Empagliflozin, Linagliptin and Metformin

TRIJARDY XR is a combination of empagliflozin, linagliptin, and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease. TRIJARDY XR is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 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.

TRIJARDY XR TRIJARDY XR contains: empagliflozin, a SGLT2 inhibitor, linagliptin, a DPP-4 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. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.

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. Initiation is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2, due to the metformin HCl component. The maximum recommended dosage of TRIJARDY XR is 25 mg empagliflozin, 5 mg linagliptin and 2,000 mg metformin HCl. Take once daily with a meal in the morning. Swallow whole, do not split, crush, dissolve, or chew. TRIJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting.

TRIJARDY XR is 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, linagliptin, metformin HCl or any of the excipients in TRIJARDY XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). Metabolic acidosis, including diabetic ketoacidosis. Hypersensitivity to empagliflozin, linagliptin, metformin HCl, or any of the excipients in TRIJARDY 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 TRIJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRIJARDY XR.

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 Pancreatitis Volume Depletion Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Lower Limb Amputation Hypersensitivity Reactions Vitamin B 12 Deficiency Severe and Disabling Arthralgia Bullous Pemphigoid Heart Failure Most common adverse reactions (5% or greater incidence) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, diarrhea, constipation, headache, and gastroenteritis.

Table 2 describes clinically relevant interactions with TRIJARDY XR. Table 2 Clinically Relevant Interactions with TRIJARDY 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 TRIJARDY 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). Protect from exposure to high humidity.