Empagliflozin and metformin: uses, appearance and warnings

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.

SYNJARDY Tablets: 5 mg empagliflozin/500 mg metformin HCl ( 3 ) 5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/500 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) SYNJARDY XR Tablets: 5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 10 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 25 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) SYNJARDY Tablets: Empagliflozin Strength Metformin HCl Strength Color/Shape Tablet Markings 5 mg 500 mg orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500". 5 mg 1,000 mg brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000". 12.5 mg 500 mg pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500". 12.5 mg 1,000 mg dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000". …

SYNJARDY tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 500 mg Metformin HCl orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500". Bottles of 60 Bottles of 180 0597-0159-60 0597-0159-18 5 mg Empagliflozin 1,000 mg Metformin HCl brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000". Bottles of 60 Bottles of 180 0597-0175-60 0597-0175-18 12.5 mg Empagliflozin 500 mg Metformin HCl pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500". Bottles of 60 Bottles of 180 0597-0180-60 0597-0180-18 12.5 mg Empagliflozin 1,000 mg Metformin HCl dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000". Bottles of 60 Bottles of 180 0597-0168-60 0597-0168-18 SYNJARDY XR extended-release tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 1,000 mg Metformin HCl olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line. Bottles of 60 Bottles of 180 0597-0290-74 0597-0290-59 10 mg Empagliflozin 1,000 mg Metformin HCl orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line. Bottles of 30 Bottles of 90 0597-0280-73 0597-0280-90 12.5 mg Empagliflozin 1,000 mg Metformin HCl blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line. Bottles of 60 Bottles of 180 0597-0300-45 0597-0300-93 25 mg Empagliflozin 1,000 mg Metformin HCl light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line. …

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 )

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. …

The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2) ] Volume Depletion [see Warnings and Precautions (5.3) ] Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.4) ] Hypoglycemia [see Warnings and Precautions (5.5) ] Lower Limb Amputation [see Warnings and Precautions (5.6) ] Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.8) ] Most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infections and fema …

See Table 4 for clinically relevant interactions with SYNJARDY or SYNJARDY XR. Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis. Intervention Consider more frequent monitoring of these patients. …