JARDIANCE 25 MG TABLET

Uses Dosage and Administration Cautions Drug Interactions

Uses

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. Empagliflozin is also 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.

Empagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

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. 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). 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. Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily with no placebo run-in phase. 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. The primary end point of the study was change from baseline in HbA_1c at week 24. 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. 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. 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.

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. 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. Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg once daily without a placebo run-in phase. 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. The primary end point of the study was change from baseline in HbA_1c at week 24. 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. 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. 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.

Efficacy and safety of the combination of empagliflozin and metformin hydrochloride as initial therapy in treatment-naive patients with type 2 diabetes mellitus is supported by results of a 24-week, randomized, double-blind trial. 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. 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.

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. Patients with HbA_1c concentrations exceeding 10% were assigned open-label treatment with empagliflozin 25 mg. 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. The primary end point of the study was change from baseline in HbA_1c at week 24. 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. 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. 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.

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. 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. The primary end point was change from baseline in HbA_1c concentrations at weeks 52 and 104. 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. 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. 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. 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). 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.

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. 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. The primary end point was change from baseline in HbA_1c concentrations at week 24. 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. 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. 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.

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). 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. Glycemic efficacy (HbA_1c reductions) with the fixed combinations of empagliflozin/linagliptin was maintained at week 52. The fixed combinations of empagliflozin and linagliptin also were associated with reductions from baseline in systolic blood pressure compared with linagliptin monotherapy. Body weight was reduced in patients receiving the fixed combinations of empagliflozin/linagliptin compared with linagliptin but not empagliflozin monotherapy.

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. 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. 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. 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. 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. 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. 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. 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.

In a randomized, double-blind, placebo-controlled, international study in 563 obese patients (body mass index [BMI] of 30-45 kg/m) 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. 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. 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). 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. The primary end point of the study was change from baseline in HbA_1c at week 18. 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. 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. 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.

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. Patients with an estimated glomerular filtration rate (eGFR) of 60-89 mL/minute per 1.73 m (mild renal impairment) received empagliflozin 10 or 25 mg or placebo once daily in addition to existing antidiabetic therapy. Patients with an eGFR of 30-59 mL/minute per 1.73 m (moderate renal impairment) or 15-29 mL/minute per 1.73 m (severe renal impairment) received empagliflozin 25 mg once daily or placebo. The primary end point was change from baseline in HbA_1c at week 24. 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. 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. Antihyperglycemic efficacy of empagliflozin 25 mg was reduced with decreasing level of renal function in the mild to moderate range. 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 m, 45-59 mL/minute per 1.73 m, and 30-44 mL/minute per 1.73 m , respectively, for patients receiving empagliflozin 25 mg. 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 m or 30-44 mL/minute per 1.73 m, respectively, and decreased by 0.1% in patients with a baseline eGFR of 45-59 mL/minute per 1.73 m for patients receiving placebo. 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.

Dosage and Administration

General

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

Administration

Empagliflozin is administered orally once daily in the morning, with or without food.

If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. 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.

Dosage

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

Special Populations

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

No dosage adjustment is necessary in patients with an estimated glomerular filtration rate (eGFR) of at least 45 mL/minute per 1.73 m. Empagliflozin should not be initiated in patients with an eGFR of less than 45 mL/minute per 1.73 m.(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 m. Renal function should be assessed before initiating empagliflozin and during therapy. More frequent monitoring is recommended in patients with eGFR less than 60 mL/minute per 1.73 m.

No dosage adjustment is necessary based solely on age. In addition, body mass index, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of empagliflozin.

Cautions

Contraindications

History of serious hypersensitivity reaction to empagliflozin.

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

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. Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).

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 . 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. 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). No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified. 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. 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. Most cases of ketoacidosis were associated with a concurrent event, most commonly dehydration, infection, or change in insulin dosage. 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 (due to illness or 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.

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. 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. Additionally, clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately. In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis. Some clinicians suggest that 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. 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.

Hypotension

Empagliflozin causes intravascular volume contraction. 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.(See Drug Interactions: Diuretics.) Prior to initiating empagliflozin, intravascular volume should be assessed and corrected if necessary. 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.

