{"adverse_reactions":["6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling : Ketoacidosis [see Warnings and Precautions ( 5.1 )] Volume Depletion [see Warnings and Precautions ( 5.2 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.3 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions ( 5.5 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] The most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infections and female genital mycotic infections ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Patients with Type 2 Diabetes Mellitus The data in Table 1 are derived from a pool of four 24 week placebo-controlled trials and 18 week data from a placebo-controlled trial with insulin in patients with type 2 diabetes. Empagliflozin was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies ( 14 )] . These data reflect exposure of 1,976 patients to empagliflozin with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), empagliflozin 10 mg (N=999), or empagliflozin 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m 2 ). Table 1 shows common adverse reactions (excluding hypoglycemia) associated with the use of empagliflozin. The adverse reactions were not present at baseline, occurred more commonly on empagliflozin than on placebo and occurred in greater than or equal to 2% of patients treated with empagliflozin 10 mg or empagliflozin 25 mg. Table 1 Adverse Reactions Reported in ≥ 2% of Patients Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Empagliflozin Monotherapy or Combination Therapy a Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis b Female genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), empagliflozin 10 mg (N=443), empagliflozin 25 mg (N=420). c Predefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia d Male genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), empagliflozin 10 mg (N=556), empagliflozin 25 mg (N=557). Adverse Reactions Placebo (%) N=995 Empagliflozin 10 mg (%) N=999 Empagliflozin 25 mg (%) N=977 Urinary tract infection a 7.6 9.3 7.6 Female genital mycotic infections b 1.5 5.4 6.4 Upper respiratory tract infection 3.8 3.1 4 Increased urination c 1 3.4 3.2 Dyslipidemia 3.4 3.9 2.9 Arthralgia 2.2 2.4 2.3 Male genital mycotic infections d 0.4 3.1 1.6 Nausea 1.4 2.3 1.1 Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Volume Depletion Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin may increase the risk of hypotension in patients at risk for volume contraction [see Use in Specific Populations ( 8.5 , 8.6 )]. Increased Urination In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on empagliflozin than on placebo (see Table 1). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Hypoglycemia The incidence of hypoglycemia by study is shown in Table 2. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea. Table 2 Incidence of Overall a and Severe b Hypoglycemic Events in Placebo-Controlled Clinical Studies c a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL b Severe hypoglycemic events: requiring assistance regardless of blood glucose c Treated set (patients who had received at least one dose of study drug) d Insulin dose could not be adjusted during the initial 18 week treatment period Monotherapy (24 weeks) Placebo (n=229) Empagliflozin 10 mg (n=224) Empagliflozin 25 mg (n=223) Overall (%) 0.4 0.4 0.4 Severe (%) 0 0 0 In Combination with Metformin (24 weeks) Placebo + Metformin (n=206) Empagliflozin 10 mg + Metformin (n=217) Empagliflozin 25 mg + Metformin (n=214) Overall (%) 0.5 1.8 1.4 Severe (%) 0 0 0 In Combination with Metformin + Sulfonylurea (24 weeks) Placebo (n=225) Empagliflozin 10 mg + Metformin + Sulfonylurea (n=224) Empagliflozin 25 mg + Metformin + Sulfonylurea (n=217) Overall (%) 8.4 16.1 11.5 Severe (%) 0 0 0 In Combination with Pioglitazone +/- Metformin (24 weeks) Placebo (n=165) Empagliflozin 10 mg + Pioglitazone +/- Metformin (n=165) Empagliflozin 25 mg + Pioglitazone +/- Metformin (n=168) Overall (%) 1.8 1.2 2.4 Severe (%) 0 0 0 In Combination with Basal Insulin +/- Metformin (18 weeks d ) Placebo (n=170) Empagliflozin 10 mg (n=169) Empagliflozin 25 mg (n=155) Overall (%) 20.6 19.5 28.4 Severe (%) 0 0 1.3 In Combination with MDI Insulin +/-Metformin (18 weeks d ) Placebo (n=188) Empagliflozin 10 mg (n=186) Empagliflozin 25 mg (n=189) Overall (%) 37.2 39.8 41.3 Severe (%) 0.5 0.5 0.5 G e n it a l Mycotic Infections In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with empagliflozin compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either empagliflozin 10 mg or 25 mg. Genital mycotic infections occurred more frequently in female than male patients (see Table 1). Phimosis occurred more frequently in male patients treated with empagliflozin 10 mg (less than 0.1%) and empagliflozin 25 mg (0.1%) than placebo (0%). Urinary Tract Infections In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with empagliflozin compared to placebo (see Table 1). Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 16.6%, 18.4%, and 17%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Use in Specific Populations ( 8.5 )] . Laboratory Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m 2 , respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with empagliflozin. Increase in Low-Density Lipoprotein Cholesterol (LDL-C) Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 mg/dL to 90.6 mg/dL across treatment groups. Increase in Hematocrit In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of empagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Constipation Infections: Necrotizing fasciitis of the perineum (Fournier's gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria)"],"adverse_reactions_table":["
Table 1 Adverse Reactions Reported in ≥ 2% of Patients Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Empagliflozin Monotherapy or Combination Therapy
a Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
b Female genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), empagliflozin
10 mg (N=443), empagliflozin 25 mg (N=420).
c Predefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia
d Male genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), empagliflozin 10 mg (N=556), empagliflozin 25 mg (N=557).
Adverse Reactions Placebo (%) N=995 Empagliflozin 10 mg (%) N=999 Empagliflozin 25 mg (%) N=977
Urinary tract infectiona 7.6 9.3 7.6
Female genital mycotic infectionsb 1.5 5.4 6.4
Upper respiratory tract infection 3.8 3.1 4
Increased urinationc 1 3.4 3.2
Dyslipidemia 3.4 3.9 2.9
Arthralgia 2.2 2.4 2.3
Male genital mycotic infectionsd 0.4 3.1 1.6
Nausea 1.4 2.3 1.1
","
Table 2 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc
a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL
b Severe hypoglycemic events: requiring assistance regardless of blood glucose
c Treated set (patients who had received at least one dose of study drug)
d Insulin dose could not be adjusted during the initial 18 week treatment period
Monotherapy (24 weeks) Placebo (n=229) Empagliflozin 10 mg (n=224) Empagliflozin 25 mg (n=223)
Overall (%) 0.4 0.4 0.4
Severe (%) 0 0 0
In Combination with Metformin (24 weeks) Placebo + Metformin (n=206) Empagliflozin 10 mg + Metformin (n=217) Empagliflozin 25 mg + Metformin (n=214)
Overall (%) 0.5 1.8 1.4
Severe (%) 0 0 0
In Combination with Metformin + Sulfonylurea (24 weeks) Placebo (n=225) Empagliflozin 10 mg + Metformin + Sulfonylurea (n=224) Empagliflozin 25 mg + Metformin + Sulfonylurea (n=217)
Overall (%) 8.4 16.1 11.5
Severe (%) 0 0 0
In Combination with Pioglitazone +/- Metformin (24 weeks) Placebo (n=165) Empagliflozin 10 mg + Pioglitazone +/- Metformin (n=165) Empagliflozin 25 mg + Pioglitazone +/- Metformin (n=168)
Overall (%) 1.8 1.2 2.4
Severe (%) 0 0 0
In Combination with Basal Insulin +/- Metformin (18 weeksd) Placebo (n=170) Empagliflozin 10 mg (n=169) Empagliflozin 25 mg (n=155)
Overall (%) 20.6 19.5 28.4
Severe (%) 0 0 1.3
In Combination with MDI Insulin +/-Metformin (18 weeksd) Placebo (n=188) Empagliflozin 10 mg (n=186) Empagliflozin 25 mg (n=189)
Overall (%) 37.2 39.8 41.3
Severe (%) 0.5 0.5 0.5
