AHFS Class:

• Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors 68:20.18

Generic Name(s):

• Empagliflozin

• Empagliflozin and Linagliptin

• Empagliflozin and Metformin Hydrochloride

Chemical Name:

• (1 S )-1,5-Anhydro-1- C -[4-chloro-3-[[4-[[(3 S )-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-d-glucitol

Molecular Formula:

• C₂₃H₂₇ClO₇

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an antidiabetic agent.1

Type 2 Diabetes Mellitus

Empagliflozin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2 Empagliflozin also is used to reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus and established cardiovascular disease.1,90 Empagliflozin is commercially available in fixed combination with immediate- or extended-release metformin hydrochloride (Synjardy^® or Synjardy^® XR, respectively) or linagliptin (Glyxambi^®); the fixed-combination preparations are used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.70,72,74 The manufacturer states that the effectiveness of the fixed combination of empagliflozin and immediate- or extended-release metformin hydrochloride or linagliptin in reducing the risk of cardiovascular death in patients with type 2 diabetes mellitus and cardiovascular disease has not been established.70,72,74 Empagliflozin also is used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione], a dipeptidylpeptidase-4 [DPP-4] inhibitor) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1,3,4,5,6,7,8,9

Glycemic Control

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 (GLP-1) receptor agonist, SGLT2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another agent) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic classes with complementary mechanisms of action. 698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704,705 (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses: Type 2 Diabetes Mellitus, in Dapagliflozin 68:20.18.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' HbA_1c.704 GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). 698,704,706 (See Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18.) In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.704

The manufacturer states that empagliflozin is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1

Empagliflozin Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, empagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) and fasting plasma glucose concentrations, and also reduces body weight.1,2 Efficacy of empagliflozin as monotherapy for the management of type 2 diabetes mellitus has been established in a phase 3, double-blind, placebo-controlled study of 24 weeks' duration in 986 adults with previously untreated type 2 diabetes mellitus (defined as receiving no oral or injected antidiabetic agents for 12 weeks prior to randomization or initiation of open-label treatment).1,2 Empagliflozin (10 mg or 25 mg once daily) improved glycemic control as evidenced by reductions in HbA_1c, fasting plasma glucose concentrations, and body weight.1,2 Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily with no placebo run-in phase.1,2 Patients with HbA_1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled received empagliflozin 10 mg once daily, empagliflozin 25 mg once daily, sitagliptin 100 mg once daily, or placebo.2 The primary end point of the study was change from baseline in HbA_1c at week 24.2 At 24 weeks, reductions (adjusted mean) in HbA_1c were 0.7, 0.8, or 0.7% in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily, respectively; an increase (adjusted mean) in HbA_1c of 0.1% was observed in patients who received placebo.1,2 Also, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentrations was 19 or 25 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, respectively, compared with an increase of 12 mg/dL in those receiving placebo.1,2 Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily had reductions (adjusted mean) in body weight of 2.8, 3.2, or 0.4%, respectively, at week 24; systolic blood pressure was reduced by 2.6 mm Hg in patients who received empagliflozin 10 mg once daily and by 3.4 mm Hg in those who received empagliflozin 25 mg once daily compared with that in placebo recipients.1,2

Combination Therapy

When given in combination with one or more oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione, a DPP-4 inhibitor) or insulin, empagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight and systolic blood pressure.1,3,4,5,7,8,9 In a 24-week phase 3, randomized, double-blind, placebo-controlled study in 637 adults with inadequately controlled type 2 diabetes mellitus who were receiving metformin hydrochloride (at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage), addition of empagliflozin 10 or 25 mg once daily resulted in reductions of HbA_1c compared with placebo.1,3 Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily without a placebo run-in phase.3 Patients with HbA_1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled following the run-in phase received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks.1,3 The primary end point of the study was change from baseline in HbA_1c at week 24.3 Following 24 weeks of therapy, the addition of empagliflozin to current metformin treatment resulted in reductions (adjusted mean) in HbA_1c of 0.7, 0.8, and 0.1% in patients who received empagliflozin 10 mg once daily, empagliflozin 25 mg once daily, and placebo, respectively.1,3 In addition, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentration was 20 or 22 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, respectively, compared with an increase of 6 mg/dL in those receiving placebo.1 Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo experienced reductions (adjusted mean) in body weight of 2.5, 2.9, or 0.5%, respectively, at week 24; systolic blood pressure was reduced compared with placebo by 4.1 mm Hg in patients who received empagliflozin 10 mg and by 4.8 mm Hg in those who received empagliflozin 25 mg.1,3

Efficacy and safety of the combination of empagliflozin and metformin hydrochloride as initial therapy in treatment-naive patients with type 2 diabetes mellitus are supported by results of a 24-week, randomized, double-blind trial.1 In this trial, concurrent therapy with empagliflozin (10 or 25 mg once daily) and metformin hydrochloride (1 or 2 g daily) substantially improved glycemic control (as evidenced by reductions in HbA_1c), compared with empagliflozin or metformin hydrochloride monotherapy.1 Reductions in HbA_1c were 2 or 2.1% with 1 or 2 g daily, respectively, of metformin hydrochloride plus empagliflozin 10 mg once daily; 1.9 or 2.1% with 1 or 2 g daily, respectively, of metformin hydrochloride plus empagliflozin 25 mg once daily; 1.2 or 1.8% with 1 or 2 g daily, respectively, of metformin hydrochloride; and 1.4% with empagliflozin 10 or 25 mg once daily.1

