Jardiance

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue JARDIANCE if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Volume Depletion: Before initiating JARDIANCE, 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 ) Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections: Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue JARDIANCE, and promptly institute appropriate medical and/or surgical intervention. ( 5.3 ) Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher regardless of insulin use. Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JARDIANCE. ( 5.4 ) Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment ( 5.5 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with JARDIANCE. If hypersensitivity reactions occur, discontinue JARDIANCE, treat promptly, and monitor until signs and symptoms resolve. ( 5.6 ) 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, JARDIANCE significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with JARDIANCE. JARDIANCE is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including JARDIANCE. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing JARDIANCE [see Clinical Pharmacology (12.2) ] ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue JARDIANCE, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting JARDIANCE. Withhold JARDIANCE, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume JARDIANCE when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3) ] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue JARDIANCE and seek medical attention immediately if signs and symptoms occur. 5.2 Volume Depletion JARDIANCE 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 JARDIANCE. 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 JARDIANCE 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 JARDIANCE. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. 5.3 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections JARDIANCE increases urinary glucose excretion [see Clinical Pharmacology (12.2) ] and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients [see Adverse Reactions (6.1) ] . Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier's gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with and without diabetes mellitus receiving SGLT2 inhibitors, including JARDIANCE [see Adverse Reactions (6.2) ]. Cases have required hospitalization. In patients with Fournier's gangrene, serious outcomes have included multiple surgeries and death. Patients with a history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using JARDIANCE. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue JARDIANCE and promptly institute appropriate medical and/or surgical intervention. 5.4 Hypoglycemia Insulin and insulin secretagogues are known to cause hypoglycemia. In adult patients, the risk of hypoglycemia may be increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with JARDIANCE regardless of insulin use [see Adverse Reactions (6.1) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Lower Limb Amputation In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four JARDIANCE outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the JARDIANCE 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36). In a long-term cardio-renal outcome trial [see Clinical Studies 14.5 ] , in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and JARDIANCE 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 JARDIANCE 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving JARDIANCE for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment. 5.6 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with JARDIANCE. If a hypersensitivity reaction occurs, discontinue JARDIANCE; treat promptly per standard of care, and monitor until signs and symptoms resolve. JARDIANCE is contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in JARDIANCE [see Contraindications (4) ] .