"],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions such as lowering both pre-and afterload of the heart and downregulating sympathetic activity. 12.2 Pharmacodynamics Urinary Glucose Excretion In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4 week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies ( 14 )] . Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg and 25 mg doses. Urinary Volume In a 5 day study, mean 24 hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment. Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin. 12.3 Pharmacokinetics Absorption The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma AUC and C max were 1,870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4,740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C max decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food. Distribution The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [ 14 C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%. Elimination The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Metabolism No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Excretion Following administration of an oral [ 14 C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug. Specific Populations Renal Impairment In patients with type 2 diabetes mellitus with mild (eGFR: 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 ), moderate (eGFR: 30 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 ), and severe (eGFR: less than 30 mL/min/1.73 m 2 ) renal impairment and patients on dialysis due to kidney failure, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and patients on dialysis due to kidney failure compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR. Hepatic Impairment In patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and C max increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Effects of Age, Body Mass Index, Gender, and Race Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations ( 8.5 )] . Drug Interactions In vitro Assessment of Drug Interactions Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters. In vivo Assessment of Drug Interactions Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes (see Figure 1). In subjects with normal renal function, coadministration 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 relevance of this observation to patients with renal impairment is unknown. Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% to 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, single dose; c empagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2). Figure 2 Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% to 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, once daily; c empagliflozin, 25 mg, single dose; d administered as simvastatin; e administered as warfarin racemic mixture; f administered as Microgynon ® ; g administered as ramipril Image Image"],"clinical_studies":["14 CLINICAL STUDIES Glycemic Control in Patients with Type 2 Diabetes Mellitus Empagliflozin has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone and insulin. Empagliflozin has also been studied in patients with type 2 diabetes with mild or moderate renal impairment. In patients with type 2 diabetes, treatment with empagliflozin reduced hemoglobin A1c (HbA1c), compared to placebo. The reduction in HbA1c for empagliflozin compared with placebo was observed across subgroups including gender, race, geographic region, baseline BMI and duration of disease. Monotherapy A total of 986 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin monotherapy. Treatment-naïve patients with inadequately controlled type 2 diabetes entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10% were randomized to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or a reference comparator. At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value < 0.0001), fasting plasma glucose (FPG), and body weight compared with placebo (see Table 4 and Figure 3). Table 4 Results at Week 24 From a Placebo-Controlled Monotherapy Study of Empagliflozin a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.4%, 9.4%, and 30.7% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA derived p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=223, for empagliflozin 25 mg, n=223, and for placebo, n=226 Empagliflozin 10 mg N=224 Empagliflozin 25 mg N=224 Placebo N=228 HbA1c (%) a Baseline (mean) 7.9 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.8 0.1 Difference from placebo (adjusted mean) (97.5% CI) -0.7 b (-0.9, -0.6) -0.9 b (-1, -0.7) -- Patients [n (%)] achieving HbA1c < 7% 72 (35%) 88 (44%) 25 (12%) FPG (mg/dL) c Baseline (mean) 153 153 155 Change from baseline (adjusted mean) -19 -25 12 Difference from placebo (adjusted mean) (95% CI) -31 (-37, -26) -36 (-42, -31) -- Body Weight Baseline (mean) in kg 78 78 78 % change from baseline (adjusted mean) -2.8 -3.2 -0.4 Difference from placebo (adjusted mean) (95% CI) -2.5 b (-3.1, -1.9) -2.8 b (-3.4, -2.2) -- Figure 3 Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT Population)-LOCF At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -2.6 mmHg (placebo-adjusted, p-value=0.0231) in patients randomized to 10 mg of empagliflozin and by -3.4 mmHg (placebo-corrected, p-value=0.0028) in patients randomized to 25 mg of empagliflozin. Add-On Combination Therapy with Metformin A total of 637 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin. Patients with type 2 diabetes inadequately controlled on at least 1,500 mg of metformin per day entered an open-label 2 week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg. At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value < 0.0001), FPG, and body weight compared with placebo (see Table 5). Table 5 Results at Week 24 From a Placebo-Controlled Study for Empagliflozin used in Combination with Metformin a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207 Empagliflozin 10 mg + Metformin N=217 Empagliflozin 25 mg + Metformin N=213 Placebo + Metformin N=207 HbA1c (%) a Baseline (mean) 7.9 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.8 -0.1 Difference from placebo + metformin (adjusted mean) (95% CI) -0.6 b (-0.7, -0.4) -0.6 b (-0.8, -0.5) -- Patients [n (%)] achieving HbA1c < 7% 75 (38%) 74 (39%) 23 (13%) FPG (mg/dL) c Baseline (mean) 155 149 156 Change from baseline (adjusted mean) -20 -22 6 Difference from placebo + metformin (adjusted mean) -26 -29 -- Body Weight Baseline mean in kg 82 82 80 % change from baseline (adjusted mean) -2.5 -2.9 -0.5 Difference from placebo (adjusted mean) (95% CI) -2 b (-2.6, -1.4) -2.5 b (-3.1, -1.9) -- At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value < 0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value < 0.0001) for empagliflozin 25 mg. Initial Combination Therapy with Metformin A total of 1,364 patients with type 2 diabetes participated in a double-blind, randomized, active-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin as initial therapy compared to the corresponding individual components. Treatment-naïve patients with inadequately controlled type 2 diabetes entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin. At Week 24, initial therapy of empagliflozin in combination with metformin provided statistically significant reductions in HbA1c (p-value < 0.01) compared to the individual components (see Table 6). Table 6 Glycemic Parameters at 24 Weeks in a Study Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy a Metformin total daily dose, administered in two equally divided doses per day. b p-value ≤ 0.0062 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c). c p-value ≤ 0.0056 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c). Empagliflozin 10 mg + Metformin 1,000 mg a N=161 Empagliflozin 10 mg + Metformin 2,000 mg a N=167 Empagliflozin 25 mg + Metformin 1,000 mg a N=165 Empagliflozin 25 mg + Metformin 2,000 mg a N=169 Empagliflozin 10 mg N=169 Empagliflozin 25 mg N=163 Metformin 1,000 mg a N=167 Metformin 2,000 mg a N=162 HbA1c (%) Baseline (mean) 8.7 8.7 8.8 8.7 8.6 8.9 8.7 8.6 Change from baseline (adjusted mean) -2 -2.1 -1.9 -2.1 -1.4 -1.4 -1.2 -1.8 Comparison vs empagliflozin (adjusted mean) (95% CI) -0.6 b (-0.9, -0.4) -0.7 b (-1, -0.5) -0.6 c (-0.8, -0.3) -0.7 c (-1, -0.5) -- -- -- -- Comparison vs metformin (adjusted mean) (95% CI) -0.8 b (-1, -0.6) -0.3 b (-0.6, -0.1) -0.8 c (-1, -0.5) -0.3 c (-0.6, -0.1) -- -- -- -- Add-On Combination Therapy with Metformin and Sulfonylurea A total of 666 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin plus a sulfonylurea. Patients with inadequately controlled type 2 diabetes on at least 1,500 mg per day of metformin and on a sulfonylurea, entered a 2 week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg. Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value < 0.0001), FPG, and body weight compared with placebo (see Table 7). Table 7 Results at Week 24 from a Placebo-Controlled Study for Empagliflozin in Combination with Metformin and Sulfonylurea a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224 Empagliflozin 10 mg + Metformin + SU N=225 Empagliflozin 25 mg + Metformin + SU N=216 Placebo + Metformin + SU N=225 HbA1c (%) a Baseline (mean) 8.1 8.1 8.2 Change from baseline (adjusted mean) -0.8 -0.8 -0.2 Difference from placebo (adjusted mean) (95% CI) -0.6 b (-0.8, -0.5) -0.6 b (-0.7, -0.4) -- Patients [n (%)] achieving HbA1c < 7% 55 (26%) 65 (32%) 20 (9%) FPG (mg/dL) c Baseline (mean) 151 156 152 Change from baseline (adjusted mean) -23 -23 6 Difference from placebo (adjusted mean) -29 -29 - Body Weight Baseline mean in kg 77 78 76 % change from baseline (adjusted mean) -2.9 -3.2 -0.5 Difference from placebo (adjusted mean) (95% CI) -2.4 b (-3, -1.8) -2.7 b (-3.3, -2.1) -- Active-Controlled Study versus Glimepiride in Combination with Metformin The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, study in 1,545 patients with type 2 diabetes with insufficient glycemic control despite metformin therapy. Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2 week run-in period were randomized to glimepiride or empagliflozin 25 mg. At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG (see Table 8, Figure 4). The difference in observed effect size between empagliflozin 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day. Table 8 Results at Week 52 from an Active-Controlled Study Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin a Modified intent to treat population. Last observation on study (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively. b Non-inferior, ANCOVA model p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region) c ANCOVA p-value < 0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) d FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779 Empagliflozin 25 mg + Metformin N=765 Glimepiride + Metformin N=780 HbA1c (%) a Baseline (mean) 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.7 Difference from glimepiride (adjusted mean) (97.5% CI) -0.07 b (-0.15, 0.01) -- FPG (mg/dL) d Baseline (mean) 150 150 Change from baseline (adjusted mean) -19 -9 Difference from glimepiride (adjusted mean) -11 -- Body Weight Baseline mean in kg 82.5 83 % change from baseline (adjusted mean) -3.9 2 Difference from glimepiride (adjusted mean) (95% CI) -5.9 c (-6.3, -5.5) -- Figure 4 Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population)-LOCF At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride. The differences between treatment groups for systolic blood pressure was statistically significant (p-value < 0.0001). At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for empagliflozin 25 mg and -0.66% for glimepiride. The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day. The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data. Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputed for empagliflozin 25 mg and 12.9% for glimepiride. At Week 104, empagliflozin 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for empagliflozin 25 mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value < 0.0001). Add-On Combination Therapy with Pioglitazone with or without Metformin A total of 498 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with pioglitazone, with or without metformin. Patients with inadequately controlled type 2 diabetes on metformin at a dose of at least 1,500 mg per day and pioglitazone at a dose of at least 30 mg per day were placed into an open-label placebo run-in for 2 weeks. Patients with inadequate glycemic control and an HbA1c between 7% and 10% after the run-in period were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg. Treatment with empagliflozin 10 mg or 25 mg daily resulted in statistically significant reductions in HbA1c (p-value < 0.0001), FPG, and body weight compared with placebo (see Table 9). Table 9 Results of Placebo-Controlled Study for Empagliflozin in Combination Therapy with Pioglitazone a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 10.9%, 8.3%, and 20.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=163 Empagliflozin 10 mg + Pioglitazone N=165 Empagliflozin 25 mg + Pioglitazone N=168 Placebo + Pioglitazone N=165 HbA1c (%) a Baseline (mean) 8.1 8.1 8.2 Change from baseline (adjusted mean) -0.6 -0.7 -0.1 Difference from placebo + pioglitazone (adjusted mean) (95% CI) -0.5 b (-0.7, -0.3) -0.6 b (-0.8, -0.4) -- Patients [n (%)] achieving HbA1c < 7% 36 (24%) 48 (30%) 12 (8%) FPG (mg/dL) c Baseline (mean) 152 152 152 Change from baseline (adjusted mean) -17 -22 7 Difference from placebo + pioglitazone (adjusted mean) (97.5% CI) -23 b (-31.8, -15.2) -28 b (-36.7, -20.2) -- Body Weight Baseline mean in kg 78 79 78 % change from baseline (adjusted mean) -2 -1.8 0.6 Difference from placebo (adjusted mean) (95% CI) -2.6 b (-3.4, -1.8) -2.4 b (-3.2, -1.6) -- Add-On Combination with Insulin with or without Metformin and/or Sulfonylureas A total of 494 patients with type 2 diabetes inadequately controlled on insulin, or insulin in combination with oral drugs participated in a double-blind, placebo-controlled study to evaluate the efficacy of empagliflozin as add-on therapy to insulin over 78 weeks. Patients entered 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 background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of empagliflozin 10 mg, empagliflozin 25 mg, or placebo. 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, insulin could be adjusted. The mean total daily insulin dose at baseline for empagliflozin 10 mg, 25 mg, and placebo was 45 IU, 48 IU, and 48 IU, respectively. Empagliflozin used in combination with insulin (with or without metformin and/or sulfonylurea) provided statistically significant reductions in HbA1c and FPG compared to placebo after both 18 weeks and 78 weeks of treatment (see Table 10). Empagliflozin 10 mg or 25 mg daily also resulted in statistically significantly greater percent body weight reduction compared to placebo. Table 10 Results at Week 18 and 78 for a Placebo-Controlled Study for Empagliflozin in Combination with Insulin a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. At Week 78, 32.5%, 38.1% and 42.4% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, and region; FPG: MMRM model includes baseline FPG, baseline HbA1c, treatment, region, visit and visit by treatment interaction. Body weight: MMRM model includes baseline body weight, baseline HbA1c, treatment, region, visit and visit by treatment interaction. c p-value=0.0049 d p-value=0.0052 e p-value=0.0463 18 weeks (no insulin adjustment) 78 weeks (adjustable insulin dose after 18 weeks) Empagliflozin 10 mg + Insulin N=169 Empagliflozin 25 mg + Insulin N=155 Placebo + Insulin N=170 Empagliflozin 10 mg + Insulin N=169 Empagliflozin 25 mg + Insulin N=155 Placebo + Insulin N=170 HbA1c (%) a Baseline (mean) 8.3 8.3 8.2 8.3 8.3 8.2 Change from baseline (adjusted mean) -0.6 -0.7 0 -0.4 -0.6 0.1 Difference from placebo (adjusted mean) (97.5% CI) -0.6 b (-0.8, -0.4) -0.7 b (-0.9, -0.5) -- -0.5 b (-0.7, -0.3) -0.7 b (-0.9, -0.5) -- Patients (%) achieving HbA1c < 7% 18 19.5 5.5 12 17.5 6.7 FPG (mg/dL) Baseline (mean) 138 146 142 138 146 142 Change from baseline (adjusted mean, SE) -17.9 (3.2) -19.1 (3.3) 10.4 (3.1) -10.1 (3.2) -15.2 (3.4) 2.8 (3.2) Difference from placebo (adjusted mean) (95% CI) -28.2 b (-37, -19.5) -29.5 b (-38.4, -20.6) -- -12.9 c (-21.9, 3.9) -17.9 b (-27, -8.8) -- Body Weight Baseline mean in kg 92 95 90 92 95 90 % change from baseline (adjusted mean) -1.8 -1.4 -0.1 -2.4 -2.4 0.7 Difference from placebo (adjusted mean) (95% CI) -1.7 d (-3, -0.5) -1.3 e (-2.5, -0) -- -3 b (-4.4, -1.7) -3 b (-4.4, -1.6) -- Add-on Combination with MDI Insulin with or without Metformin A total of 563 patients with type 2 diabetes inadequately controlled on multiple daily injections (MDI) of insulin (total daily dose > 60 IU), alone or in combination with metformin, participated in a double-blind, placebo-controlled study to evaluate the efficacy of empagliflozin as add-on therapy to MDI insulin over 18 weeks. Patients entered a 2 week placebo run-in period on MDI insulin with or without metformin background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of empagliflozin 10 mg, empagliflozin 25 mg, or placebo. 