Jardiance

1 INDICATIONS AND USAGE JARDIANCE is indicated: • to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure. • to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. • to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. JARDIANCE is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: • To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure. ( 1 ) • To reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. ( 1 ) • To reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. ( 1 ) • As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. ( 1 ) Limitations of Use: • Not recommended for use to improve glycemic control 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 patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . ( 1 ) • Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. JARDIANCE is not expected to be effective in these populations. ( 1 ) Limitations of Use JARDIANCE is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.1) ] . JARDIANCE is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . JARDIANCE is likely to be ineffective in this setting based upon its mechanism of action. JARDIANCE is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease [see Clinical Studies (14.5) ] . JARDIANCE is not expected to be effective in these populations.

2 DOSAGE AND ADMINISTRATION • Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. ( 2.1 ) • Recommended dosage is 10 mg orally once daily in the morning, taken with or without food. ( 2.2 ) • For additional glycemic control, dosage may be increased to 25 mg orally once daily in patients tolerating JARDIANCE. ( 2.2 ) • Withhold JARDIANCE for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.3 ) 2.1 Testing Prior to Initiation of JARDIANCE • Assess renal function before initiating JARDIANCE and as clinically indicated [see Warnings and Precautions (5.2) ] . o Use for glycemic control is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Use in Specific Populations (8.6) ]. • Assess volume status. In patients with volume depletion, correct this condition before initiating JARDIANCE [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5 , 8.6) ]. 2.2 Recommended Dosage Table 1 presents the recommended dosage of JARDIANCE in adult and pediatric patients aged 10 years and older. Table 1 Recommended Dosage of JARDIANCE Population Indication Recommended Dosage Adults Reduce the risk of cardiovascular death and hospitalization in patients with heart failure • 10 mg orally once daily in the morning, taken with or without food. Reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus with established cardiovascular disease Glycemic control in type 2 diabetes mellitus • 10 mg orally once daily in the morning, taken with or without food. • For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily. Pediatric patients aged 10 years and older Glycemic control in type 2 diabetes mellitus • 10 mg orally once daily in the morning, taken with or without food. • For additional glycemic control, may increase to 25 mg orally once daily in patients tolerating 10 mg once daily. 2.3 Temporary Interruption for Surgery Withhold JARDIANCE for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume JARDIANCE when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ]. 2.4 Recommendations Regarding Missed Dose • If a dose is missed, instruct patients to take the dose as soon as possible. • Advise patients not to double up the next dose.

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 i…

4 CONTRAINDICATIONS JARDIANCE is contraindicated in patients: • with a hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred [see Warnings and Precautions (5.6) ] . • Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE. ( 4 )

7 DRUG INTERACTIONS See Table 4 for clinically relevant interactions with JARDIANCE. Table 4Clinically Relevant Interactions with JARDIANCE 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 JARDIANCE, 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. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. Intervention Coadministration of JARDIANCE with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during JARDIANCE initiation and dosage changes. 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. See full prescribing information for information on drug interactions and interference of JARDIANCE with laboratory tests. ( 7 )

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, JARDIANCE is not recommended during the second and third trimesters of pregnancy. The limited available data with JARDIANCE 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, 10, 30, 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).

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 2Adverse 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 mycot…