Efficacy of empagliflozin 10 or 25 mg once daily in combination with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage) plus a sulfonylurea was established in 666 adults with type 2 diabetes mellitus in an international 24-week, phase 3, randomized, double-blind, placebo-controlled study.1,4 Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg.4 Patients with HbA_1c concentrations of 7-10% entered a placebo run-in period for 2 weeks, and those who remained inadequately controlled received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily.1,4 The primary end point of the study was change from baseline in HbA_1c at week 24.4 Following 24 weeks of therapy, add-on therapy with empagliflozin reduced HbA_1c by 0.8, 0.8, or 0.2% (adjusted mean values) in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively.1,4 Also, at 24 weeks, the reduction (adjusted mean) in fasting plasma glucose concentrations was 23 mg/dL in patients who received empagliflozin 10 or 25 mg once daily, compared with an increase of 6 mg/dL in those receiving placebo.1 Patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily had reductions (adjusted mean) in body weight of 2.9, 3.2, or 0.5%, respectively, at week 24.1

Efficacy of empagliflozin 25 mg in combination with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage) in an international phase 3, randomized, double-blind study was established in 1545 adults with type 2 diabetes mellitus.1,5,6 Patients with inadequately controlled type 2 diabetes mellitus (HbA_1c concentration of 7-10%) received empagliflozin 25 mg once daily or glimepiride 1-4 mg once daily (mean daily dosage of 2.7 mg) following a 2-week run-in period.1,5 The primary end point was change from baseline in HbA_1c concentrations at weeks 52 and 104.5,6 At week 52, add-on therapy with empagliflozin 25 mg or glimepiride 1-4 mg in patients receiving metformin resulted in a reduction in HbA_1c concentration of 0.7% for both drugs.1,5 At week 52, add-on therapy with empagliflozin 25 mg or glimepiride 1-4 mg reduced fasting plasma glucose concentrations by 19 or 9 mg/dL, respectively.1 Body weight was reduced by 3.9 or increased by 2% in those who received empagliflozin 25 mg or glimepiride 1-4 mg, respectively, plus metformin at week 52.1 At week 52, the reduction in systolic blood pressure in patients who received empagliflozin (3.6 mm Hg) was not appreciably different from that in patients who received glimepiride (2.2 mm Hg).1 Empagliflozin demonstrated noninferiority to glimepiride in glycemic control at weeks 52 and 104; the reduction (adjusted mean) in HbA_1c with empagliflozin was 0.11% greater than that with glimepiride at week 104.1,5

In a 24-week, double-blind, placebo-controlled study in 498 adults with type 2 diabetes mellitus receiving pioglitazone (dosage of at least 30 mg daily, or maximum tolerated dosage, or maximum labeled dosage) with or without metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage), addition of empagliflozin 10 or 25 mg once daily reduced HbA_1c, fasting plasma glucose concentrations, and body weight.1,7 Following an open-label placebo run-in period of 2 weeks, patients with inadequate glycemic control (HbA_1c concentrations of 7-10%) received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, in addition to existing antidiabetic therapy with pioglitazone with or without metformin.1,7 The primary end point was change from baseline in HbA_1c concentrations at week 24.7 Addition of empagliflozin 10 or 25 mg to existing antidiabetic therapy resulted in reductions (adjusted mean) in HbA_1c of 0.6 or 0.7%, respectively, at week 24 compared with a reduction of 0.1% in patients receiving placebo.1,7 Patients receiving empagliflozin 10 or 25 mg had reductions (adjusted mean) in fasting plasma glucose concentrations of 17 or 22 mg/dL, respectively, at week 24 compared with an increase of 7 mg/dL with placebo.1,7 Reductions in body weight were 2.0, 1.8, or 0.6% in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively.1,7

In an international, phase 3, randomized, double-blind trial, add-on therapy with empagliflozin and linagliptin in fixed combination was more effective in reducing HbA_1c and fasting plasma glucose concentrations than add-on empagliflozin or linagliptin monotherapy in 686 adults with type 2 diabetes mellitus inadequately controlled with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage).1,44 At 24 weeks, reduction in mean HbA_1c from baseline was 1.19% with empagliflozin 25 mg/linagliptin 5 mg, 1.08% with empagliflozin 10 mg/linagliptin 5 mg, 0.62% with empagliflozin 25 mg, 0.66% with empagliflozin 10 mg, and 0.7% with linagliptin 5 mg.44 Glycemic efficacy (HbA_1c reductions) with the fixed combinations of empagliflozin/linagliptin was maintained at week 52.1,44 The fixed combinations of empagliflozin and linagliptin also were associated with reductions from baseline in systolic blood pressure compared with linagliptin monotherapy.44 Body weight was reduced in patients receiving the fixed combinations of empagliflozin/linagliptin compared with linagliptin but not empagliflozin monotherapy.1,44

In a double-blind, placebo-controlled study in 494 adults with inadequately controlled type 2 diabetes mellitus while receiving insulin with or without metformin and/or a sulfonylurea, add-on therapy with empagliflozin 10 or 25 mg once daily reduced HbA_1c, fasting plasma glucose concentrations, and body weight after 18 and 78 weeks of treatment.1 Following a 2-week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or sulfonylurea therapy, patients received empagliflozin 10 or 25 mg or placebo once daily in addition to existing antidiabetic therapy.1 Patients were maintained on a stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment; for the remaining 60 weeks, adjustment of insulin dosage was permitted.1 Mean total daily insulin dosages at baseline for patients receiving empagliflozin 10 mg, empagliflozin 25 mg, or placebo were 45, 48, or 48 units, respectively.1 At 18 weeks, add-on therapy with empagliflozin 10 or 25 mg reduced HbA_1c concentration by 0.6 or 0.7% (adjusted mean values), respectively, compared with no change in HbA_1c concentration in patients who received placebo.1 Also, at 78 weeks, addition of empagliflozin 10 or 25 mg reduced HbA_1c concentration by 0.4 or 0.6% (adjusted mean values), respectively, compared with an increase of 0.1% in patients who received placebo.1 Following 18 weeks of treatment, the reduction in fasting plasma glucose concentrations in patients who received empagliflozin 10 or 25 mg plus existing antidiabetic therapy was 17.9 or 19.1 mg/dL, compared with an increase of 10.4 mg/dL in those who received placebo; at 78 weeks, the reduction in fasting plasma glucose concentrations in patients who received empagliflozin 10 or 25 mg was 10.1 or 15.2 mg/dL, compared with an increase of 2.8 mg/dL in those receiving placebo.1 Furthermore, reductions in body weight at 18 weeks in patients who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo were 1.8, 1.4, or 0.1%, respectively; at 78 weeks, patients who received empagliflozin 10 or 25 mg had reductions of 2.4% in body weight, while those receiving placebo had an increase of 0.7% in body weight.1

