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.

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. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

A patient with type 2 diabetes previously well-controlled on KOMBIGLYZE XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.

Before initiating KOMBIGLYZE XR, obtain an estimated glomerular filtration rate (eGFR).

KOMBIGLYZE XR is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m².

Initiation of KOMBIGLYZE XR is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m².

Obtain an eGFR at least annually in all patients taking KOMBIGLYZE XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

In patients taking KOMBIGLYZE XR whose eGFR later falls below 45 mL/minute/1.73 m², assess the benefit and risk of continuing therapy.

In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group. Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment.

Consider the risks and benefits of KOMBIGLYZE XR prior to initiating treatment in patients at a higher risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure, and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KOMBIGLYZE XR.

Reports of decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include 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.

There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors.

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP‑4 inhibitor use.

There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin.

When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with KOMBIGLYZE XR.

Strong Inhibitors of CYP3A4/5 Enzymes: Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of saxagliptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor.

Carbonic Anhydrase Inhibitors: 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 KOMBIGLYZE XR may increase the risk for lactic acidosis.

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.

Some medications can predispose to hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Limited available data with KOMBIGLYZE XR or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Animal studies: minor skeletal abnormalities and death, moribundity, or abortion.

There is no information regarding the presence of KOMBIGLYZE XR or saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk.

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• Use in patients under the age of 18. GoToSource

• Polycystic ovary syndrome. GoToSource

Bullous pemphigoid (blistering skin condition) and severe arthralgias (joint pain). GoToSource

Vitamin B12 deficiency. GoToSource

Lactic acidosis (too much acid in the body). GoToSource

Angioedema (swelling in deep layers of skin). GoToSource

Hemolytic anemia (red blood cells are destroyed faster than they can be made). GoToSource

Heart failure, hypoglycemia (low blood sugar) and pancreatitis (inflammation of the pancreas). GoToSource

Lawsuits filed for heart failure.