JARDIANCE

JARDIANCE tablets for oral use contain empagliflozin, an inhibitor of the SGLT2. The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S). Its molecular formula is C 23 H 27 ClO 7 and the molecular weight is 450.91. The structural formula is: Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene. Each film-coated tablet of JARDIANCE contains 10 mg or 25 mg of empagliflozin (free base) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the film coating contains the following inactive ingredients: hypromellose, polyethylene glycol, talc, titanium dioxide, and yellow ferric oxide. Chemical Structure

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.

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 major surgery or procedures associated with prolonged fasting. ( 2.4 ) 2.1 Testing Prior to Initiation of JARDIANCE Assess renal function before initiating JARDIANCE and as clinically indicated [see Warnings and Precautions (5.2) ] . 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 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Do not double up the next dose. 2.4 Temporary Interruption for Surgery Withhold JARDIANCE for at least 3 days, if possible, prior to major 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) ].

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 (5.8) ] . Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE. ( 4 )

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) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3) ] Hypoglycemia [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 (5.8) ] 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 (5.7) ]. 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)

See Table 4 for clinically relevant interactions with JARDIANCE. Table 4 Clinically 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 )

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].