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1) ] Volume Depletion [see Warnings and Precautions (5.2) ] Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.3) ] Hypoglycemia [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] Most common adverse reactions (5% or greater incidence) were urinary tract infections and female genital mycotic infections ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 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. JARDIANCE has been evaluated in clinical trials in adult and pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, in adults with heart failure, and in adults with chronic kidney disease. The overall safety profile of JARDIANCE was generally consistent across the studied indications. Clinical Trials in Adults with Type 2 Diabetes Mellitus The data in Table 2 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with insulin in adult patients with type 2 diabetes mellitus. JARDIANCE was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies (14.1) ] . These data reflect exposure of 1,976 adult patients to JARDIANCE with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE 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 mellitus more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes mellitus 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 2 shows adverse reactions (excluding hypoglycemia) that were not present at baseline, occurred more commonly in JARDIANCE-treated patients than on placebo and occurred in greater than or equal to 2% JARDIANCE-treated patients. Table 2 Adverse Reactions Reported in ≥2% of Adults with Type 2 Diabetes Mellitus Treated with JARDIANCE and Greater than Placebo in Pooled Placebo-Controlled Clinical Trials of JARDIANCE Monotherapy or Combination Therapy Adverse Reactions Placebo (%) N=995 JARDIANCE 10 mg (%) N=999 JARDIANCE 25 mg (%) N=977 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), JARDIANCE 10 mg (N=443), JARDIANCE 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), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557). 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 4.0 Increased urination c 1.0 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, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Volume Depletion JARDIANCE 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 in adults, 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, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. JARDIANCE 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 in adults, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on JARDIANCE than on placebo (see Table 2 ). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Hypoglycemia in Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus The incidence of hypoglycemia in adults by trial is shown in Table 3 . The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea. Table 3 Incidence of Overall a and Severe b Hypoglycemic Events in Placebo-Controlled Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus 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 dosage of trial drug) d Insulin dosage could not be adjusted during the initial 18-week treatment period Monotherapy (24 weeks) Placebo (n=229) JARDIANCE 10 mg (n=224) JARDIANCE 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) JARDIANCE 10 mg + Metformin (n=217) JARDIANCE 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) JARDIANCE 10 mg + Metformin + Sulfonylurea (n=224) JARDIANCE 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) JARDIANCE 10 mg + Pioglitazone +/- Metformin (n=165) JARDIANCE 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) JARDIANCE 10 mg (n=169) JARDIANCE 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) JARDIANCE 10 mg (n=186) JARDIANCE 25 mg (n=189) Overall (%) 37.2 39.8 41.3 Severe (%) 0.5 0.5 0.5 Other Adverse Reactions in Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus Genital Mycotic Infections : In the pool of five placebo-controlled clinical trials in adults, 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 JARDIANCE compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either JARDIANCE 10 mg or 25 mg. Genital mycotic infections occurred more frequently in female than male patients (see Table 2 ). Phimosis occurred more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%) and JARDIANCE 25 mg (0.1%) than placebo (0%). Urinary Tract Infections : In the pool of five placebo-controlled clinical trials in adults, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with JARDIANCE compared to placebo (see Table 2 ). 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, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Use in Specific Populations (8.5) ] . Clinical Trial in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus JARDIANCE was administered to 52 patients in a trial of 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus with a mean exposure to JARDIANCE of 23.8 weeks [see Clinical Studies (14.2) ] . Background therapies as adjunct to diet and exercise included metformin (51%), a combination of metformin and insulin (40.1%), insulin (3.2%), or none (5.7%). The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years. The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older. Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity. The mean BMI was 36.0 kg/m 2 and mean BMI Z-score was 3.0. Approximately 25% of the trial population had microalbuminuria or macroalbuminuria. The risk of hypoglycemia was higher in pediatric patients treated with JARDIANCE regardless of concomitant insulin use. Hypoglycemia, defined as a blood glucose <54 mg/dL, occurred in 10 (19.2%) patients and in 4 (7.5%) patients treated with JARDIANCE and placebo, respectively. No severe hypoglycemic events occurred (severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrates, glucagon or take other corrective actions). Clinical Trials in Adults with Heart Failure No new adverse reactions were identified in EMPEROR-Reduced or EMPEROR-Preserved heart failure trials. Clinical Trial in Adults with Chronic Kidney Disease The safety profile in patients with chronic kidney disease was generally consistent with that observed across the studied indications. In a long-term cardio-renal outcome trial [see Clinical Studies 14.5 ] , in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and JARDIANCE 10 mg treatment arms, respectively [see Warnings and Precautions (5.5) ]. Laboratory Test Abnormalities in Clinical Trials Increases in Serum Creatinine and Decreases in eGFR Initiation of JARDIANCE causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a trial of adults with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes 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 JARDIANCE. Increase in Low-Density Lipoprotein Cholesterol (LDL-C) Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in adults treated with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups. Increase in Hematocrit In a pool of four placebo-controlled trials in adults, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in JARDIANCE 10 mg and 2.8% in JARDIANCE 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, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of JARDIANCE. 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 width="75%" ID="table2"><caption>Table 2 Adverse Reactions Reported in &#x2265;2% of Adults with Type 2 Diabetes Mellitus Treated with JARDIANCE and Greater than Placebo in Pooled Placebo-Controlled Clinical Trials of JARDIANCE Monotherapy or Combination Therapy</caption><col width="34%" align="left" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="center" valign="top"/><thead><tr><th align="center" styleCode="Lrule Rrule">Adverse Reactions</th><th styleCode="Rrule">Placebo (%) N=995 </th><th styleCode="Rrule">JARDIANCE 10 mg (%) N=999 </th><th styleCode="Rrule">JARDIANCE 25 mg (%) N=977 </th></tr></thead><tfoot><tr><td colspan="4" align="left">^aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis ^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), JARDIANCE 10 mg (N=443), JARDIANCE 25 mg (N=420). ^cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia ^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), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557). </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection ^a</td><td styleCode="Rrule">7.6</td><td styleCode="Rrule">9.3</td><td styleCode="Rrule">7.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Female genital mycotic infections ^b</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">5.4</td><td styleCode="Rrule">6.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">3.8</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">4.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased urination ^c</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">3.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyslipidemia</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">3.9</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">2.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Male genital mycotic infections ^d</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">1.1</td></tr></tbody></table>

<table width="75%" ID="table3"><caption>Table 3 Incidence of Overall ^aand Severe ^bHypoglycemic Events in Placebo-Controlled Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus ^c</caption><col width="30%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><tfoot><tr><td align="left" colspan="4">^aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL ^bSevere hypoglycemic events: requiring assistance regardless of blood glucose ^cTreated set (patients who had received at least one dosage of trial drug) ^dInsulin dosage could not be adjusted during the initial 18-week treatment period </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Monotherapy (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=229) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg (n=224)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg (n=223)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Metformin (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo + Metformin (n=206) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg + Metformin (n=217) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg + Metformin (n=214) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Metformin + Sulfonylurea (24 weeks) </content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=225)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg + Metformin + Sulfonylurea (n=224)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg + Metformin + Sulfonylurea (n=217)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">8.4</td><td styleCode="Rrule">16.1</td><td styleCode="Rrule">11.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Pioglitazone +/- Metformin (24 weeks) </content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=165)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg + Pioglitazone +/- Metformin (n=165) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg + Pioglitazone +/- Metformin (n=168) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">2.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Basal Insulin +/- Metformin (18 weeks ^d) </content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=170)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg (n=169) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg (n=155) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">20.6</td><td styleCode="Rrule">19.5</td><td styleCode="Rrule">28.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with MDI Insulin +/-Metformin (18 weeks ^d) </content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=188)</content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 10 mg (n=186) </content></td><td styleCode="Rrule"><content styleCode="bold">JARDIANCE 25 mg (n=189) </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">37.2</td><td styleCode="Rrule">39.8</td><td styleCode="Rrule">41.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">0.5</td></tr></tbody></table>