psusa-00010388-201610-epar-scientific-conclusions-grounds-variation-terms-marketing_en.pdf. Published May 18, 2017. Accessed March 20, 2020.

FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-confirms-increased-risk-leg-and-foot-amputations-diabetes-medicine. Published July 13, 2017. Accessed March 20, 2020.

FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious. Published December 4, 2015. Accessed August 25, 2020.

FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin. Published June 17, 2016. Accessed August 25, 2020.

FDA Drug Safety Communication: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes. Published September 7, 2018. Accessed August 25, 2020.

FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Food and Drug Administration website. https://www.fda.gov/media/92185/download Accessed May 15, 2015.

Fisher A, Fralick M, Filion KB, et al. Sodium-glucose co-transporter-2 inhibitors and the risk of urosepsis: A multi-site, prevalent new-user cohort study. Diabetes Obes Metab. 2020;22(9):1648-1658. doi:10.1111/dom.14082[PubMed 32383792]

Fitchett D. A safety update on sodium glucose co-transporter 2 inhibitors. Diabetes Obes Metab. 2019;21(suppl 2):34-42. doi:10.1111/dom.13611[PubMed 31081590]

Formoso G, Ginestra F, Di Dalmazi G, Consoli A. Empagliflozin, metformin and insulin degludec, during pregnancy: a case report. Acta Diabetol. 2018;55(7):759-761.

Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103(3):373-381. doi:10.1016/j.diabres.2013.12.052[PubMed 24529566]

Gilbert RE, Thorpe KE. Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: A meta-analysis of cardiovascular outcome trials. Diabetes Obes Metab. 2019;21(8):1996-2000. doi:10.1111/dom.13754[PubMed 31050116]

Hahn K, Ejaz AA, Kanbay M, Lanaspa MA, Johnson RJ. Acute kidney injury from SGLT2 inhibitors: potential mechanisms. Nat Rev Nephrol. 2016;12(12):711-712. doi:10.1038/nrneph.2016.159[PubMed 27847389]

Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753-762. doi:10.4158/EP161292.PS[PubMed 27082665]

Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2013;36(11):3396-3404. doi:10.2337/dc12-2673[PubMed 23963895]

Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(1):e4-e5. doi:10.2337/dc17-1551[PubMed 29133344]

Jardiance (empagliflozin) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; January 2020.

Khouri C, Cracowski JL, Roustit M. SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect? Diabetes Obes Metab. 2018;20(6):1531-1534. doi:10.1111/dom.13255[PubMed 29430814]

Kohler S, Salsali A, Hantel S, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38(6):1299-1313. doi:10.1016/j.clinthera.2016.03.031[PubMed 27085585]

Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34(7):1707-1726. doi:10.1007/s12325-017-0573-0[PubMed 28631216]

Kufel WD, Scrimenti A, Steele JM. A case of septic shock due to Serratia marcescens pyelonephritis and bacteremia in a patient receiving empagliflozin. J Pharm Pract. 2017;30(6):672-675. doi:10.1177/0897190016679760[PubMed 27876693]

LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of diabetes in older adults: an Endocrine Society* clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1520-1574. doi:10.1210/jc.2019-00198[PubMed 30903688]

Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348-355. doi:10.1111/dom.12825[PubMed 27862830]

Macha S, Rose P, Matteus M, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014;16(2):118-123. doi:10.1111/dom.12183[PubMed 23859534]

Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6(6):e004007. doi:10.1161/JAHA.116.004007[PubMed 28546454]

McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. Am J Cardiol. 2019;124(suppl 1):S45-S52. doi:10.1016/j.amjcard.2019.10.029[PubMed 31741440]

Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi:10.1016/j.soard.2012.12.010[PubMed 23537696]

Melissas J, Leventi A, Klinaki I, et al. Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study. Ann Surg. 2013;258(6):976-982. doi:10.1097/SLA.0b013e3182774522[PubMed 23160151]

Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925[PubMed 28605608]

Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7(11):845-854. doi:10.1016/S2213-8587(19)30256-6[PubMed 31495651]

Nichols GA, Brodovicz KG, Kimes TM, Déruaz-Luyet A, Bartels DB. Prevalence and incidence of urinary tract and genital infections among patients with and without type 2 diabetes. J Diabetes Complications. 2017;31(11):1587-1591. doi:10.1016/j.jdiacomp.2017.07.018[PubMed 28888425]

Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351(9117):1693-1697. doi:10.1016/S0140-6736(97)09137-X[PubMed 9734886]

Nyirjesy P, Sobel JD. Genital mycotic infections in patients with diabetes. Postgrad Med. 2013;125(3):33-46. doi:10.3810/pgm.2013.05.2650[PubMed 23748505]

O'Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015;309(3):F227-F234. doi:10.1152/ajprenal.00689.2014[PubMed 26041448]

Perkovic V, Badve SV, Bakris GL. Treatment of diabetic kidney disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 13, 2020.

Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560-2569. doi:10.2337/dc18-1749[PubMed 30287422]

Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev. 2017;33(6). doi: 10.1002/dmrr.2903.[PubMed 28440590]

Schaefer-Graf UM, Hartmann R, Pawliczak J, et al. Association of breast-feeding and early childhood overweight in children from mothers with gestational diabetes mellitus. Diabetes Care. 2006;29(5):1105-1107.[PubMed 16644645]

Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016;18(12):1199-1206. doi:10.1111/dom.12742[PubMed 27407013]

Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(8):1106-1115. doi:10.1111/dom.12917[PubMed 28240446]

Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849-2852. doi:10.1210/jc.2015-1884[PubMed 26086329]

Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi:10.2337/dc14-1096[PubMed 25271206]

To D, Bradshaw S, Lipson J. Case report of empagliflozin-induced cutaneous polyarteritis nodosa. J Cutan Med Surg. 2018;22(5):516-518. doi:10.1177/1203475418760457[PubMed 29457486]

van Niekerk C, Wallace J, Takata M, Yu R. Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin [published online August 20, 2018]. BMJ Case Rep. doi: 10.1136/bcr-2017-221527.[PubMed 30131409]

Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920[PubMed 27299675]

Wanner C, Lachin JM, Inzucchi SE, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137(2):119-129. doi: 10.1161/CIRCULATIONAHA.117.028268[PubMed 28904068]

Wexler DJ. Management of persistent hyperglycemia in type 2 diabetes mellitus. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 18, 2020.

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389[PubMed 30415602]

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X[PubMed 30424892]

Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720[PubMed 26378978]

Brand Names: International

Diacurimap (EG); Dzhardins (UA); Gibtulio (IN); Glimpacare (EG); Jardiance (AE, AR, AT, AU, BB, BE, BH, BR, CH, CN, CZ, DE, DK, EC, EE, EG, ES, GB, HK, HR, HU, ID, IE, IL, IS, JP, KR, KW, LB, LT, LU, LV, MT, MY, NL, NO, PE, PH, PL, PT, RO, SE, SG, SI, SK, TH, VN); Jardianz (CR, DO, GT, HN, NI, PA, SV)

Last Updated 9/22/20