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. The mean total daily insulin dose at baseline for empagliflozin 10 mg, empagliflozin 25 mg, and placebo was 88.6 IU, 90.4 IU, and 89.9 IU, respectively. Empagliflozin 10 mg or 25 mg daily used in combination with MDI insulin (with or without metformin) provided statistically significant reductions in HbA1c compared to placebo after 18 weeks of treatment (see Table 11). Table 11 Results at Week 18 for a Placebo-Controlled Study for Empagliflozin in Combination with Insulin and with or without Metformin a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18. At Week 18, 23.7%, 22.8% and 23.4% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, geographical region, and background medication). Empagliflozin 10 mg + Insulin +/- Metformin N=186 Empagliflozin 25 mg + Insulin +/- Metformin N=189 Placebo + Insulin +/- Metformin N=188 HbA1c (%) a Baseline (mean) 8.4 8.3 8.3 Change from baseline (adjusted mean) -0.9 -1 -0.5 Difference from placebo (adjusted mean) (95% CI) -0.4 b (-0.6, -0.3) -0.5 b (-0.7, -0.4) -- During an extension period with treatment for up to 52 weeks, insulin could be adjusted to achieve defined glucose target levels. The change from baseline in HbA1c was maintained from 18 weeks to 52 weeks with both empagliflozin 10 mg and 25 mg. After 52 weeks, empagliflozin 10 mg or 25 mg daily resulted in statistically greater percent body weight reduction compared to placebo (p-value < 0.0001). The mean change in body weight from baseline was -1.95 kg for empagliflozin 10 mg, and -2.04 kg for empagliflozin 25 mg. Renal Impairment A total of 738 patients with type 2 diabetes and a baseline eGFR less than 90 mL/min/1.73 m 2 participated in a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of empagliflozin in patients with type 2 diabetes and renal impairment. The trial population comprised of 290 patients with mild renal impairment (eGFR 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 ), 374 patients with moderate renal impairment (eGFR 30 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 ), and 74 with severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ). A total of 194 patients with moderate renal impairment had a baseline eGFR of 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 and 180 patients a baseline eGFR of 45 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 . At Week 24, empagliflozin 25 mg provided statistically significant reduction in HbA1c relative to placebo in patients with mild to moderate renal impairment (see Table 12). A statistically significant reduction relative to placebo was also observed with empagliflozin 25 mg in patients with either mild [-0.7 (95% CI: -0.9, -0.5)] or moderate [-0.4 (95% CI: -0.6, -0.3)] renal impairment and with empagliflozin 10 mg in patients with mild [-0.5 (95% CI: -0.7, -0.3)] renal impairment. The glucose lowering efficacy of empagliflozin 25 mg decreased with decreasing level of renal function in the mild to moderate range. Least square mean HbA1c changes at 24 weeks were -0.6%, -0.5%, and -0.2% for those with a baseline eGFR of 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 , 45 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 , and 30 mL/min/1.73 m 2 to less than 45 mL/min/1.73 m 2 , respectively [see Dosage and Administration ( 2 ) and Use in Specific Populations ( 8.6 )] . For placebo, least square mean HbA1c changes at 24 weeks were 0.1%, -0.1%, and 0.2% for patients with a baseline eGFR of 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 , 45 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 , and 30 mL/min/1.73m 2 to less than 45 mL/min/1.73 m 2 , respectively. Table 12 Results at Week 24 (LOCF) of Placebo-Controlled Study for Empagliflozin in Patients with Type 2 Diabetes and Renal Impairment a p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication) b eGFR 30 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 - Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 24.6% and 26.2% was imputed for patients randomized to empagliflozin 25 mg and placebo, respectively . Mild and Moderate Impairment b Empagliflozin 25 mg HbA1c Number of patients n=284 Comparison vs placebo (adjusted mean) (95% CI) -0.5 a (-0.6, -0.4) For patients with severe renal impairment, the analyses of changes in HbA1c and FPG showed no discernible treatment effect of empagliflozin 25 mg compared to placebo [see Indications and Usage ( 1 ), Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . 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Table 4 Results at Week 24 From a Placebo-Controlled Monotherapy Study of Empagliflozin
aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.4%, 9.4%, and 30.7% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
bANCOVA derived p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
cFPG (mg/dL); for empagliflozin 10 mg, n=223, for empagliflozin 25 mg, n=223, and for placebo, n=226
Empagliflozin 10 mg N=224 Empagliflozin 25 mg N=224 Placebo N=228
HbA1c (%)a
Baseline (mean) 7.9 7.9 7.9
Change from baseline (adjusted mean) -0.7 -0.8 0.1
Difference from placebo (adjusted mean) (97.5% CI) -0.7b (-0.9, -0.6) -0.9b (-1, -0.7) --
Patients [n (%)] achieving HbA1c < 7% 72 (35%) 88 (44%) 25 (12%)
FPG (mg/dL)c
Baseline (mean) 153 153 155
Change from baseline (adjusted mean) -19 -25 12
Difference from placebo (adjusted mean) (95% CI) -31 (-37, -26) -36 (-42, -31) --
Body Weight
Baseline (mean) in kg 78 78 78
% change from baseline (adjusted mean) -2.8 -3.2 -0.4
Difference from placebo (adjusted mean) (95% CI) -2.5b (-3.1, -1.9) -2.8b (-3.4, -2.2) --
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Table 5 Results at Week 24 From a Placebo-Controlled Study for Empagliflozin used in Combination with Metformin
a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207
Empagliflozin 10 mg + Metformin N=217 Empagliflozin 25 mg + Metformin N=213 Placebo + Metformin N=207
HbA1c (%)a
Baseline (mean) 7.9 7.9 7.9
Change from baseline (adjusted mean) -0.7 -0.8 -0.1
Difference from placebo + metformin (adjusted mean) (95% CI) -0.6b (-0.7, -0.4) -0.6b (-0.8, -0.5) --
Patients [n (%)] achieving HbA1c < 7% 75 (38%) 74 (39%) 23 (13%)
FPG (mg/dL)c
Baseline (mean) 155 149 156
Change from baseline (adjusted mean) -20 -22 6
Difference from placebo + metformin (adjusted mean) -26 -29 --
Body Weight
Baseline mean in kg 82 82 80
% change from baseline (adjusted mean) -2.5 -2.9 -0.5
Difference from placebo (adjusted mean) (95% CI) -2b (-2.6, -1.4) -2.5b (-3.1, -1.9) --
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Table 6 Glycemic Parameters at 24 Weeks in a Study Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy
a Metformin total daily dose, administered in two equally divided doses per day.
b p-value ≤ 0.0062 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).
c p-value ≤ 0.0056 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).
Empagliflozin 10 mg + Metformin 1,000 mga N=161 Empagliflozin 10 mg + Metformin 2,000 mga N=167 Empagliflozin 25 mg + Metformin 1,000 mga N=165 Empagliflozin 25 mg + Metformin 2,000 mga N=169 Empagliflozin 10 mg N=169 Empagliflozin 25 mg N=163 Metformin 1,000 mga N=167 Metformin 2,000 mga N=162
HbA1c (%)
Baseline (mean) 8.7 8.7 8.8 8.7 8.6 8.9 8.7 8.6
Change from baseline (adjusted mean) -2 -2.1 -1.9 -2.1 -1.4 -1.4 -1.2 -1.8
Comparison vs empagliflozin (adjusted mean) (95% CI) -0.6b (-0.9, -0.4) -0.7b (-1, -0.5) -0.6c (-0.8, -0.3) -0.7c (-1, -0.5) -- -- -- --
Comparison vs metformin (adjusted mean) (95% CI) -0.8b (-1, -0.6) -0.3b (-0.6, -0.1) -0.8c (-1, -0.5) -0.3c (-0.6, -0.1) -- -- -- --
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Table 7 Results at Week 24 from a Placebo-Controlled Study for Empagliflozin in Combination with Metformin and Sulfonylurea
a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224
Empagliflozin 10 mg + Metformin + SU N=225 Empagliflozin 25 mg + Metformin + SU N=216 Placebo + Metformin + SU N=225
HbA1c (%)a
Baseline (mean) 8.1 8.1 8.2
Change from baseline (adjusted mean) -0.8 -0.8 -0.2
Difference from placebo (adjusted mean) (95% CI) -0.6b (-0.8, -0.5) -0.6b (-0.7, -0.4) --
Patients [n (%)] achieving HbA1c < 7% 55 (26%) 65 (32%) 20 (9%)
FPG (mg/dL)c
Baseline (mean) 151 156 152
Change from baseline (adjusted mean) -23 -23 6
Difference from placebo (adjusted mean) -29 -29 -
Body Weight
Baseline mean in kg 77 78 76
% change from baseline (adjusted mean) -2.9 -3.2 -0.5
Difference from placebo (adjusted mean) (95% CI) -2.4b (-3, -1.8) -2.7b (-3.3, -2.1) --
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Table 8 Results at Week 52 from an Active-Controlled Study Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin
a Modified intent to treat population. Last observation on study (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively.