Renal Effects

Empagliflozin may increase serum creatinine concentration and decrease eGFR. Acute kidney injury has been reported with other SGLT2 inhibitors (canagliflozin, dapagliflozin). The risk of impaired renal function is increased in geriatric patients and patients with moderate renal impairment, and more frequent monitoring is recommended in these patients. Renal function should be evaluated prior to initiation of empagliflozin and periodically thereafter.

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. Therefore, patients receiving empagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.

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). In clinical trials, patients with a history of chronic or recurrent genital mycotic infections were more likely to develop such infections. Genital mycotic infections also occurred more frequently in female than male patients. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.

Urosepsis and Pyelonephritis

Empagliflozin may increase the risk of serious urinary tract infections.

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. In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment. The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days). 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. Patients with a history of chronic or recurrent urinary tract infections were also more likely to develop such infections.

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. Patients should be monitored for urinary tract infections and treatment instituted if indicated.

Effects on Lipoproteins

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

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). FDA is continuing to evaluate the risk of bone fracture with SGLT2 inhibitors.

Macrovascular Outcomes

Evidence of macrovascular risk reduction with empagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.

Laboratory Test Interferences

SGLT2 inhibitors such as empagliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests. In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors. Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.

Specific Populations

Pregnancy

Category C.

There are no adequate and well-controlled studies using empagliflozin in pregnant women. In studies conducted in rats, empagliflozin crossed the placenta and reached fetal tissues. Based on results of reproductive and developmental toxicity studies in animals, empagliflozin use during pregnancy may affect renal development and maturation. During pregnancy, appropriate alternative therapies should be considered, especially during the second and third trimesters. Empagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Empagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk. 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.

Pediatric Use

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

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. Geriatric patients with renal impairment are expected to experience reduced efficacy when treated with empagliflozin. The risk of volume depletion-related adverse effects and urinary tract infections is increased in patients 75 years of age or older.

Hepatic Impairment

Empagliflozin may be used in patients with hepatic impairment. 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; peak plasma concentrations of the drug in patients with mild, moderate, or severe hepatic function were increased by approximately 4, 23, or 48%, respectively.

Renal Impairment

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

In patients with mild (eGFR 60 to less than 90 mL/minute per 1.73 m), moderate (eGFR 30 to less than 60 mL/minute per 1.73 m), or severe (eGFR less than 30 mL/minute per 1.73 m) 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. 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; 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.

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. However, the fraction of empagliflozin excreted unchanged in urine and urinary glucose excretion declined with decrease in eGFR.

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.

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, female genital mycotic infections, upper respiratory tract infection, increased urination, dyslipidemia, arthralgia, male genital mycotic infections, and nausea.

Drug Interactions

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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. Empagliflozin is not a substrate of OAT1. 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.

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.

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. The manufacturer states the effect of UGT induction on empagliflozin exposure has not been established.

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. Empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates based on in vitro studies.

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.

Antidiabetic Agents

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

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. No adjustment of digoxin dosage is necessary.

Diuretics

Concomitant use of empagliflozin with diuretics may increase urine volume and frequency of urination, which may increase the risk of volume depletion. Patients should be assessed for volume contraction, and volume status should be corrected if indicated before initiating empagliflozin. 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.

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. No adjustment of empagliflozin dosage is necessary when administered with gemfibrozil.

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. No adjustment in either drug's dosage is necessary.

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. 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. No adjustment of ethinyl estradiol or levonorgestrel dosage is necessary when administered concomitantly with empagliflozin.

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. No adjustment in either drug's dosage is necessary.(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. No adjustment in either drug's dosage is necessary.

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. No adjustment in either drug's dosage is necessary.

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. 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. No adjustment of empagliflozin dosage is necessary.

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. However, this effect was not clinically relevant. No adjustment of empagliflozin dosage is necessary when administered with probenecid. 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. The manufacturer states that the relevance of this observation to patients with renal impairment is not known.

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. No adjustment of ramipril or empagliflozin dosage is necessary.

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. However, this effect was not clinically relevant. No adjustment of empagliflozin dosage is necessary when administered with rifampin.

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. No adjustment of simvastatin or empagliflozin dosage is necessary.

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. No adjustment in either drug's dosage is necessary.

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. No adjustment in either drug's dosage is necessary.

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. No adjustment of verapamil dosage is necessary.

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-warfarin or on the pharmacokinetics of empagliflozin. No adjustment in either drug's dosage is necessary.

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