In a randomized, double-blind, placebo-controlled, international study in 563 obese patients (body mass index [BMI] of 30-45 kg/m²) with inadequately controlled type 2 diabetes mellitus (HbA_1c concentrations 7.5-10%) despite multiple daily injections of insulin with or without metformin, add-on therapy with empagliflozin reduced HbA_1c and body weight.1,8 Following a 2-week, open-label, placebo run-in period, patients received empagliflozin 10 or 25 mg or placebo once daily as add-on therapy to insulin, with or without metformin hydrochloride (dosage of at least 1.5 g daily, maximum tolerated dosage, or maximum labeled dosage), for 52 weeks.1,8 The total daily dosage of insulin was adjusted to achieve a preprandial glucose target of less than 100 mg/dL and a postprandial glucose target of less than 140 mg/dL, except during the first 18 weeks (adjusted to be within 10% of prescribed dosage at randomization) and during weeks 41-52 (adjusted to be within 10% of the prescribed dosage at week 40 except for safety reasons).8 Metformin hydrochloride dosage was not adjusted during the study, although rescue therapy (e.g., metformin, insulin) could be initiated at any time during treatment if patients experienced clinically important hyperglycemia.8 The primary end point of the study was change from baseline in HbA_1c at week 18.8 At week 18, the reduction in HbA_1c was 0.94 or 1.02% in patients who received empagliflozin 10 or 25 mg once daily, respectively, as add-on therapy, compared with a reduction of 0.5% in patients who received placebo.1,8 At week 52, insulin titration resulted in additional reductions in HbA_1c of 1.18, 1.27, or 0.81% in those who received empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily, respectively.8 Also, at week 52, patients who received empagliflozin 10 or 25 mg once daily experienced reductions in body weight of 1.95 or 2.04 kg, respectively, compared with an increase in body weight of 0.44 kg in patients receiving placebo.1,8

Efficacy and safety of empagliflozin in 738 adults with inadequately controlled type 2 diabetes mellitus (HbA_1c concentrations of 7-10%) and renal impairment were established in a phase 3, randomized, double-blind, placebo-controlled study.1,9 Patients with an estimated glomerular filtration rate (eGFR) of 60-89 mL/minute per 1.73 m² (mild renal impairment) received empagliflozin 10 or 25 mg or placebo once daily in addition to existing antidiabetic therapy.1,9 Patients with an eGFR of 30-59 mL/minute per 1.73 m² (moderate renal impairment) or 15-29 mL/minute per 1.73 m² (severe renal impairment) received empagliflozin 25 mg once daily or placebo.1,9 The primary end point was change from baseline in HbA_1c at week 24.9 At 24 weeks, empagliflozin 25 mg reduced HbA_1c concentration by 0.5% in the combined group of patients with mild or moderate renal impairment.1,9 Empagliflozin 25 mg also reduced HbA_1c concentration in patients with either mild (0.7% reduction) or moderate (0.4% reduction) renal impairment, and empagliflozin 10 mg reduced HbA_1c concentration by 0.5% in patients with mild renal impairment.1,9 Antihyperglycemic efficacy of empagliflozin 25 mg was reduced with decreasing level of renal function in the mild to moderate range.1,9 Mean reductions in HbA_1c at 24 weeks were 0.6, 0.5, and 0.2% for those with a baseline eGFR of 60-89 mL/minute per 1.73 m², 45-59 mL/minute per 1.73 m², and 30-44 mL/minute per 1.73 m² , respectively, for patients receiving empagliflozin 25 mg.1 In contrast, mean HbA_1c at 24 weeks increased by 0.1 or 0.2% in patients with a baseline eGFR of 60-89 mL/minute per 1.73 m² or 30-44 mL/minute per 1.73 m², respectively, and decreased by 0.1% in patients with a baseline eGFR of 45-59 mL/minute per 1.73 m² for patients receiving placebo.1 For patients with severe renal impairment, the analyses of changes in HbA_1c and fasting plasma glucose concentrations showed no discernible treatment effect of empagliflozin 25 mg compared with placebo.1

Reduction in Risk of Cardiovascular Death

Empagliflozin is used to reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus and established cardiovascular disease.1,90,698,699,704,705,706

Empagliflozin and some other SGLT2 inhibitors have demonstrated the ability to reduce the risk of cardiovascular events in patients with type 2 diabetes mellitus and established cardiovascular disease.1,698,699,704,705,706 In addition to lowering blood glucose, SGLT2 inhibitors appear to modify several nonglycemic cardiovascular risk factors such as blood pressure, body weight, adiposity, and arterial stiffness.84,85 In the EMPA-REG OUTCOME study, adults (mean age: 63 years; 72% Caucasian) with type 2 diabetes mellitus and established, stable ASCVD (documented history of coronary artery disease [76%], stroke [23%], or peripheral artery disease [21%]) received empagliflozin (10 or 25 mg) once daily or placebo for a median duration of 2.6 years.1,90 During the study, additional antidiabetic agents and cardiovascular therapies were modified to achieve standard-of-care treatment targets with respect to blood glucose, lipids, and blood pressure.1 Concomitant use of other standard-of-care treatments for diabetes mellitus and ASCVD (renin-angiotensin system inhibitors [81%], β-blockers [65%], diuretics [43%], statins or ezetimibe [77%], antiplatelet agents [86%]) was permitted.1,90 A greater proportion of patients in the placebo group received additional antidiabetic agents (e.g., sulfonylurea, insulin), antihypertensive agents (e.g., diuretics), and anticoagulants during the study than those in the empagliflozin group.90 The primary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.1,90 In this study, patients who received empagliflozin had substantially lower rates of the primary cardiovascular outcome compared with those who received placebo (event rate 10.5 versus 12.1%, respectively).1,90 The lower rate of the composite outcome was driven by the substantial reduction in death from cardiovascular causes; there was no substantial difference between groups with regard to myocardial infarction or stroke.1,90 Patients receiving empagliflozin had an increased rate of genital infections but not in other adverse events.1,90

