Limitations of Use

JARDIANCE is not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.1)] .

JARDIANCE is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2. JARDIANCE is likely to be ineffective in this setting based upon its mechanism of action.

2.1 Prior to Initiation of JARDIANCE

• Assess renal function before initiating JARDIANCE and as clinically indicated [see Warnings and Precautions (5.2)] .
• In patients with volume depletion, correct this condition before initiating JARDIANCE [see Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6)].

2.2 Recommended Dosage

The recommended dose of JARDIANCE is 10 mg once daily in the morning, taken with or without food.

For additional glycemic control, the dose may be increased to 25 mg in patients tolerating JARDIANCE.

Use for glycemic control is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2.

Data are insufficient to provide a dosing recommendation in patients;

who have type 2 diabetes and established cardiovascular disease with an eGFR less than 30 mL/min/1.73 m 2, or

who have heart failure with an eGFR less than 20 mL/min/1.73 m 2 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)] .

JARDIANCE is contraindicated in patients on dialysis [see Contraindications (4)] .

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 JARDIANCE. Fatal cases of ketoacidosis have been reported in patients taking JARDIANCE. 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. JARDIANCE is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)] .

Patients treated with JARDIANCE 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 JARDIANCE may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, JARDIANCE 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 JARDIANCE, 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 JARDIANCE for at least 3 days prior to surgery [see Clinical Pharmacology (12.2, 12.3)] .

Consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE 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 JARDIANCE.

Educate 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 Urosepsis and Pyelonephritis

There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including JARDIANCE. 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 JARDIANCE 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 JARDIANCE.

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 JARDIANCE. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with JARDIANCE 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 JARDIANCE, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.6 Genital Mycotic Infections

JARDIANCE 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 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)] .

6.1 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 patients with type 2 diabetes mellitus and in patients with heart failure. The overall safety profile of JARDIANCE was generally consistent across the studied indications.

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.

• Ketoacidosis
• Urosepsis and Pyelonephritis
• Necrotizing Fasciitis of the Perineum (Fournier's gangrene)
• Angioedema
• Acute Kidney Injury
• Skin Reactions (e.g., rash, urticaria)

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of JARDIANCE have not been established in pediatric patients.

8.5 Geriatric Use

In glycemic control studies in patients with type 2 diabetes mellitus, a total of 2721 (32%) patients treated with JARDIANCE were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)] . The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] .

In heart failure studies, EMPEROR-Reduced included 1188 (64%) patients treated with JARDIANCE 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2402 (80%) patients treated with JARDIANCE 65 years of age and older, and 1281 (43%) patients 75 years of age and older. Safety and efficacy were similar for patients 65 years and younger and those older than 65 years.

8.6 Renal Impairment

The efficacy and safety of JARDIANCE for glycemic control were evaluated in a study of patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m 2) [see Clinical Studies (14)] . In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m 2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m 2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m 2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)] . Use of JARDIANCE for glycemic control in patients without established cardiovascular disease or cardiovascular risk factors is not recommended when eGFR is less than 30 mL/min/1.73 m 2.

In a large cardiovascular outcomes study of patients with type 2 diabetes and established cardiovascular disease, there were 1819 patients with eGFR below 60 mL/min/1.73 m 2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)].

Studies of patients with heart failure [see Clinical Studies (14)] enrolled patients with eGFR equal to or above 20 mL/min/1.73 m 2. No dose adjustment is recommended for these patients. There are insufficient data to support a dosing recommendation in patients with eGFR below 20 mL/min/1.73 m 2.

Efficacy and safety studies with JARDIANCE did not enroll patients with an eGFR less than 20 mL/min/1.73 m 2. JARDIANCE is contraindicated in patients on dialysis [see Contraindications (4)].

8.7 Hepatic Impairment

JARDIANCE may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)] .

12.1 Mechanism of Action

Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions such as lowering both pre-and afterload of the heart and downregulating sympathetic activity.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Glycemic Control in Patients with Type 2 Diabetes Mellitus

JARDIANCE has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, linagliptin, and insulin. JARDIANCE has also been studied in patients with type 2 diabetes with mild or moderate renal impairment.

In patients with type 2 diabetes, treatment with JARDIANCE reduced hemoglobin A1c (HbA1c), compared to placebo. The reduction in HbA1c for JARDIANCE compared with placebo was observed across subgroups including gender, race, geographic region, baseline BMI and duration of disease.

In vivo Assessment of Drug Interactions

Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2).

Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% - 125%)]

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single dose

Figure 2 Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% - 125%)]

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon ®; gadministered as ramipril

Heart Failure

EMPEROR-Reduced (NCT03057977) was a double-blind study conducted in patients with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy and safety of JARDIANCE as adjunct to standard of care heart failure therapy.

Of 3730 patients, 1863 were randomized to JARDIANCE 10 mg and 1867 to placebo and were followed for a median of 16 months. The mean age of the study population was 67 years (range: 25 to 94 years) and 76% were men, 24% were women, and 27% were 75 years of age or older. Approximately 71% of the study population were White, 18% Asian and 7% Black or African American. At baseline, 50% of the patients had type 2 diabetes mellitus.

At randomization, 75% of patients were NYHA class II, 24% were class III and 0.5% were class IV. The mean LVEF was 28%. At baseline, the mean eGFR was 62 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g. Approximately half of the patients (52%) had eGFR equal to or above 60 mL/min/1.73 m 2, 24% had eGFR 45 to less than 60 mL/min/1.73 m 2, 19% had eGFR 30 to less than 45 mL/min/1.73 m 2 and 5% had eGFR 20 to less than 30 mL/min/1.73 m 2.

