Important Safety Information for KOMBIGLYZE XR

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.

If lactic acidosis is suspected, discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Contraindications

• Severe renal impairment (eGFR below 30 mL/min/1.73 m²)
• Prior serious hypersensitivity reaction to saxagliptin or hypersensitivity to metformin hydrochloride
• Metabolic acidosis, including diabetic ketoacidosis

Warnings and Precautions

Pancreatitis: There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin, and in the SAVOR cardiovascular outcomes trial. Observe for pancreatitis. If pancreatitis is suspected, discontinue KOMBIGLYZE XR.

Heart Failure: In the SAVOR cardiovascular outcomes trial, more patients treated with saxagliptin were hospitalized for heart failure compared to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. If heart failure develops, consider discontinuation of KOMBIGLYZE XR.

Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.

Hypoglycemia: When saxagliptin was used in combination with a sulfonylurea or with insulin, the incidence of confirmed hypoglycemia was increased over that of placebo. Consider lowering the dose of these agents when coadministered with KOMBIGLYZE XR.

Hypoglycemia could occur when caloric intake is deficient, strenuous exercise is not compensated by caloric supplementation, or when KOMBIGLYZE XR is used with other glucose-lowering agents or ethanol.

Hypersensitivity: Serious reactions have been reported in patients treated with saxagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR. Use caution in patients with a history of angioedema to another DPP-4 inhibitor.

Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider discontinuing drug if appropriate.

Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If suspected, discontinue KOMBIGLYZE XR.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR.

Adverse Reactions

Most common adverse reactions reported in =5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%).

Adverse reactions reported in >5% of patients treated with metformin XR and more commonly than in patients treated with placebo were diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).

Adverse reactions reported in =5% of treatment-naive patients treated with coadministered saxagliptin and metformin IR and more commonly than in patients treated with metformin IR alone were headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).

Drug Interactions

Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with KOMBIGLYZE XR significantly increases saxagliptin concentrations. Recommend limiting saxagliptin dosage to 2.5 mg once daily.

Use in Specific Populations

Assess renal function prior to initiation of KOMBIGLYZE XR and periodically thereafter. If eGFR falls below 45 mL/minute/1.73 m², assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Discontinue KOMBIGLYZE XR if eGFR falls below 30 mL/minute/1.73 m².

Indication and Limitations of Use

• KOMBIGLYZE XR is 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
• KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis

Please see US Full Prescribing Information for KOMBIGLYZE XR (5/500•5/1000•2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis, and Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.