Beneficial Effects on Renal Function

SGLT2 inhibitors reduce renal tubular glucose reabsorption, weight, systemic blood pressure, intraglomerular pressure, and albuminuria and slow glomerular filtration rate (GFR) loss through mechanisms that appear to be independent of glucose-lowering effects.706 In several cardiovascular outcomes trials involving the use of SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus at high risk for cardiovascular disease or with existing cardiovascular disease, beneficial effects on renal function have been observed as a secondary outcome.84,704,706 Some experts state that the use of an SGLT2 inhibitor should be considered to reduce the risk of CKD progression, cardiovascular events, or both in patients with type 2 diabetes mellitus and diabetic kidney disease with albuminuria† (an eGFR of at least 30 mL/minute per 1.73 m² and urinary albumin exceeding 30 mg/g creatinine, particularly in those with urinary albumin exceeding 300 mg/g creatinine.706

A clinical study evaluating the use of canagliflozin in patients with type 2 diabetes mellitus, CKD (eGFR 30-89 mL/minute per 1.73 m²; mean: 56.2 mL/minute per 1.73 m²), and albuminuria (urine albumin:creatinine ratio exceeding 300 but less than 5000 mg/g) found that canagliflozin therapy reduced the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure.100 In another study (EMPA-REG OUTCOME)(see Reduction in Risk of Cardiovascular Death under Uses: Type 2 Diabetes Mellitus), empagliflozin therapy was associated with slower progression of kidney disease and lower rates of renal events.91 Compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (composite of urine:creatinine ratio exceeding 300 mg/g creatinine, doubling of serum creatinine, end-stage renal disease, or death from end-stage renal disease) by 39%.91,706

General

Volume depletion should be corrected before initiating empagliflozin.1 In addition, renal function should be assessed prior to treatment and periodically thereafter.1 (See Special Populations under Dosage and Administration: Dosage.)

Administration

Empagliflozin or the fixed combination of empagliflozin and linagliptin is administered orally once daily in the morning, with or without food.1,70 The fixed combination of empagliflozin and immediate-release metformin hydrochloride should be administered twice daily with meals.72 The fixed combination of empagliflozin and extended-release metformin hydrochloride should be administered once daily with the morning meal; the tablet should be swallowed whole and should not be crushed, chewed, or cut.74

If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1,14,71,72,73,74,75 If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.1,14,71,72,73,74,75

Dosage

Type 2 Diabetes Mellitus

Empagliflozin Monotherapy

The recommended dosage of empagliflozin for the management of type 2 diabetes mellitus in adults is 10 mg once daily in the morning.1 If this dosage is well tolerated, the dosage may be increased to 25 mg once daily in patients who require additional glycemic control.1

Empagliflozin/Linagliptin Fixed-combination Therapy

The recommended dosage of the fixed-combination preparation is 10 mg of empagliflozin and 5 mg of linagliptin once daily in the morning.70 If this dosage is well tolerated, the dosage may be increased to 25 mg of empagliflozin and 5 mg of linagliptin once daily.70

Empagliflozin/Metformin Hydrochloride Fixed-combination Therapy

The dosage of empagliflozin in fixed combination with metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen.72,74 The dosage of the fixed-combination preparation may be increased gradually based on effectiveness and tolerability up to a maximum of 25 mg of empagliflozin and 2 g of metformin hydrochloride daily.72,74

In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 10 mg of empagliflozin and a metformin hydrochloride dosage similar to the patient's existing total daily dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).72,74

In patients currently receiving empagliflozin, the recommended initial total daily dosage of the fixed combination is the same daily dosage of empagliflozin and 1 g metformin hydrochloride, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).72,74

In patients currently receiving both empagliflozin and metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is the same daily dosage of empagliflozin and a metformin hydrochloride dosage similar to the patient's total daily existing dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).72,74

Special Populations

Body mass index, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of empagliflozin.1

Hepatic Impairment

Empagliflozin Monotherapy

Empagliflozin may be used in patients with hepatic impairment.1 No dosage adjustment is necessary in patients with mild, moderate, or severe hepatic impairment.13

Empagliflozin/Linagliptin Fixed-combination Therapy

The fixed combination of empagliflozin and linagliptin may be used in patients with hepatic impairment.70

Empagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Use of the fixed-combination preparation of empagliflozin and immediate- or extended-release metformin hydrochloride is not recommended in patients with hepatic impairment.72,74

Renal Impairment

Empagliflozin Monotherapy

No dosage adjustment is necessary in patients with an estimated glomerular filtration rate (eGFR) of at least 45 mL/minute per 1.73 m².1 Empagliflozin should not be initiated in patients with an eGFR of less than 45 mL/minute per 1.73 m².1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) The drug should be discontinued if the eGFR is persistently less than 45 mL/minute per 1.73 m².1 Renal function should be assessed before initiating empagliflozin and during therapy.1 More frequent monitoring is recommended in patients with eGFR less than 60 mL/minute per 1.73 m².1