b Non-inferior, ANCOVA model p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region)
c ANCOVA p-value < 0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
d FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779
Empagliflozin 25 mg + Metformin N=765 Glimepiride + Metformin N=780
HbA1c (%)a
Baseline (mean) 7.9 7.9
Change from baseline (adjusted mean) -0.7 -0.7
Difference from glimepiride (adjusted mean) (97.5% CI) -0.07b (-0.15, 0.01) --
FPG (mg/dL)d
Baseline (mean) 150 150
Change from baseline (adjusted mean) -19 -9
Difference from glimepiride (adjusted mean) -11 --
Body Weight
Baseline mean in kg 82.5 83
% change from baseline (adjusted mean) -3.9 2
Difference from glimepiride (adjusted mean) (95% CI) -5.9c (-6.3, -5.5) --
","
Table 9 Results of Placebo-Controlled Study for Empagliflozin in Combination Therapy with Pioglitazone
a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 10.9%, 8.3%, and 20.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
c FPG (mg/dL); for empagliflozin 10 mg, n=163
Empagliflozin 10 mg + Pioglitazone N=165 Empagliflozin 25 mg + Pioglitazone N=168 Placebo + Pioglitazone N=165
HbA1c (%)a
Baseline (mean) 8.1 8.1 8.2
Change from baseline (adjusted mean) -0.6 -0.7 -0.1
Difference from placebo + pioglitazone (adjusted mean) (95% CI) -0.5b (-0.7, -0.3) -0.6b (-0.8, -0.4) --
Patients [n (%)] achieving HbA1c < 7% 36 (24%) 48 (30%) 12 (8%)
FPG (mg/dL)c
Baseline (mean) 152 152 152
Change from baseline (adjusted mean) -17 -22 7
Difference from placebo + pioglitazone (adjusted mean) (97.5% CI) -23b (-31.8, -15.2) -28b (-36.7, -20.2) --
Body Weight
Baseline mean in kg 78 79 78
% change from baseline (adjusted mean) -2 -1.8 0.6
Difference from placebo (adjusted mean) (95% CI) -2.6b (-3.4, -1.8) -2.4b (-3.2, -1.6) --
","
Table 10 Results at Week 18 and 78 for a Placebo-Controlled Study for Empagliflozin in Combination with Insulin
a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively. At Week 78, 32.5%, 38.1% and 42.4% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, and region; FPG: MMRM model includes baseline FPG, baseline HbA1c, treatment, region, visit and visit by treatment interaction. Body weight: MMRM model includes baseline body weight, baseline HbA1c, treatment, region, visit and visit by treatment interaction.
c p-value=0.0049
d p-value=0.0052
e p-value=0.0463
18 weeks (no insulin adjustment) 78 weeks (adjustable insulin dose after 18 weeks)
Empagliflozin 10 mg + Insulin N=169 Empagliflozin 25 mg + Insulin N=155 Placebo + Insulin N=170 Empagliflozin 10 mg + Insulin N=169 Empagliflozin 25 mg + Insulin N=155 Placebo + Insulin N=170
HbA1c (%)a
Baseline (mean) 8.3 8.3 8.2 8.3 8.3 8.2
Change from baseline (adjusted mean) -0.6 -0.7 0 -0.4 -0.6 0.1
Difference from placebo (adjusted mean) (97.5% CI) -0.6b (-0.8, -0.4) -0.7b (-0.9, -0.5) -- -0.5b (-0.7, -0.3) -0.7b (-0.9, -0.5) --
Patients (%) achieving HbA1c < 7% 18 19.5 5.5 12 17.5 6.7
FPG (mg/dL)
Baseline (mean) 138 146 142 138 146 142
Change from baseline (adjusted mean, SE) -17.9 (3.2) -19.1 (3.3) 10.4 (3.1) -10.1 (3.2) -15.2 (3.4) 2.8 (3.2)
Difference from placebo (adjusted mean) (95% CI) -28.2b (-37, -19.5) -29.5b (-38.4, -20.6) -- -12.9c (-21.9, 3.9) -17.9b (-27, -8.8) --
Body Weight
Baseline mean in kg 92 95 90 92 95 90
% change from baseline (adjusted mean) -1.8 -1.4 -0.1 -2.4 -2.4 0.7
Difference from placebo (adjusted mean) (95% CI) -1.7d (-3, -0.5) -1.3e (-2.5, -0) -- -3b (-4.4, -1.7) -3b (-4.4, -1.6) --
","
Table 11 Results at Week 18 for a Placebo-Controlled Study for Empagliflozin in Combination with Insulin and with or without Metformin
a Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18. At Week 18, 23.7%, 22.8% and 23.4% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
b ANCOVA p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, geographical region, and background medication).
Empagliflozin 10 mg + Insulin +/- Metformin N=186 Empagliflozin 25 mg + Insulin +/- Metformin N=189 Placebo + Insulin +/- Metformin N=188
HbA1c (%)a
Baseline (mean) 8.4 8.3 8.3
Change from baseline (adjusted mean) -0.9 -1 -0.5
Difference from placebo (adjusted mean) (95% CI) -0.4b (-0.6, -0.3) -0.5b (-0.7, -0.4) --
","
Table 12 Results at Week 24 (LOCF) of Placebo-Controlled Study for Empagliflozin in Patients with Type 2 Diabetes and Renal Impairment
a p-value < 0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication)
b eGFR 30 mL/min/1.73 m2 to less than 90 mL/min/1.73 m2 - Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 24.6% and 26.2% was imputed for patients randomized to empagliflozin 25 mg and placebo, respectively .
Mild and Moderate Impairmentb
Empagliflozin 25 mg
HbA1c
Number of patients n=284
Comparison vs placebo (adjusted mean) (95% CI) -0.5a (-0.6, -0.4)
"],"contraindications":["4 CONTRAINDICATIONS Hypersensitivity to empagliflozin or any of the excipients in empagliflozin, reactions such as angioedema have occurred [see Warnings and Precautions ( 5.7 )]. Patients on dialysis [see Use in Specific Populations ( 8.6 )]. Hypersensitivity to empagliflozin or any of the excipients in empagliflozin tablets ( 4 ) Patients on dialysis ( 4 )"],"description":["11 DESCRIPTION Empagliflozin tablets for oral use contain empagliflozin, an inhibitor of the sodium-glucose co-transporter 2 (SGLT2). The chemical name of empagliflozin is (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol. Its molecular formula is C 23 H 27 ClO 7 and the molecular weight is 450.91. The structural formula is: Empagliflozin is premixed with copovidone, which is a white to yellowish solid, hygroscopic powder. It is soluble in methanol. Each film-coated tablet of empagliflozin contains 10 mg or 25 mg of empagliflozin and the following inactive ingredients: colloidal silicon dioxide, copovidone, crospovidone, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide. Image"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION Assess volume status and correct volume depletion before initiating ( 2.1 ) The recommended dose of empagliflozin is 10 mg once daily in the morning, taken with or without food ( 2.2 ) For additional glycemic control, dose may be increased to 25 mg in patients tolerating empagliflozin ( 2.2 ) 2.1 Prior to Initiation of Empagliflozin Assess renal function before initiating empagliflozin and as clinically indicated [see Warnings and Precautions ( 5.2 )]. In patients with volume depletion, correct this condition before initiating empagliflozin [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.5 , 8.6 )]. 2.2 Recommended Dosage The recommended dose of empagliflozin is 10 mg once daily in the morning, taken with or without food. For additional glycemic control, the dose may be increased to 25 mg in patients tolerating empagliflozin. Use for glycemic control is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2 . Empagliflozin is contraindicated in patients on dialysis [see Contraindications ( 4 )]."],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS Empagliflozin tablets, 10 mg are white to off-white, round, film-coated tablets, debossed with '1453' on one side and plain on other side. Empagliflozin tablets, 25 mg are white to off-white, oval, film-coated tablets, debossed with '1454' on one side and plain on other side. Tablets: 10 mg, 25 mg ( 3 )"],"drug_interactions":["7 DRUG INTERACTIONS Table 3 Clinically Relevant Interactions with Empagliflozin Diuretics Clinical Impact Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. Intervention Before initiating empagliflozin, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating empagliflozin. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. Intervention Coadministration of empagliflozin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control."],"drug_interactions_table":["
Table 3 Clinically Relevant Interactions with Empagliflozin
Diuretics
Clinical Impact Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
Intervention Before initiating empagliflozin, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating empagliflozin. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Insulin or Insulin Secretagogues
Clinical Impact The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention Coadministration of empagliflozin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Positive Urine Glucose Test
Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.
