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Empagliflozin

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

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 of type 2 diabetes mellitus (noninsulin dependent, NIDDM) 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

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

Canadian labeling: Additional contraindications (not in US labeling): eGFR <45 mL/minute/1.73 m2

Dosing: Adult

Note: If present, correct volume depletion prior to initiation

Diabetes mellitus, type 2: Oral: Initial: 10 mg once daily; may increase to 25 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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 in patients already taking empagliflozin, discontinue therapy when eGFR is persistently <45 mL/minute/1.73 m2. Empagliflozin, however, has been shown to have beneficial effects on preservation of renal function in select patients with an eGFR ≥30 mL/minute/1.73 m2 (Wanner 2016).

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

ESRD, dialysis: Use is contraindicated.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; may be used in patients with hepatic impairment.

Administration

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

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

Insulin: SGLT2 Inhibitors may enhance the hypoglycemic effect of Insulin. 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

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

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

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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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

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: 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 OAT3 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

>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 (4%; females: 5% to 6%; males: 2% to 3%)

Frequency not defined: Endocrine & metabolic: Increased LDL cholesterol

<1%, postmarketing, and/or case reports: Acute renal failure, decreased estimated GFR (eGFR), hypotension, hypovolemia, increased serum creatinine, ketoacidosis, phimosis, pyelonephritis, urosepsis

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Increased incidence of bone fractures may occur. According to the American Diabetes Association guidelines, sodium glucose co-transporter-2 (SGLT2) inhibitors should be avoided in patients with fracture risk factors (ADA 2016a).

• 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.

• 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, a serious and life-threatening condition resulting in urgent hospitalization, 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) (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 SGLT2 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; if indicated, consider interruption or discontinuation of therapy.

• Lipid abnormality: May cause low-density lipoprotein cholesterol (LDL-C) elevation; monitor LDL-C and treat as needed.

• 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. 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:

• Renal impairment: Glycemic efficacy may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. 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. Use is contraindicated in severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, and in dialysis patients. Empagliflozin has been shown to reduce the occurrence of incident or worsening nephropathy in select diabetic patients receiving standard care with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk over a period of approximately 3.1 years (Wanner 2016).

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 (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

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 2016b); 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; ketoacidosis

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Use is not recommended during the second and third trimesters.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). 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 (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008). Agents other than empaglifozin are currently recommended to treat diabetes in pregnant women (ADA 2017c).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of acidosis (confusion, fast breathing, tachycardia, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), signs of vaginal yeast infection, or signs of penile yeast infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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