Empagliflozin/Linagliptin Fixed-combination Therapy

No dosage adjustment is necessary in patients with an eGFR of at least 45 mL/minute per 1.73 m².70 The fixed combination should not be initiated in patients with an eGFR less than 45 mL/minute per 1.73 m².70 The fixed-combination preparation should be discontinued if the eGFR is persistently less than 45 mL/minute per 1.73 m².70

Empagliflozin/Metformin Hydrochloride Fixed-combination Therapy

No dosage adjustment is necessary in patients with an eGFR of at least 45 mL/minute per 1.73 m².72,74 Use of the fixed-combination preparation of empagliflozin and immediate- or extended-release metformin hydrochloride is contraindicated in patients with an eGFR less than 45 mL/minute per 1.73 m².72,74

Geriatric Patients

Empagliflozin Monotherapy

No dosage adjustment is necessary based solely on age.1

Empagliflozin/Metformin Hydrochloride Fixed-combination Therapy

Renal function should be monitored frequently after initiating the fixed-combination preparation of empagliflozin and immediate- or extended-release metformin hydrochloride.72,74

Contraindications

History of serious hypersensitivity reaction to empagliflozin or any ingredient in the formulation.1

Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m²), end-stage renal disease, or dialysis.1

Warnings/Precautions

Ketoacidosis

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization.1,39,40,41,42,50 Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).1,39,40,41,42,50

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015 .40,41,50 DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication was not specified.39,40,50 The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days).50 No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified.50 In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted.39,50 In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported.50 Most cases of ketoacidosis were associated with a concurrent event, most commonly dehydration, infection, or change in insulin dosage.50 Potential factors for the development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.1,50

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to ketoacidosis such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse.1,50

Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration.39,40,50 For patients who undergo scheduled surgery, temporary discontinuation of empagliflozin for at least 3 days prior to surgery should be considered.1 Clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in other clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).1,50 If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately.39,40,50 In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis.39 Risk factors for the development of ketoacidosis should be resolved prior to restarting empagliflozin therapy.1

Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations.1,40,42,50 Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.1,39,42,50

Hypotension

Empagliflozin causes intravascular volume contraction.1 Following initiation of empagliflozin, symptomatic hypotension may occur, particularly in patients with impaired renal function, geriatric patients, patients with low systolic blood pressure, or patients receiving diuretics.1 (See Drug Interactions: Diuretics.) Prior to initiating empagliflozin, intravascular volume should be assessed and corrected if necessary.1 Patients should be monitored for signs and symptoms of hypotension after initiating therapy; monitoring should be increased in clinical situations in which volume contraction is expected.1

Renal Effects

Empagliflozin causes intravascular volume contraction and can cause renal impairment.1 Empagliflozin may increase serum creatinine concentration and decrease eGFR; patients with hypovolemia may be more susceptible to these changes.1 Abnormalities in renal function can occur following initiation of the drug.1 Patients should be monitored for acute kidney injury, and more frequent monitoring is recommended for patients with an eGFR less than 60 mL/minute per 1.73 m².1 If acute kidney injury occurs during empagliflozin therapy, the drug should be discontinued and appropriate therapy initiated.1

There have been postmarketing reports of acute kidney injury in patients receiving SGLT2 inhibitors, including empagliflozin.1 FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in FAERS between March 2013 and October 2015.51 Hospitalization for evaluation and management of kidney injury was warranted in most cases, and in some cases required admission to an intensive care unit and initiation of dialysis.1,51 In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating canagliflozin or dapagliflozin therapy, and most patients' kidney function improved after stopping the drug.51

Prior to initiating empagliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant drug therapy (e.g., diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]).1,51 Clinicians should consider temporarily discontinuing empagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).1,51

Concomitant Therapy with Hypoglycemic Agents

When empagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the risk of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1 Therefore, patients receiving empagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Fournier Gangrene

Fournier gangrene (necrotizing fasciitis of the perineum), a rare but serious or life-threatening bacterial infection requiring urgent surgical intervention, has been reported during postmarketing surveillance in men and women with type 2 diabetes mellitus receiving an SGLT2 inhibitor, including empagliflozin.1,60 Permanent disfigurement, prolonged hospitalization, disability, and complications from sepsis all may be associated with Fournier gangrene.59 Although diabetes mellitus is a risk factor for developing Fournier gangrene, this condition is still rare among patients with diabetes mellitus.60

FDA identified 12 cases of Fournier gangrene in patients taking an SGLT2 inhibitor reported in FAERS and the medical literature between March 2013 and May 2018.60,61,62 Since FDA's review, additional cases of Fournier gangrene have been reported.59 In the initial cases reviewed by FDA, the average time to onset of infection was 9.2 months (range 7 days to 25 months) after initiation of therapy with an SGLT2 inhibitor.60 Some experts speculate that the variation in time to diagnosis of Fournier gangrene might be due to fluctuating glycemic control, microvascular complications, or an inciting event associated with SGLT2 inhibitors (e.g., urinary tract infection, mycotic infection, skin or mucosal breakdown due to pruritus).59 In all reported cases, hospitalization and surgery were required.60 Among these cases, some patients required multiple disfiguring surgeries, some developed complications (e.g., diabetic ketoacidosis, acute kidney injury, septic shock), and 1 patient died.60 In a review of other antidiabetic drugs (e.g., insulin, biguanides, sulfonylureas, dipeptidyl peptidase-4 inhibitors) over a period of more than 30 years, only 6 cases of Fournier gangrene were identified; all of theses cases occurred in men.60

Patients receiving empagliflozin who develop pain or tenderness, erythema, or swelling in the genital or perineal area, in addition to fever or malaise, should be assessed for necrotizing fasciitis.1,60 If Fournier gangrene is suspected, empagliflozin should be discontinued and treatment should be initiated with broad-spectrum antibiotics; surgical debridement should be performed if necessary.1,60 Blood glucose concentrations should be closely monitored; alternative antidiabetic agents should be initiated to maintain glycemic control.1,60

