Linagliptin and Metformin

JENTADUETO is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use JENTADUETO is not recommended in patients with type 1 diabetes mellitus. JENTADUETO has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using JENTADUETO. JENTADUETO is a combination of 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 in patients with type 1 diabetes mellitus. Has not been studied in patients with a history of pancreatitis

JENTADUETO JENTADUETO contains: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. 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. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels.

Individualize the starting dosage of JENTADUETO based on the patient's current regimen. The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily. Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin. Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). Do not use in patients with eGFR below 30 mL/min/1.73 m 2 Initiation is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m 2 Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 Discontinue if eGFR falls below 30 mL/min/1.73 m 2 JENTADUETO may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures

JENTADUETO is contraindicated in patients with: severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). acute or chronic metabolic acidosis, including diabetic ketoacidosis. hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). Metabolic acidosis, including diabetic ketoacidosis. Hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO

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. Lactic Acidosis: See boxed warning. Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO. Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JENTADUETO. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with JENTADUETO.

The following serious adverse reactions are described below or elsewhere in the prescribing information: Lactic Acidosis Pancreatitis Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Hypersensitivity Reactions Vitamin B 12 Deficiency Severe and Disabling Arthralgia Bullous Pemphigoid Heart Failure Most common adverse reactions (incidence ≥5% and more often than placebo) were nasopharyngitis and diarrhea

Table 2 describes clinically relevant interactions with JENTADUETO. Table 2 Clinically Relevant Interactions with JENTADUETO Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with JENTADUETO 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.