Pharmaceutical Approval Update: part 3
Metformin tablet. Hypoglycemia does not usually occur in patients receiving metformin alone, but it can occur when caloric intake is deficient, when patients do not compensate for strenuous exercise with caloric supplementation, or during concomitant use with other glucose-lowering agents (e.g., sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in older patients and in patients taking beta-adrenergic blocking drugs.
Concomitant medications affecting renal function or metformin disposition: Caution should be used with concomitant drugs that can affect renal function, that can cause significant hemodynamic changes, or that can interfere with the disposition of metformin (e.g., cationic drugs eliminated by renal tubular secretion).
Radiological studies with contrast materials. Intra-vascular contrast studies with iodinated materials, such as IV urograms, IV cholangiography, angiography, and computed tomography scans with intravascular contrast, can lead to acute alterations in renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, when these studies are planned, sitagliptin/metformin HCl tablets should be temporarily discontinued at the time of or before the procedure, and they should be withheld for 48 hours after the procedure. They should be re-instituted only after renal function has been re-evaluated and has been found to be normal.
Hypoxic states. Cardiovascular collapse (shock) from any cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. If such events occur in patients taking sitagliptin/metformin, the drug should be promptly discontinued.
Loss of glycemic control. When patients who have been stabilized on any diabetic regimen are exposed to stress (fever, trauma, infection, or surgery), glycemic control may be lost temporarily. It may be necessary to withhold sitagliptin/met-formin tablets and administer insulin for a while. The tablets may be re-instituted after the acute episode is resolved.
Dosage and Administration. The dosage of antihyper-glycemic therapy should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of sitagliptin 100 mg and metformin 2,000 mg. The tablets should generally be given twice daily with meals, with gradual dose escalation, to reduce GI side effects resulting from metformin. The following doses are available: sitagliptin 50 mg/metformin 500 mg and sitagliptin 50 mg/metformin 1,000 mg.
Inadequate glycemic control with metformin mono-therapy: If glucose control is inadequate with metformin alone, the usual starting dose should be equal to sitagliptin 100 mg daily (or 50 mg twice daily) plus the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose is sitagliptin 50 mg/metformin 1,000 mg twice daily.
Inadequate glycemic control with sitagliptin mono-therapy: If glucose is not adequately controlled with sitagliptin alone, the usual starting dose is sitagliptin 50 mg/metformin
500 mg twice daily. Doses may be titrated up to sitagliptin 50 mg/metformin 1,000 mg twice daily. If patients are taking sitagliptin monotherapy and the dose is adjusted for renal insufficiency, they should not be switched to sitagliptin/met-formin tablets.
Switching from sitagliptin/metformin: For patients switching from sitagliptin coadministered with metformin, the combination tablets may be initiated at the dose of sitagliptin and metformin already being taken. No studies have specifically focused on patients who had been previously treated with other oral antihyperglycemic agents and who were then switched to sitagliptin/metformin tablets. Any changes in therapy for type-2 diabetes should be undertaken with care and appropriate monitoring, because glycemic control can be affected.
Commentary: Type-2 diabetes is characterized by elevated blood glucose levels and a lack of proper production of insulin. In the U.S., nearly 21 million people have diabetes, and type-2 accounts for 90% to 95% of cases.
Sitagliptin/metformin HCl tablets were approved as an adjunct to diet and exercise to improve glucose control in type-2 diabetic adults whose glucose levels were not adequately controlled with metformin or sitagliptin alone or in patients already using the combination.
The tablets target the three key defects of type-2 diabetes for improved glycemic control: diminished insulin release, uncontrolled production of glucose, and insulin resistance. Sitagliptin addresses diminished insulin release and uncontrolled production of glucose. Metformin drug addresses insulin resistance and improves insulin sensitivity by increasing glucose uptake and utilization by muscles and tissues. The tablets lower glycosylated hemoglobin values by reducing both postprandial and fasting glucose levels.