"],"effective_time":"20250411","geriatric_use":["8.5 Geriatric Use In glycemic control studies in patients with type 2 diabetes mellitus, a total of 2,721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. Empagliflozin is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations ( 8.6 )] . The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] ."],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING Empagliflozin tablets, 10 mg are white to off-white, round, film-coated tablets, debossed with '1453' on one side and plain on other side and are supplied as follows: NDC 70710-1453-3 in bottles of 30 tablets with child-resistant closure. NDC 70710-1453-9 in bottles of 90 tablets with child-resistant closure. NDC 70710-1453-7 in cartons of 30 (3 x 10) unit-dose tablets Empagliflozin tablets, 25 mg are white to off-white, oval, film-coated tablets, debossed with '1454' on one side and plain on other side and are supplied as follows: NDC 70710-1454-3 in bottles of 30 tablets with child-resistant closure. NDC 70710-1454-9 in bottles of 90 tablets with child-resistant closure. NDC 70710-1454-7 in cartons of 30 (3 x 10) unit-dose tablets Dispense in a well-closed container as defined in the USP. Storage Store at 20 ° C to 25 ° C (68 ° F to 77 ° F); excursions permitted to 15 ° C to 30 ° C (59 ° F to 86 ° F) [see USP Controlled Room Temperature]. Protect from moisture."],"id":"03babb7f-2e83-4978-87f1-d39f11047a7c","indications_and_usage":["1 INDICATIONS AND USAGE Empagliflozin tablets are indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Empagliflozin tablets are not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions ( 5.1 )]. Empagliflozin tablets are not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . Empagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. Empagliflozin tablets are sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients ( 1 ) Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 ( 1 )"],"information_for_patients":["17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Ketoacidosis Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of empagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue empagliflozin and seek medical attention immediately [see Warnings and Precautions ( 5.1 )] . Volume Depletion Inform patients that symptomatic hypotension may occur with empagliflozin and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions ( 5.2 )] . Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions ( 5.3 )] . Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Inform patients that the incidence of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 )] . Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Inform patients that necrotizing infections of the perineum (Fournier's gangrene) have occurred with empagliflozin. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions ( 5.5 )]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions ( 5.6 )] . Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions ( 5.6 )] . Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with empagliflozin. Advise patients to report immediately any skin reaction or angioedema, and to discontinue drug until they have consulted prescribing healthcare provider [see Warnings and Precautions ( 5.7 )] . Laboratory Tests Inform patients that elevated glucose in urinalysis is expected when taking empagliflozin. Pregnancy Advise pregnant patients, and patients of reproductive potential, of the potential risk to a fetus with treatment with empagliflozin [see Use in Specific Populations ( 8.1 )]. Instruct patients to report pregnancies to their healthcare provider as soon as possible. Lactation Advise patients that breastfeeding is not recommended during treatment with empagliflozin [see Use in Specific Populations ( 8.2 )]. Missed Dose Instruct patients to take empagliflozin only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose. The brands listed are the registered trademarks of their respective owners."],"mechanism_of_action":["12.1 Mechanism of Action Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions such as lowering both pre-and afterload of the heart and downregulating sympathetic activity."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenesis was evaluated in 2 year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100 mg/kg/day, 300 mg/kg/day, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from a 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100 mg/kg/day, 300 mg/kg/day, or 1,000 mg/kg/day (up to 62 times the exposure from a 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1,000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with a metabolic pathway predominantly present in the male mouse kidney. Mutagenesis Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk +/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats. Impairment of Fertility Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively)."],"openfda":{},"overdosage":["10 OVERDOSAGE In the event of an overdose with empagliflozin, contact the Poison Control Center. Removal of empagliflozin by hemodialysis has not been studied."],"package_label_principal_display_panel":["PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Empagliflozin Tablets, 10 mg NDC 70710-1453-3 30 Tablets Rx only Zydus Empagliflozin Tablets, 25 mg NDC 70710-1454-3 30 Tablets Rx only Zydus image image"],"pediatric_use":["8.4 Pediatric Use The safety and effectiveness of empagliflozin have not been established in pediatric patients."],"pharmacodynamics":["12.2 Pharmacodynamics Urinary Glucose Excretion In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4 week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies ( 14 )] . Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg and 25 mg doses. Urinary Volume In a 5 day study, mean 24 hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment. Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin."],"pharmacokinetics":["12.3 Pharmacokinetics Absorption The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma AUC and C max were 1,870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4,740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time. Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C max decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food. Distribution The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [ 14 C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%. Elimination The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Metabolism No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Excretion Following administration of an oral [ 14 C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug. Specific Populations Renal Impairment In patients with type 2 diabetes mellitus with mild (eGFR: 60 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 ), moderate (eGFR: 30 mL/min/1.73 m 2 to less than 60 mL/min/1.73 m 2 ), and severe (eGFR: less than 30 mL/min/1.73 m 2 ) renal impairment and patients on dialysis due to kidney failure, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and patients on dialysis due to kidney failure compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR. Hepatic Impairment In patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and C max increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Effects of Age, Body Mass Index, Gender, and Race Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations ( 8.5 )] . Drug Interactions In vitro Assessment of Drug Interactions Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters. In vivo Assessment of Drug Interactions Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes (see Figure 1). In subjects with normal renal function, coadministration 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 relevance of this observation to patients with renal impairment is unknown. Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% to 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, single dose; c empagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2). Figure 2 Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% to 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, once daily; c empagliflozin, 25 mg, single dose; d administered as simvastatin; e administered as warfarin racemic mixture; f administered as Microgynon ® ; g administered as ramipril"],"pregnancy":["8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, empagliflozin is not recommended during the second and third trimesters of pregnancy. The limited available data with empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible [see Data] . The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20% to 25% in women with HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13 times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13 week drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48 times (rats) and 128 times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154 times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139 times the 25 mg maximum clinical dose. In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose)."],"recent_major_changes":["RECENT MAJOR CHANGES Indications and Usage ( 1 ) 2/2022 Dosage and Administration ( 2.1 ) 6/2021 Dosage and Administration ( 2.2 ) 8/2021 Dosage and Administration (2.3) – Removed 8/2021 Contraindications ( 4 ) 6/2021 Warnings and Precautions ( 5.1 , 5.2 ) 6/2021 Warnings and Precautions ( 5.3 , 5.5 ) 8/2021 Warnings and Precautions (5.9) – Removed 6/2021"],"recent_major_changes_table":["
Indications and Usage (1) 2/2022
Dosage and Administration (2.1) 6/2021
Dosage and Administration (2.2) 8/2021
Dosage and Administration (2.3) – Removed 8/2021
Contraindications (4) 6/2021
Warnings and Precautions (5.1, 5.2) 6/2021
Warnings and Precautions (5.3, 5.5) 8/2021
Warnings and Precautions (5.9) – Removed 6/2021
