Empagliflozin and Metformin

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. CV death and hospitalization for heart failure in adults with heart failure.

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.

Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. Individualize the starting dosage based on the patient's current regimen and renal function. The maximum recommended dosage is 25 mg/day of empagliflozin and 2,000 mg/day of metformin HCl. 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: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. 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.

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

Boxed warning (lactic acidosis): Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. 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.

The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Volume Depletion Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections Hypoglycemia Lower Limb Amputation Hypersensitivity Reactions Vitamin B 12 Deficiency Most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infections and female genital mycotic infections. Most common adverse reactions associated with metformin HCl (>5%) are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

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.

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).