FDA label 03babb7f-2e83-4978-87f1-d39f11047a7c

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 )] .

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)

<table ID="ID213" width="373" styleCode="Noautorules"><caption> Table 1 Adverse Reactions Reported in &#x2265; 2% of Patients Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Empagliflozin Monotherapy or Combination Therapy </caption><col/><col width="126"/><col width="120"/><col width="127"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^bFemale 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 </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">10 mg (N=443), empagliflozin 25 mg (N=420). </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^dMale 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).</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Reactions</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo (%)</content> <content styleCode="bold"> N=995</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg (%)</content> <content styleCode="bold"> N=999</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin</content> <content styleCode="bold"> 25 mg (%)</content> <content styleCode="bold"> N=977</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Urinary tract infection^a </td><td styleCode=" Botrule Rrule" align="center"> 7.6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9.3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7.6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Female genital mycotic infections^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Upper respiratory tract infection </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased urination^c </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dyslipidemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.9 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Arthralgia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Male genital mycotic infections^d </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3.1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.1 </td></tr></tbody></table>

<table ID="ID217" width="0" styleCode="Noautorules"><caption> Table 2 Incidence of Overall^a and Severe^b Hypoglycemic Events in Placebo-Controlled Clinical Studies^c</caption><col width="175"/><col width="150"/><col width="186"/><col width="156"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^bSevere hypoglycemic events: requiring assistance regardless of blood glucose </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^cTreated set (patients who had received at least one dose of study drug) </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^dInsulin dose could not be adjusted during the initial 18 week treatment period</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Monotherapy</content> <content styleCode="bold"> (24 weeks)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n=229)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg (n=224)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg (n=223)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> In Combination with Metformin </content> <content styleCode="bold"> (24 weeks)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo + Metformin </content> <content styleCode="bold"> (n=206)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg + Metformin </content> <content styleCode="bold"> (n=217)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg + Metformin (n=214)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> In Combination with Metformin + Sulfonylurea </content> <content styleCode="bold"> (24 weeks)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n=225)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg + Metformin + Sulfonylurea </content> <content styleCode="bold"> (n=224)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg + Metformin + Sulfonylurea (n=217)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16.1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11.5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> In Combination with Pioglitazone +/- Metformin </content> <content styleCode="bold"> (24 weeks)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n=165)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg + Pioglitazone +/- Metformin </content> <content styleCode="bold"> (n=165)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg + Pioglitazone +/- Metformin </content> <content styleCode="bold"> (n=168)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> In Combination with Basal Insulin +/- Metformin </content> <content styleCode="bold"> (18 weeks^d)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n=170)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg (n=169)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg (n=155)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 20.6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> In Combination with MDI Insulin +/-Metformin (18 weeks^d)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (n=188)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 10 mg (n=186)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Empagliflozin 25 mg (n=189)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Overall (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 37.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 39.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 41.3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Severe (%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.5 </td></tr></tbody></table>