Metformin and Saxagliptin

Saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Saxagliptin and metformin hydrochloride extended-release tablets are a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) 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 the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Saxagliptin and Metformin Hydrochloride Extended-Release Tablets Saxagliptin and metformin hydrochloride extended-release tablets contain two antihyperglycemic medications: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin HCl, a biguanide. Saxagliptin Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved.

• Administer once daily with the evening meal. • Individualize the starting dosage based on the patient’s current regimen then adjust the dosage based on effectiveness and tolerability. • Do not exceed a daily dosage of 5 mg saxagliptin/2,000 mg metformin HCl extended-release. • Swallow whole. Never crush, cut, or chew. • Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole).

Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. • A history of a serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported. • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). • Metabolic acidosis, including diabetic ketoacidosis.

Boxed warning (lactic acidosis •): Post-marketing 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. • Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets. • Heart Failure: Consider the risks and benefits of saxagliptin and metformin hydrochloride extended-release tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. • Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually.

The following serious adverse reactions are described below or elsewhere in the prescribing information: • Lactic Acidosis • Pancreatitis • Heart Failure • Vitamin B 12 Deficiency • Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues • Hypersensitivity Reactions • Severe and disabling arthralgia • Bullous pemphigoid • Most common adverse reactions with metformin HCl extended-release (incidence > 5% and more often than placebo) are: diarrhea and nausea/vomiting. • Most common adverse reactions with saxagliptin (incidence ≥ 5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. • Adverse reactions with coadministered saxagliptin and metformin HCl (incidence ≥ 5% and more often than placebo) are: headache and nasopharyngitis.

The concomitant use of saxagliptin and metformin hydrochloride extended-release tablets 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. Therefore, consider more frequent monitoring of patients. 7 DRUG INTERACTIONS • Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with saxagliptin and metformin hydrochloride extended-release tablets significantly increases saxagliptin concentrations. Limit saxagliptin and metformin hydrochloride extended-release tablets dosage to 2.5 mg/1,000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor. • Carbonic anhydrase inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring.

Store at 20° to 25°C (68° to 77°F).