empagliflozin 25 MG Oral Tablet [Jardiance]

INDICATIONS AND USAGE SYNJARDY SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated 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. SYNJARDY XR SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Cardiovascular (CV) death in adults with established CV disease. ( 1 ) CV death and hospitalization for heart failure in adults with heart failure. ( 1 ) Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. ( 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 ) Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, 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. Empagliflozin is not expected to be effective in these populations. ( 1 ) SYNJARDY SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated 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 . SYNJARDY XR SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Cardiovascular (CV) death in adults with established CV disease. • CV death and hospitalization for heart failure in adults with heart failure. • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. Limitations of Use • SYNJARDY and SYNJARDY XR are 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 (5.2) ] . • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, 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) ] . Empagliflozin is not expected to be effective in these populations.

DOSAGE AND ADMINISTRATION Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. ( 2.1 ) Individualize the starting dosage based on the patient's current regimen and renal function. ( 2.2 , 2.3 , 2.4 ) The maximum recommended dosage is 25 mg/day of empagliflozin and 2,000 mg/day of metformin HCl. ( 2.2 , 2.3 ) Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. ( 2.4 ) SYNJARDY: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. ( 2.2 , 2.3 ) SYNJARDY XR: take orally once daily with a meal in the morning, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. Swallow whole; do not split, crush, dissolve, or chew. ( 2.2 ) SYNJARDY or SYNJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 ) Withhold SYNJARDY or SYNJARDY XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 ) 2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated [see Warnings and Precautions (5.1 , 5.3) ] . Assess volume status. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6) ] . 2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults When switching to SYNJARDY or SYNJARDY XR from: Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg. Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg. Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component. Recommended dosage of SYNJARDY or SYNJARDY XR: The recommended total daily dosage of empagliflozin is 10 mg. For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. Take SYNJARDY orally twice daily with meals. Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew. 2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older Individualize the dosage of SYNJARDY based on the patient's current regimen. Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg . Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ]. 2.4 Dosage Recommendations in Patients with Renal Impairment Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] . 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart SYNJARDY or SYNJARDY XR if renal function is stable [see Warnings and Precautions (5.1) ] . 2.6 Temporary Interruption for Surgery Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . 2.7 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.

WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk of ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue SYNJARDY or SYNJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.2 ) Volume Depletion: Before initiating SYNJARDY or SYNJARDY XR, 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. ( 5.3 ) 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 SYNJARDY or SYNJARDY XR, and promptly institute appropriate medical and/or surgical intervention. ( 5.4 ) 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 SYNJARDY or SYNJARDY XR. ( 5.5 ) Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. ( 5.6 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with empagliflozin. If hypersensitivity reactions occur, discontinue SYNJARDY or SYNJARDY XR, treat promptly, and monitor until signs and symptoms resolve. ( 5.7 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.8 ) 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of SYNJARDY or SYNJARDY XR. In SYNJARDY or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery . Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY or SYNJARDY XR and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] : Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR). SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications (4) ]. Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions: The concomitant use of SYNJARDY or SYNJARDY XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7) ] . Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] . Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY or SYNJARDY XR if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY or SYNJARDY XR should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue SYNJARDY or SYNJARDY XR. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR. Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of SYNJARDY or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease. 5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, empagliflozin, a component of SYNJARDY or SYNJARDY XR, 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 sodiu

CONTRAINDICATIONS SYNJARDY and SYNJARDY XR are contraindicated in patients with: severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ]. acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1) ]. hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR, reactions such as angioedema have occurred [see Warnings and Precautions (5.7) ] . Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR ( 4 )

Mechanism of Action SYNJARDY or SYNJARDY XR SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin HCl, a biguanide. Empagliflozin Empagliflozin is an inhibitor of 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 including, but not restricted to, increasing tubuloglomerular feedback and reducing intraglomerular pressure, lowering both pre- and afterload of the heart and downregulating sympathetic activity. Metformin HCl Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin HCl does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.5) ] and does not cause hyperinsulinemia. With metformin HCl therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.