Genital Mycotic Infections

Empagliflozin may increase the risk of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital fungal infection, vulvovaginal candidiasis, fungal vulvitis).1 In clinical trials, patients with a history of chronic or recurrent genital mycotic infections were more likely to develop such infections.1 Genital mycotic infections also occurred more frequently in female than male patients.1 Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.1

Urosepsis and Pyelonephritis

Empagliflozin may increase the risk of serious urinary tract infections.1

FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014.50 In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment.50 The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).50 In clinical studies of empagliflozin, urinary tract infections occurred more frequently in female patients compared with male patients, and risk of urinary tract infections increased in patients 75 years of age or older.1 Patients with a history of chronic or recurrent urinary tract infections were also more likely to develop such infections.1

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to serious urinary tract infections such as a history of difficulty urinating; or infections of the bladder, kidneys, or urinary tract.50 Patients should be monitored for urinary tract infections and treatment instituted if indicated.1,50

Effects on Lipoproteins

Dose-related increases in low-density lipoprotein (LDL)-cholesterol concentration have been observed during empagliflozin therapy.1 Serum LDL-cholesterol concentrations should be monitored during treatment with empagliflozin and such lipid elevations should be treated according to the standard of care.1

Potential Risk of Bone Fracture

An increased risk of bone fracture, along with dose-related decreases in bone mineral density in older adults, has been observed in patients receiving another drug in the SGLT2 inhibitor class (canagliflozin).43 (See Risk of Bone Fracture under Cautions: Warnings/Precautions, in Canagliflozin.) FDA is continuing to evaluate the risk of bone fracture with SGLT2 inhibitors.43

Laboratory Test Interferences

SGLT2 inhibitors such as empagliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests.1 Data from healthy volunteers receiving a single 10- or 25-mg dose of empagliflozin indicate the elevation in urinary glucose excretion approaches baseline in approximately 3 days.1 In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors.1 Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.1

Use of Fixed Combinations

When empagliflozin is used in fixed combination with metformin hydrochloride, linagliptin, or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) must be considered in addition to those associated with empagliflozin.70,72,74

Sensitivity Reactions

Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been reported with empagliflozin treatment.1 If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.1 Empagliflozin is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin or any excipient in the drug formulation.1

Specific Populations

Pregnancy

Data on the use of empagliflozin in pregnant women are lacking.1 Based on the results of reproductive and developmental toxicity studies in animals, empagliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy.1 Limited data with empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus; however, empagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.1

Lactation

Empagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions in nursing infants from empagliflozin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of empagliflozin have not been established in pediatric patients younger than 18 years of age.1

Geriatric Use

In clinical studies, 2721 (32%) patients treated with empagliflozin were 65 years of age or older and 491 (6%) were 75 years of age or older.1 Geriatric patients with renal impairment are expected to experience reduced efficacy when treated with empagliflozin.1 The risk of volume depletion-related adverse effects and urinary tract infections is increased in patients 75 years of age or older.1

Hepatic Impairment

Empagliflozin may be used in patients with hepatic impairment.1 Compared with values in individuals with normal hepatic function, empagliflozin area under the concentration-time curve (AUC) was increased by approximately 23, 47, or 75% in patients with mild, moderate, or severe (Child-Pugh class A, B, or C) hepatic impairment, respectively;1 peak plasma concentrations of the drug in patients with mild, moderate, or severe hepatic function were increased by approximately 4, 23, or 48%, respectively.1,13

Renal Impairment

Safety and efficacy of empagliflozin were evaluated in a study that included patients with mild or moderate renal impairment.1 Of those who received empagliflozin, 195 patients had an eGFR of 60-90 mL/minute per 1.73 m², 91 patients had an eGFR of 45-60 mL/minute per 1.73 m², and 97 patients had an eGFR of 30-45 mL/minute per 1.73 m².1 The glucose-lowering effect of empagliflozin 25 mg was reduced in patients with worsening renal function.1 In addition, the risk of renal impairment and of adverse effects related to volume depletion, and urinary tract infection increased with worsening renal function.1

In patients with mild (eGFR 60 to less than 90 mL/minute per 1.73 m²), moderate (eGFR 30 to less than 60 mL/minute per 1.73 m²), or severe (eGFR less than 30 mL/minute per 1.73 m²) renal impairment, and in patients with renal failure/end-stage renal disease, AUC of empagliflozin increased by approximately 18, 20, 66, and 48%, respectively, compared with those with normal renal function.1 Peak plasma concentrations of empagliflozin were similar in patients with moderate renal impairment or renal failure/end-stage renal disease compared with those with normal renal function;1 however, peak plasma concentrations of empagliflozin were approximately 20% higher in patients with mild or severe renal impairment compared with such concentrations in individuals with normal renal function.1

Population pharmacokinetic studies demonstrated that the apparent oral clearance of empagliflozin was reduced, with a reduction in eGFR resulting in an increase in drug exposure.1 However, the fraction of empagliflozin excreted unchanged in urine and urinary glucose excretion declined with decrease in eGFR.1

Efficacy and safety of empagliflozin have not been established in patients with severe renal impairment or end-stage renal disease, or in those receiving dialysis; empagliflozin is not expected to be effective in these patients.1

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving empagliflozin in clinical trials and more commonly than with placebo include urinary tract infection,1,2,4,5,7,8,9 female genital mycotic infections,1 upper respiratory tract infection,1,4,5 increased urination,1 dyslipidemia,1 arthralgia,1 male genital mycotic infections,1 and nausea.1

Adverse effects reported in at least 5% of patients receiving empagliflozin and linagliptin in clinical trials include urinary tract infection,70 nasopharyngitis,70 and upper respiratory tract infection.70

Adverse effects reported in at least 5% of patients receiving empagliflozin concomitantly with metformin and a sulfonylurea include hypoglycemia,72 urinary tract infection,72 and nasopharyngitis.72