At baseline, 88% of patients were treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or angiotensin receptor-neprilysin inhibitors (ARNI), 95% with beta-blockers, 71% with mineralocorticoid receptor antagonists (MRA), and 95% with diuretics.

The primary endpoint was the time to first event of either cardiovascular death (CV) or hospitalization for heart failure (HHF). First and recurrent HHF was assessed as a key secondary endpoint.

JARDIANCE was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalization for heart failure compared with placebo, mostly through a reduction in hospitalization for heart failure. JARDIANCE reduced the risk of first and recurrent HHF (see Table 14 and Figures 7 and 8).

Figure 7 Time to First Occurrence of the Primary Composite Endpoint of Cardiovascular Death or Hospitalization for Heart Failure

Figure 8 Time to Event of Hospitalization for Heart Failure (First and Recurrent)

The results of the primary composite were generally consistent across the pre-specified subgroups (see Figure 9).

Figure 9 Treatment Effects for the Primary Composite Endpoint (Cardiovascular Death and Hospitalization for Heart Failure) Subgroup Analysis (EMPEROR-Reduced)

LVEF >30%: Includes both above and below the median NT-proBNP. To be eligible for inclusion, patients with an LVEF >30% were required to meet a higher NT-proBNP threshold than those with LVEF ≤30%, unless they additionally had a history of HHF within the past 12 months.

EMPEROR-Preserved (NCT03057951) was a double-blind study conducted in patients with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy and safety of JARDIANCE as adjunct to standard of care therapy.

Of 5988 patients, 2997 were randomized to JARDIANCE 10 mg and 2991 to placebo and were followed for a median of 26 months. The mean age of the study population was 72 years (range: 22 to 100 years) and 55% were men, 45% were women, and 43% were 75 years of age or older. Approximately 76% of the study population were White, 14% Asian and 4% Black or African American.

At randomization, 82% of patients were NYHA class II, 18% were class III and 0.3% were class IV. The EMPEROR-Preserved study population included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%). At baseline, the mean eGFR was 61 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g. Approximately half of the patients (50%) had eGFR equal to or above 60 mL/min/1.73 m 2, 26% had eGFR 45 to less than 60 mL/min/1.73 m 2, 19% had eGFR 30 to less than 45 mL/min/1.73 m 2, and 5% had eGFR 20 to less than 30 mL/min/1.73 m 2.

At baseline, 81% of patients were treated with ACE inhibitors, ARBs, or ARNI, 86% with beta-blockers, 38% with MRAs, and 86% with diuretics.

The primary endpoint was the time to first event of either CV death or HHF. First and recurrent HHF was assessed as a key secondary endpoint.

JARDIANCE was superior in reducing the risk of the primary composite endpoint compared with placebo, mostly through a reduction in hospitalization for heart failure. JARDIANCE reduced the risk of first and recurrent HHF (see Table 15 and Figures 10 and 11).

Table 14 Treatment Effect for the Primary Composite Endpoint, its Components, and Key Secondary Endpoints

CV death or HHF a 462 (24.7%) 361 (19.4%) 0.75 (0.65, 0.86) <0.0001

CV death a,b 202 (10.8%) 187 (10.0%) 0.92 (0.75, 1.12)

HHF a 342 (18.3%) 246 (13.2%) 0.69 (0.59, 0.81)

Number of Events

First and recurrent HHF c 553 388 0.70 (0.58, 0.85) 0.0003

Placebo



N=1867 JARDIANCE 10 mg



N=1863 Hazard ratio vs placebo



(95% CI) p-value

Number of Patients (%) aTime to first event



bIncludes deaths following hospitalization



cJoint frailty model accounting for CV death

Figure 10 Time to First Occurrence of the Primary Composite Endpoint of Cardiovascular Death or Hospitalization for Heart Failure

Figure 11 Time to Event of Hospitalization for Heart Failure (First and Recurrent)

The results of the primary composite endpoint were consistent across the pre-specified subgroups (see Figure 12).

Figure 12 Treatment Effects for the Primary Composite Endpoint (Cardiovascular Death or Hospitalization for Heart Failure) Subgroup Analysis (EMPEROR-Preserved)

Table 15 Treatment Effect for the Primary Composite Endpoint, its Components, and Key Secondary Endpoints

CV death or HHF a 511 (17.1%) 415 (13.8%) 0.79 (0.69, 0.90) 0.0003

CV death a,b 244 (8.2%) 219 (7.3%) 0.91 (0.76, 1.09)

HHF a 352 (11.8%) 259 (8.6%) 0.71 (0.60, 0.83)

Number of Events

First and recurrent HHF c 541 407 0.73 (0.61, 0.88) 0.0009

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of JARDIANCE, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue JARDIANCE and seek medical attention immediately [see Warnings and Precautions (5.1)] .

Volume Depletion

Inform patients that symptomatic hypotension may occur with JARDIANCE and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)] . Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.3)] .

Hypoglycemia

Inform patients that the incidence of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4)] .

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier's gangrene) have occurred with JARDIANCE. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.5)] .

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)] .

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Inform male patients that yeast infection of the penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)] .

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with JARDIANCE. Advise patients to report immediately any skin reaction or angioedema, and to discontinue drug until they have consulted prescribing healthcare provider [see Warnings and Precautions (5.7)] .

Laboratory Tests

Inform patients that elevated glucose in urinalysis is expected when taking JARDIANCE.

Pregnancy

Advise pregnant patients, and patients of reproductive potential, of the potential risk to a fetus with treatment with JARDIANCE [see Use in Specific Populations (8.1)] . Instruct patients to report pregnancies to their healthcare provider as soon as possible.

Lactation

Advise patients that breastfeeding is not recommended during treatment with JARDIANCE [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients to take JARDIANCE only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.