Sitaglip (Sitagliptin + Metformin HCI) tablets contain two oral antidiabetic
medications used in the management of type 2 diabetes; Sitagliptin and Metformin HCI. Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzymes.
Mechanism of Action
It is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones, Including 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 by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.
Metformin HCI is a biguanide Mat improves glycemic control in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
The absolute bioavailability of sitagliptin is approximately 87%. Co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.
The absolute bioavailability of a metformin HCI 500mg tablet given under fasting conditions is approximately 50-60%.
The fraction of Sitagliptin reversibly bound to plasma proteins is low (38%).
Metformin HCl is negligibly bound to plasma proteins. At usual clinical doses and dosing schedules of metformin HCI. steady-state plasma concentrations of metformin HCI are reached within 24-48 hours and are generally <1mcg/ml.
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being minor pathway of elimination.
Intravenous single-dose studies in normal subjects demonstrate that Metformin HCl is excreted unchanged in the urine and does not undergo hepatic Metabolism or biliary excretion.
The apparent terminal T1/2 following a 100mg oral dose of sitagliptin is approximately 12.4 hours and renal clearance is approximately 350mL/min. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin HCI. Following oral administration, Approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours
Sitaglip-DS Tab 50/1000mg
|Each Film Coated Tablet Contains:|
|Sitagliptin (as Phosphate Monohydrate)||50 mg|
|Metformin HCl||1000 mg|
|Sitaglip (Sitagliptin + Metformin HCI) is indicated:
• As initial therapy in patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise do not provide adequate glycemic control, when dual sitagliptin and metformin HCI therapy is appropriate (i.e. high initial HbA1c levels and poor prospects of response to monotherapy).
• As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus inadequately controlled on sitagliptin or metformin HCI alone or in patients already being treated with the combination of Sitagliptin and Metformin HCI.
• In combination with a sulphonyl urea is an adjunct to diet and exercise In patients with type 2 diabetes mellitus when combination therapy with metformin HCI and sulphonyl urea does not provide adequate glycemic control.
• As an adjunct to diet and exercise to improve glycemic control in combination with insulin In patients with type 2 diabetes mellitus inadequately controlled on insulin and metformin HCl or in patients already being treated with the combination of sitagliptin, Metformin HCI and insulin.
The dosage of Sitaglip (Sitagliptin + Metformin HCI) should be individualized on the basis of the patients current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100mg Sitagliptin and 2000mg Metformin HCl.
Sitaglip, (Sitagliptin + Metformin HCI) should be given once daily with a meal preferably in the evening. The dose should be escalated gradually to reduce the gastrointestInal (GI) side effects due to metformin HCl. For patients using 50mg sitaglIptin & 500mg metformin HCI tablet or the 50mg SitaglIptin & 1000mg Metformin HCI tablet, two tablets should be taken together once daily
As initial therapy
For patients with type 2 diabetes mellitus, whose hyperglycemia is inadequately controlled with diet and exercise alone, when dual therapy is appropriate, the recommended total daily starting dose of Sitaglip is 100mg Sitagliptin and 1000mg Metformln HCI.
For patients inadequately controlled on sitagliptin monotheist:
For patients inadequately controlled on sitagliptin alone, the recommended starting dose of Sitagip is 100mg sitagliptIn and 1000mg metformin HCI daily.
For patients inadequately controlled on Metformin HCI Monotherapy
For patients not adequately controlled on metformin HCI alone, the usual starting dose of Sitaglip should provide sitagliptin 100mg total daily dose plus the dose of metformin HCI already being taken.
For patients switching from sitagliptin coadministered with metformin HCI
For patients switching from sitagliptin coadministrated with metformin HCI, Sitaglip may be initiated at the dose of sitagliptin and metformin HCl already being taken.
For patients inadequately controlled on dual combination therapy with metformin HCl and a Sulphonylurea
The usual starting dose of Sitaglip should provide sitagliptin 100mg total daily dose and the dose of metformin HCI already being taken:
For patients inadequately controlled on dual combination therapy with metformin HCI and insulin
The usual starling dose of Sitaglip should provide 100mg total daily dose of sitagliptin. In determining the starting dose of the metformin HCI component, the patient's level of glycemIc control and current dose of Metformin HCI should be considered.
Metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension and resistant brady arrhythmias. Symptoms Included malaise. myalgias, respiratory distress, somnolence and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate rebound metformin plasma levels generally >5 mcg/ml. If lactic acidosis is suspected, discontinue sitagliptin + metformin HCl and institute general supportive measures in a hospital setting, Prompt hemodialysis is recommended.
After initiation of sitagliptin + metformin HCI, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, sitagliptin + metformin HCI should
promptly be discontinued and appropriate management should be initiated.
Impaired Hepatic Function
Sitagliptin + metformin HCl should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
An association between dipeptidyl peptidase-4 (DPP4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes. Consider the risks and benefits of sitagliptin + metformin HCI, prior to Initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment and observe these patients for signs and symptoms of heart failure during therapy. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of sitagliptin + metformin HCI.
Assessment of Renal Function
Before initiation of therapy with sitagliptin + metformin HCI and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and sitagliptin + metformin HCI discontinued if evidence of renal impairment is present.
Vitamin B12 Levels
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 two to three years intervals may be useful.
Alcohol Intake .
Alcohol potentiates the effect of metformin HCl on lactate metabolism, Patients should be warned against excessive alcohol intake while receiving Sitagliptin + Metformin HCl.
Use of Sitagliptin + Metformin HCI should be temporarily discontinued while patients have restricted food and fluid intake. Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment .
Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
If acidosis of either form (ketoacidosis & lactic acidosis) occurs, sitagliptin + metformin HCI must be stopped immediately and other appropriate corrective measures initiated. Evaluation should Include serum electrolytes and ketones, blood glucose and if indicated blood pH, lactate, pyruvate and metformin HCI levels
|Sitagliptin Metformin HCI is contraindicated in patients with: |
• Known hypersensitivity to sitagliptin and metformin HCI or to any of excipient of the product.
• Renal disease or renal dysfunction, e.g. as suggested by serum creatinine levels >=133 micromol/L [males] or >=124 micromol/L [females], or abnormal creatinine clearance (<60 mL/min), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicaemia
• Acute or chronic metabolic acidosis, including diabetic Ketoacidosis, With or without coma.
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 as indicated by the patient's clinical status. Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
In case of metformin HCl overdose (greater than 50g), hypoglycemia was reported in approximately 10% of cases but no casual association with metformin HCI has been established. Metfromin HCI is diatyzable with a clearance of up to 170mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin HCI overdosage is suspected.