KOMBIGLYZE XR is a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. (1, 14)

Limitations of Use:

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Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.1)

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Has not been studied in patients with a history of pancreatitis. (1.1, 5.2)

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Administer once daily with the evening meal. (2.1)

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Individualize the starting dose based on the patient’s current regimen then adjust the dosage based on effectiveness and tolerability. (2.1)

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Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin HCl extended-release. (2.1)

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Swallow whole. Never crush, cut, or chew. (2.1)

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Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). (2.2, 7.1)

Tablets:

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5 mg saxagliptin/500 mg metformin HCl extended-release (3)

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5 mg saxagliptin/1000 mg metformin HCl extended-release (3)

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2.5 mg saxagliptin/1000 mg metformin HCl extended-release (3)

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Renal impairment. (4)

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Hypersensitivity to metformin hydrochloride. (4)

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Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)

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History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to KOMBIGLYZE XR or saxagliptin. (4)

WARNINGS AND PRECAUTIONS

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Lactic Acidosis: Warn patients against excessive alcohol intake. KOMBIGLYZE XR not recommended in hepatic impairment and contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue KOMBIGLYZE XR in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. (4, 5.1, 5.3, 5.4, 5.7, 5.10, 5.11)

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Acute Pancreatitis (postmarketing reports): If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR. (5.2, 6.2)

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Vitamin B12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. (5.5, 6.1)

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Hypoglycemia: In the saxagliptin add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.9, 6.1)

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Hypersensitivity-Related Events (e.g., urticaria, facial edema): More common in patients treated with saxagliptin than in patients treated with placebo; and postmarketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. Promptly discontinue KOMBIGLYZE XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.13, 6.1, 6.2)

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Macrovascular Outcomes: No conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other antidiabetic drug. (5.14)

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Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo are: diarrhea and nausea/vomiting. (6.1)

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Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache. (6.1)

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Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin and more commonly than in patients treated with metformin alone are: headache and nasopharyngitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole) significantly increases saxagliptin concentrations. Limit KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily. (2.2, 7.1)

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Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. (5.10, 7.2)

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No adequate and well-controlled studies in pregnant women. (8.1)