"],"set_id":"01d6ac81-4b01-41db-a9c6-f0aab96fd3ec","spl_medguide":["MEDICATION GUIDE Empagliflozin (em\" pa gli floe' zin) Tablets, for oral use What is the most important information I should know about empagliflozin tablets? Empagliflozin tablets can cause serious side effects, including: Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with empagliflozin tablets. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with empagliflozin tablets. Ketoacidosis is a serious condition, which needs to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with empagliflozin tablets even if your blood sugar is less than 250 mg/dL. Stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room if you get any of the following symptoms: nausea tiredness vomiting trouble breathing stomach-area (abdominal) pain If you get any of these symptoms during treatment with empagliflozin tablets, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL. Dehydration. Empagliflozin tablets can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking empagliflozin tablets. You may be at higher risk of dehydration if you: o take medicines to lower your blood pressure, including diuretics (water pills) o are on low sodium (salt) diet o have kidney problems o are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Talk to your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you are sick or cannot eat, or start to lose liquids from your body, for example from vomiting, diarrhea or being in the sun too long. What are empagliflozin tablets? Empagliflozin tablets are a prescription medicine used to: o lower blood sugar along with diet and exercise in adults with type 2 diabetes. Empagliflozin tablets are not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine). Empagliflozin tablets are not for use to lower blood sugar in adults with type 2 diabetes who have severe kidney problems, because it may not work. It is not known if empagliflozin tablets are safe and effective in children. Who should not take empagliflozin tablets? Do not take empagliflozin tablets if you: are allergic to empagliflozin or any of the ingredients in empagliflozin tablets. See the end of this Medication Guide for a complete list of ingredients in empagliflozin tablets. Symptoms of a serious allergic reaction to empagliflozin tablets may include: swelling of your face, lips, throat and other areas of your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) If you have any of these symptoms, stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room. are on dialysis. What should I tell my healthcare provider before taking empagliflozin tablets? Before taking empagliflozin tablets, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems. have liver problems. have a history of infection of the vagina or penis. have a history of urinary tract infections or problems with urination. are going to have surgery. Your healthcare provider may stop your empagliflozin tablets before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking empagliflozin tablets and when to start it again. are eating less, or there is a change in your diet. have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas. drink alcohol very often or drink a lot of alcohol in the short term (\"binge\" drinking). have type 1 diabetes. Empagliflozin tablets should not be used to treat people with type 1 diabetes. are pregnant or plan to become pregnant. Empagliflozin tablets may harm your unborn baby. If you become pregnant while taking empagliflozin tablets, tell your healthcare provider as soon as possible. Talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. are breastfeeding or plan to breastfeed. Empagliflozin may pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking empagliflozin tablets. Do not breastfeed while taking empagliflozin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Empagliflozin tablets may affect the way other medicines work, and other medicines may affect how empagliflozin tablet works. Especially tell your healthcare provider if you take: diuretics (water pills) insulin or other medicines that can lower your blood sugar Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take empagliflozin tablets? Take empagliflozin tablets exactly as your healthcare provider tells you to take it. Take empagliflozin tablets by mouth 1 time in the morning each day, with or without food. Your healthcare provider may change your dose if needed. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of empagliflozin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. Your healthcare provider may tell you to take empagliflozin tablets along with other diabetes medicines. Low blood sugar can happen more often when empagliflozin tablets is taken with certain other diabetes medicines. See \"What are the possible side effects of empagliflozin tablets?\" If you take too much empagliflozin tablets, call your healthcare provider or go to the nearest hospital emergency room right away. When taking empagliflozin tablets, you may have sugar in your urine, which will show up on a urine test. Your healthcare provider may do blood tests to check how well your kidneys are working before and during your treatment with empagliflozin tablets. What are the possible side effects of empagliflozin tablets? Empagliflozin tablets may cause serious side effects, including: See \"What is the most important information I should know about empagliflozin tablets?\" Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking empagliflozin tablets. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting. Low blood sugar (hypoglycemia). If you take empagliflozin tablets with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take empagliflozin tablets. Signs and symptoms of low blood sugar may include: headache irritability confusion dizziness drowsiness hunger shaking or feeling jittery sweating weakness fast heartbeat A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take empagliflozin tablets. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals: pain or tenderness swelling redness of skin (erythema) Vaginal yeast infection. Symptoms of a vaginal yeast infection include: vaginal odor white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese) vaginal itching Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: redness, itching, or swelling of the penis rash of the penis foul smelling discharge from the penis pain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking empagliflozin tablets. Symptoms may include: o swelling of your face, lips, throat and other areas of your skin o difficulty with swallowing or breathing. o raised, red areas on your skin (hives) If you have any of these symptoms, stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room. The most common side effects of empagliflozin tablets include: urinary tract infections yeast infections in females These are not all the possible side effects of empagliflozin tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store empagliflozin tablets? Store empagliflozin tablets at room temperature between 68°F to 77°F (20°C to 25°C). Protect from moisture. Empagliflozin tablets come in child-resistant bottles of 30's and 90's. Keep empagliflozin tablets and all medicines out of the reach of children. General information about the safe and effective use of empagliflozin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use empagliflozin tablets for a condition for which it is not prescribed. Do not give empagliflozin tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about empagliflozin tablets that is written for health professionals. What are the ingredients in empagliflozin tablets? Active Ingredient: empagliflozin Inactive Ingredients: colloidal silicon dioxide, copovidone, crospovidone, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide. For more information, write to MedicalAffairs@zydususa.com or call 1-877-933-8779. The brands listed are the registered trademarks of their respective owners. Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev: 06/22 This MEDICATION GUIDE has been approved by the U.S. Food and Drug Administration."],"spl_medguide_table":["
MEDICATION GUIDE Empagliflozin (em" pa gli floe' zin) Tablets, for oral use
What is the most important information I should know about empagliflozin tablets? Empagliflozin tablets can cause serious side effects, including: Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with empagliflozin tablets. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with empagliflozin tablets. Ketoacidosis is a serious condition, which needs to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with empagliflozin tablets even if your blood sugar is less than 250 mg/dL. Stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room if you get any of the following symptoms:
nauseatiredness
vomitingtrouble breathing
stomach-area (abdominal) pain
If you get any of these symptoms during treatment with empagliflozin tablets, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL. Dehydration. Empagliflozin tablets can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking empagliflozin tablets. You may be at higher risk of dehydration if you: o take medicines to lower your blood pressure, including diuretics (water pills) o are on low sodium (salt) diet o have kidney problems o are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Talk to your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you are sick or cannot eat, or start to lose liquids from your body, for example from vomiting, diarrhea or being in the sun too long.
What are empagliflozin tablets? Empagliflozin tablets are a prescription medicine used to: o lower blood sugar along with diet and exercise in adults with type 2 diabetes. Empagliflozin tablets are not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine). Empagliflozin tablets are not for use to lower blood sugar in adults with type 2 diabetes who have severe kidney problems, because it may not work. It is not known if empagliflozin tablets are safe and effective in children.
Who should not take empagliflozin tablets? Do not take empagliflozin tablets if you: are allergic to empagliflozin or any of the ingredients in empagliflozin tablets. See the end of this Medication Guide for a complete list of ingredients in empagliflozin tablets. Symptoms of a serious allergic reaction to empagliflozin tablets may include:swelling of your face, lips, throat and other areas of your skindifficulty with swallowing or breathingraised, red areas on your skin (hives) If you have any of these symptoms, stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room. are on dialysis.
