Indication
This is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Sitagliptin and Metformin is appropriate.
Pharmacology
Sitagliptin: The DPP-4 inhibitors are a class of agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, Sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. This mechanism is unlike the mechanism seen with sulfonylureas; sulfonylureas cause insulin release even when glucose levels are low, which can lead to sulfonylurea-induced hypoglycemia in patients with type ll diabetes and in normal subjects. Sitagliptin demonstrates high selectivity for DPP-4 and does not inhibit closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, and stimulates intracellular glycogen synthesis by acting on glycogen synthase. In muscle, it increases insulin sensitivity, improving peripheral glucose uptake and utilization. Metformin also delays intestinal glucose absorption. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.
Dosage
The dosage of Sitagliptin & Metformin should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.Sitagliptin & Metformin should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin. The starting dose of Sitagliptin & Metformin should be based on the patient's current regimen. The recommended starting dose in patients NOT currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of Sitagliptin & Metformin is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Co-administration of Sitagliptin & Metformin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. No studies have been performed specifically examining the safety and efficacy of Sitagliptin & Metformin in patientspreviously treated with other oral antihyperglycemic agents and switched to Sitagliptin & Metformin. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur
Interaction
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine,triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems.Co-administration of Digoxin and Sitagliptin may slightly increase the mean peak drug concentration of Digoxin. But no dosage adjustment of digoxin or Sitagliptin is recommended
Contradiction
Sitagliptin + Metformin HCl is contraindicated in patients with:
Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels 1.5 mg/dL [males], 1.4 mg/dL [females].
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
History of a serious hypersensitivity reaction to the combination or sitagliptin, such as anaphylaxis or angioedema.
Side Effect
The most common adverse reactions reported in > 5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. Nasopharyngitis was the only adverse reaction reported in > 5% of patients treated with sitagliptin monotherapy. Hypoglycemia was also reported more commonly in patients treated with the combination of Sitagliptin and sulfonylurea, with or without Metformin, than in patients given the combination of placebo and sulfonylurea, with or without Metformin. The most common established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
Pregnancy
Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women with the combination of Metformin/ Sitagliptin or its individual components; therefore, the safety of the combination in pregnant women is not known. The combination of Sitagliptin & Metformin should be used during pregnancy only if clearly needed. Lactation: It is not known whether Sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this combination is administered to a nursing woman.
Precaution
Do not use the combination of Sitagliptin & Metformin in patients with hepatic disease.
Before initiating the combination and at least annually thereafter, assess renal function and verify as normal.
May need to discontinue the combination and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery
Overdose
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.Hypoglycemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.
Storage
Store in a cool and dry place. Protect from light and moisture. Keep out of the reach of children