The major metabolic pathway for empagliflozin is glucuronidation; the drug is principally glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 2B7, 1A3, 1A8, and 1A9.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Empagliflozin did not inhibit, inactivate, or induce cytochrome P-450 (CYP) isoforms in vitro;1 no effect of empagliflozin is expected on concomitantly administered drugs that are substrates of the major CYP isoforms.1

Drugs Affecting or Affected by Organic Anion Transporters

Empagliflozin is a substrate of organic anion transporter (OAT) 3 and organic anion transport proteins (OATP) 1B1 and 1B3.1 Empagliflozin is not a substrate of OAT1.1 Empagliflozin does not inhibit any of these transporters at clinically relevant plasma concentrations, and no effect of empagliflozin is expected on concomitantly administered drugs that are substrates of these uptake transporters.1

Drugs Affecting or Affected by Organic Cation Transporters

Empagliflozin is not a substrate of organic cation transporter (OCT) 2, nor does it inhibit OCT2 at clinically relevant plasma concentrations; no effect of empagliflozin is expected on concomitantly administered drugs that are substrates of this uptake transporter.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase

Empagliflozin does not inhibit UGT isoenzymes 1A1, 1A3, 1A8, 1A9, or 2B7, and no effect of empagliflozin is expected on concomitantly administered drugs that are substrates of these UGT isoenzymes.1 The manufacturer states the effect of UGT induction on empagliflozin exposure has not been established.1

Drugs Affecting or Affected by P-glycoprotein Transport

Empagliflozin is a substrate of P-glycoprotein (P-gp), but it does not inhibit P-gp at therapeutic doses.1 Empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates based on in vitro studies.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Empagliflozin is a substrate of breast cancer resistance protein (BCRP), but it does not inhibit BCRP at therapeutic doses.1

Antidiabetic Agents

Concomitant use of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia.1 Patients receiving empagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Digoxin

Administration of a single dose of digoxin (0.5 mg) in healthy individuals receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of digoxin.1,10 No adjustment of digoxin dosage is necessary.10

Diuretics

Concomitant use of empagliflozin with diuretics may increase urine volume and frequency of urination, which may increase the risk of volume depletion.1 Patients should be assessed for volume contraction, and volume status should be corrected if indicated before initiating empagliflozin.1 Patients should be monitored for signs and symptoms of hypotension after initiating therapy, and monitoring should be increased in clinical situations where volume contraction is expected.1

Gemfibrozil

Concomitant administration of gemfibrozil 600 mg twice daily and a single dose of empagliflozin 25 mg resulted in an increase in area under the concentration-time curve (AUC) of empagliflozin, although this effect was not considered clinically relevant.1 No adjustment of empagliflozin dosage is necessary when administered with gemfibrozil.1

Glimepiride

Administration of a single dose of glimepiride (1 mg) in healthy individuals receiving empagliflozin 50 mg once daily did not have a clinically relevant effect on the pharmacokinetics of glimepiride or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10

Hormonal Contraceptives

Administration of 30 mcg of ethinyl estradiol once daily in healthy individuals receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of ethinyl estradiol.1,10 Also, concomitant administration of levonorgestrel 150 mcg once daily and empagliflozin 25 mg once daily had no clinically relevant effect on the pharmacokinetics of levonorgestrel.1,10 No adjustment of ethinyl estradiol or levonorgestrel dosage is necessary when administered concomitantly with empagliflozin.10

Hydrochlorothiazide

Administration of hydrochlorothiazide 25 mg once daily in healthy individuals receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of hydrochlorothiazide or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10 (See also Drug Interactions: Diuretics.)

Linagliptin

Administration of linagliptin 5 mg once daily in healthy individuals receiving empagliflozin 50 mg once daily did not have a clinically relevant effect on the pharmacokinetics of linagliptin or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10

Metformin

Administration of metformin hydrochloride 1 g twice daily in healthy individuals receiving empagliflozin 50 mg once daily did not have a clinically relevant effect on the pharmacokinetics of metformin or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10

Pioglitazone

Concomitant use of pioglitazone 45 mg once daily in healthy individuals receiving empagliflozin 50 mg once daily did not have a clinically relevant effect on the pharmacokinetics of empagliflozin.1 Similarly, administration of pioglitazone 45 mg once daily in patients receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of pioglitazone.1 No adjustment of empagliflozin dosage is necessary.1

Probenecid

Concomitant use of probenecid 500 mg twice daily in healthy individuals receiving a single dose of empagliflozin 10 mg resulted in an increase in AUC of empagliflozin.1 However, this effect was not clinically relevant.1 No adjustment of empagliflozin dosage is necessary when administered with probenecid.1 In patients with normal renal function, concomitant use of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion.1 The manufacturer states that the relevance of this observation to patients with renal impairment is not known.1

Ramipril

Concomitant use of ramipril 5 mg once daily in healthy individuals receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of ramipril or its active metabolite ramiprilat, or on empagliflozin pharmacokinetics.1,10 No adjustment of ramipril or empagliflozin dosage is necessary.10

Rifampin

Administration of a single dose of rifampin 600 mg in healthy individuals also receiving a single dose of empagliflozin 10 mg resulted in an increase in AUC of empagliflozin.1 However, this effect was not clinically relevant.1 No adjustment of empagliflozin dosage is necessary when administered with rifampin.1

Simvastatin

Administration of a single dose of simvastatin 40 mg in healthy individuals also receiving a single dose of empagliflozin 25 mg did not have a clinically relevant effect on the pharmacokinetics of simvastatin or its active metabolite simvastatin acid, or on empagliflozin pharmacokinetics.1,10 No adjustment of simvastatin or empagliflozin dosage is necessary.10

Sitagliptin

Concomitant administration of sitagliptin 100 mg once daily in healthy individuals receiving empagliflozin 50 mg once daily did not have a clinically relevant effect on the pharmacokinetics of sitagliptin or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10