What should I tell my healthcare provider before taking empagliflozin tablets? Before taking empagliflozin tablets, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems.have liver problems.have a history of infection of the vagina or penis.have a history of urinary tract infections or problems with urination.are going to have surgery. Your healthcare provider may stop your empagliflozin tablets before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking empagliflozin tablets and when to start it again.are eating less, or there is a change in your diet.have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.drink alcohol very often or drink a lot of alcohol in the short term ("binge" drinking).have type 1 diabetes. Empagliflozin tablets should not be used to treat people with type 1 diabetes.are pregnant or plan to become pregnant. Empagliflozin tablets may harm your unborn baby. If you become pregnant while taking empagliflozin tablets, tell your healthcare provider as soon as possible. Talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. Empagliflozin may pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking empagliflozin tablets. Do not breastfeed while taking empagliflozin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Empagliflozin tablets may affect the way other medicines work, and other medicines may affect how empagliflozin tablet works. Especially tell your healthcare provider if you take: diuretics (water pills)insulin or other medicines that can lower your blood sugar Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take empagliflozin tablets? Take empagliflozin tablets exactly as your healthcare provider tells you to take it.Take empagliflozin tablets by mouth 1 time in the morning each day, with or without food.Your healthcare provider may change your dose if needed.If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of empagliflozin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose.Your healthcare provider may tell you to take empagliflozin tablets along with other diabetes medicines. Low blood sugar can happen more often when empagliflozin tablets is taken with certain other diabetes medicines. See "What are the possible side effects of empagliflozin tablets?"If you take too much empagliflozin tablets, call your healthcare provider or go to the nearest hospital emergency room right away.When taking empagliflozin tablets, you may have sugar in your urine, which will show up on a urine test.Your healthcare provider may do blood tests to check how well your kidneys are working before and during your treatment with empagliflozin tablets.
What are the possible side effects of empagliflozin tablets? Empagliflozin tablets may cause serious side effects, including: See "What is the most important information I should know about empagliflozin tablets?" Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking empagliflozin tablets. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting. Low blood sugar (hypoglycemia). If you take empagliflozin tablets with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take empagliflozin tablets. Signs and symptoms of low blood sugar may include:
headacheirritabilityconfusiondizziness
drowsinesshungershaking or feeling jitterysweating
weaknessfast heartbeat
A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take empagliflozin tablets. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals:
pain or tendernessswellingredness of skin (erythema)
Vaginal yeast infection. Symptoms of a vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking empagliflozin tablets. Symptoms may include: o swelling of your face, lips, throat and other areas of your skin o difficulty with swallowing or breathing. o raised, red areas on your skin (hives) If you have any of these symptoms, stop taking empagliflozin tablets and call your healthcare provider right away or go to the nearest hospital emergency room. The most common side effects of empagliflozin tablets include: urinary tract infectionsyeast infections in females These are not all the possible side effects of empagliflozin tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store empagliflozin tablets? Store empagliflozin tablets at room temperature between 68°F to 77°F (20°C to 25°C). Protect from moisture.Empagliflozin tablets come in child-resistant bottles of 30's and 90's. Keep empagliflozin tablets and all medicines out of the reach of children.
General information about the safe and effective use of empagliflozin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use empagliflozin tablets for a condition for which it is not prescribed. Do not give empagliflozin tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about empagliflozin tablets that is written for health professionals.
What are the ingredients in empagliflozin tablets? Active Ingredient: empagliflozin Inactive Ingredients: colloidal silicon dioxide, copovidone, crospovidone, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide. For more information, write to MedicalAffairs@zydususa.com or call 1-877-933-8779. The brands listed are the registered trademarks of their respective owners.
Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534
Rev: 06/22
This MEDICATION GUIDE has been approved by the U.S. Food and Drug Administration.
"],"spl_product_data_elements":["empagliflozin empagliflozin EMPAGLIFLOZIN EMPAGLIFLOZIN ANHYDROUS LACTOSE COPOVIDONE K25-31 CROSPOVIDONE HYPROMELLOSE 2910 (6 MPA.S) MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 4000 SILICON DIOXIDE TALC TITANIUM DIOXIDE off-white 1453 empagliflozin empagliflozin EMPAGLIFLOZIN EMPAGLIFLOZIN ANHYDROUS LACTOSE COPOVIDONE K25-31 CROSPOVIDONE HYPROMELLOSE 2910 (6 MPA.S) MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 4000 SILICON DIOXIDE TALC TITANIUM DIOXIDE off-white 1454"],"spl_unclassified_section":["Manufactured by: Zydus Lifesciences Ltd. Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev: 06/22"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Pregnancy : Advise females of the potential risk to a fetus especially during the second and third trimesters ( 8.1 ) Lactation : Empagliflozin is not recommended when breastfeeding ( 8.2 ) Geriatric Patients : Higher incidence of adverse reactions related to volume depletion and reduced renal function ( 5.2 , 8.5 , 8.6 ) Renal Impairment : Higher incidence of adverse reactions related to reduced renal function ( 2.2 , 5.2 , 8.6 ) 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, empagliflozin is not recommended during the second and third trimesters of pregnancy. The limited available data with empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible [see Data] . The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c > 7 and has been reported to be as high as 20% to 25% in women with HbA1c > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13 times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13 week drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48 times (rats) and 128 times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154 times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139 times the 25 mg maximum clinical dose. In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose). 8.2 Lactation Risk Summary There is limited information regarding the presence of empagliflozin in human milk, the effects of empagliflozin on the breastfed infant or the effects on milk production. Empagliflozin is present in the milk of lactating rats [see Data] . Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of empagliflozin is not recommended while breastfeeding. Data Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 hours to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 8.4 Pediatric Use The safety and effectiveness of empagliflozin have not been established in pediatric patients. 8.5 Geriatric Use In glycemic control studies in patients with type 2 diabetes mellitus, a total of 2,721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. Empagliflozin is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations ( 8.6 )] . The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . 8.6 Renal Impairment The efficacy and safety of empagliflozin for glycemic control were evaluated in a study of patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 mL/min/1.73 m 2 to less than 90 mL/min/1.73 m 2 ) [see Clinical Studies ( 14 )] . In this study, 195 patients exposed to empagliflozin had an eGFR between 60 mL/min/1.73 m 2 and 90 mL/min/1.73 m 2 , 91 patients exposed to empagliflozin had an eGFR between 45 mL/min/1.73 m 2 and 60 mL/min/1.73 m 2 and 97 patients exposed to empagliflozin had an eGFR between 30 mL/min/1.73 m 2 and 45 mL/min/1.73 m 2 . The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions ( 5.2 )] . Efficacy and safety studies with empagliflozin did not enroll patients with an eGFR less than 20 mL/min/1.73 m 2 . Empagliflozin is contraindicated in patients on dialysis [see Contraindications ( 4 )]. 8.7 Hepatic Impairment Empagliflozin may be used in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] ."],"version":"2","warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue empagliflozin, evaluate and treat promptly. Before initiating empagliflozin, consider risk factors for ketoacidosis. Patients on empagliflozin may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. ( 5.1 ) Volume Depletion: Before initiating empagliflozin, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. ( 5.2 , 6.1 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.3 ) Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating empagliflozin ( 5.4 ) Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. ( 5.5 ) Genital Mycotic Infections: Monitor and treat as appropriate ( 5.6 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with empagliflozin. If hypersensitivity reactions occur, discontinue empagliflozin, treat promptly, and monitor until signs and symptoms resolve. ( 5.7 ) 5.1 Ketoacidosis Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Empagliflozin is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage ( 1 )] . Patients treated with empagliflozin who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with empagliflozin may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, empagliflozin should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement. In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. Before initiating empagliflozin, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo scheduled surgery, consider temporarily discontinuing empagliflozin for at least 3 days prior to surgery [see Clinical Pharmacology ( 12.2 , 12.3 )] . Consider monitoring for ketoacidosis and temporarily discontinuing empagliflozin in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting empagliflozin. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue empagliflozin and seek medical attention immediately if signs and symptoms occur. 5.2 Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions ( 6.1 )]. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating empagliflozin in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating empagliflozin. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. 5.3 Urosepsis and Pyelonephritis There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions ( 6 )]. 5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see Adverse Reactions ( 6.1 )] . Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with empagliflozin. 5.5 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with empagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue empagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.6 Genital Mycotic Infections Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions ( 6.1 )] . Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate. 5.7 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin. If a hypersensitivity reaction occurs, discontinue empagliflozin; treat promptly per standard of care, and monitor until signs and symptoms resolve. Empagliflozin is contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in empagliflozin [see Contraindications ( 4 )] ."]}