Torsemide

Concomitant use of torsemide 5 mg once daily in healthy individuals receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of torsemide or empagliflozin.1,10 No adjustment in either drug's dosage is necessary.10

Verapamil

Administration of a single dose of verapamil 120 mg in healthy individuals also receiving a single dose of empagliflozin 25 mg did not have a clinically relevant effect on the pharmacokinetics of empagliflozin.1,10 No adjustment of verapamil dosage is necessary.10

Warfarin

Administration of a single dose (25 mg) of warfarin sodium in healthy individuals also receiving empagliflozin 25 mg once daily did not have a clinically relevant effect on the pharmacokinetics of R - or S -warfarin1,10 or on the pharmacokinetics of empagliflozin.1,10,13 No adjustment in either drug's dosage is necessary.10

Description

Empagliflozin is an orally active inhibitor of sodium-glucose cotransporter 2 (SGLT2), the transporter principally responsible for the reabsorption of glucose from the glomerular filtrate back into the circulation.1,11,12 Through inhibition of SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion and reducing blood glucose concentrations, independent of insulin secretion.1,11,12

Following oral administration of empagliflozin 10 or 25 mg under fasting conditions, empagliflozin is rapidly absorbed; median time to peak plasma concentration of the drug was 1 hour for both doses.13 Empagliflozin exposure increased in proportion to the dose.1,13 Administration of empagliflozin 25 mg following intake of a high-fat and high-calorie meal resulted in slightly lower exposure.1 Peak concentration and area under the concentration-time curve decreased by approximately 37 and 16%, respectively, compared with fasting conditions.1 Effect of food on empagliflozin pharmacokinetics was not considered clinically relevant, and empagliflozin can be administered with or without food.1 Empagliflozin is 86.2% bound to plasma proteins.1 The apparent terminal elimination half-life of empagliflozin is approximately 12.4 hours.1 Following administration of a radiolabeled dose of empagliflozin, 41.2% of the administered dose was eliminated in feces and 54.4% was eliminated in urine.1

Results of bioequivalence studies indicate that the fixed-combination tablets containing empagliflozin and immediate-release metformin hydrochloride or empagliflozin and linagliptin are bioequivalent to corresponding doses of empagliflozin, metformin hydrochloride, or linagliptin given concurrently as individual tablets.70,72

Advice to Patients

When empagliflozin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1,70,72,74

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,14,70,71,72,73,74,75

Importance of informing patients of the potential risks and benefits of empagliflozin and of alternative therapies.1 Importance of informing patients that use of empagliflozin with other antidiabetic agents may increase risk of hypoglycemia.1,14 Importance of not using empagliflozin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

Importance of informing patients that ketoacidosis, which can be a life-threatening condition, has been reported with empagliflozin therapy (sometimes associated with illness or surgery among other risk factors).1,14 Importance of informing patients receiving empagliflozin and their caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes).1,14,39,42,50 If signs or symptoms of acidosis occur, importance of discontinuing empagliflozin and seeking medical attention immediately.50 Advise patients to use a ketone dipstick to check for ketones in their urine (when possible) if symptoms of ketoacidosis occur, even if blood glucose is not elevated (e.g., less than 250 mg/dL).1,14,50

Importance of informing patients that hypotension may occur with empagliflozin and to report such symptoms to their clinicians.1,14 Inform patients that empagliflozin-induced dehydration may increase the risk of hypotension and that patients should maintain adequate fluid intake.1,14

Importance of informing patients that acute kidney injury has been reported with empagliflozin therapy.1 Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue empagliflozin in those situations.1

Importance of informing female patients that vaginal yeast infections (e.g., vulvovaginitis) may occur.1,14 Importance of informing male patients that yeast infections may occur (e.g., balanitis, balanoposthitis), especially in uncircumcised males.1,14 Importance of informing patients that yeast infections occur more frequently in females and in patients with chronic and recurrent infections.1 Importance of informing female patients of the signs and symptoms of vaginal yeast infections (e.g., vaginal discharge, odor, itching) and male patients of the signs and symptoms of balanitis or balanoposthitis (e.g. rash or redness of the glans or foreskin of the penis, foul-smelling discharge from the penis, pain in skin around penis).1,14 Advise patients of treatment options and when to seek medical advice.1

Importance of informing patients of the potential for urinary tract infections, which may be serious, with empagliflozin therapy.1,14,50 Advise patients of the signs and symptoms of urinary tract infection (e.g., dysuria, cloudy urine, pelvic or back pain) and the need to contact a clinician if such signs and symptoms occur.1,14,50

Importance of informing patients that necrotizing infections of the perineum (Fournier gangrene) have occurred with empagliflozin therapy.1,60 Advise patients to seek prompt medical attention if they experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, occurring with a fever above 38°C or malaise.1,60

Risk of serious hypersensitivity reactions, such as urticaria and angioedema.1 If signs or symptoms of such reactions occur, importance of discontinuing empagliflozin and informing clinician promptly.1

Importance of informing patients that due to the mechanism of action of empagliflozin, patients taking the drug will test positive for glucose in urine.1,14 Importance of not using urine glucose tests to monitor glycemic status while taking empagliflozin.1 (See Laboratory Test Interferences under Cautions: Warnings/Precautions.)

Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1,14

Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as drug dosage requirements may change.1,14

Importance of informing patient not to take empagliflozin if allergic to the drug or any ingredients in the formulation.1,14

Importance of taking empagliflozin exactly as directed by clinician.14 Importance of informing patients that if a dose is missed, it should be taken as soon as remembered; the dose should not be doubled to make up for the missed dose.1,14 (See Dosage and Administration: Administration.)

Importance of informing patients that renal function should be assessed prior to initiation of empagliflozin and monitored periodically thereafter.1

Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1,14

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,14

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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