Sitagliptin phosphate monohydrate, metformin hydrochloride.
Each 50/500 mg combipack contains: 14 film-coated tablet Sitagliptin (as phosphate monohydrate) 50 mg and 14 film-coated tablet Metfromin Hydrochloride 500 mg.
Each 100/500 mg combipack contains: 14 film-coated tablet Sitagliptin (as phosphate monohydrate) 100 mg and 14 film-coated tablet Metfromin Hydrochloride 500 mg.
Metformin Hydrochloride: A white, odorless or almost odorless, hygrospic, crystalline powder. It is soluble in water; slightly soluble in alcohol; practically insoluble in chloroform.
Pharmacology: Mechanism of Action: Sitagliptin: Sitagliptin is a Dipeptidyl Peptidase-4 (DPP-4) inhibitor, which is believed to exert its actions in patients with type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. 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 Adenosine Monophosphate (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. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
Pharmacokinetics: The pharmacokinetics of Sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a 100 mg dose to healthy subjects, Sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma Area Under the Curve (AUC) of Sitagliptin was 8.52 µM·hr, Cmax was 950 nM, and apparent terminal half-life (t½) was 12.4 hours. Plasma AUC of Sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for Sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of Sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Sitagliptin: Used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Metformin Hydrochloride: It is given by mouth in the treatment of type 2 diabetes mellitus.
Sitagliptin: As monotherapy or as combination therapy with metformin, a sulfonylurea, insulin (with or without metformin), a Peroxisome Proliferator-Activated Receptor (PPARγ agonist) (e.g., thiazolidinedione), metformin plus a sulfonylurea or metformin plus a PPARγ agonist: 100 mg once daily.
When Sitagliptin is used in combination with a sulfonylurea or with insulin, a lower dose of sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia.
For patients with mild renal insufficiency (Creatine Clearance [CrCl] ≥50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage adjustment for Sitagliptin phosphate is required.
For patients with moderate renal insufficiency (CrCl ≥30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to ≤3 mg/dL in men and >1.5 to ≤2.5 mg/dL in women): 50 mg once daily.
For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3 mg/dL in men and >2.5 mg/dL in women) or with End Stage Renal Disease (ESRD) requiring hemodialysis or peritoneal dialysis: is 25 mg once daily.
Sitagliptin may be administered without regard to the timing of hemodialysis.
Sitagliptin can be taken orally with or without food.
Metformin Hydrochloride: Given by mouth in the treatment of non-insulin-dependent diabetes mellitus in an initial dosage of 500 mg two or three times a day or gradually increased if necessary to a maximum of 3 g daily or as prescribed by the physician.
Sitagliptin: Type 1 diabetes mellitus, diabetic ketoacidosis. Patients who are hypersensitive to Sitagliptin or to any components of the product.
Metformin Hydrochloride: Diabetic coma, ketoacidosis, impaired renal function, chronic liver disease, cardiac failure, recent myocardial infarction, alcoholism, tissue hypoxia, lactic acidosis, severe infections, trauma, surgery, dehydration.
Sitagliptin: Sitagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Pancreatitis: In post-marketing experience, there have been reports of acute pancreatitis including fatal and nonfatal hemorrhagic or necrotizing pancreatitis in patients taking Sitagliptin. Because these reports are made voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patients should be informed of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of Sitagliptin. If pancreatitis is suspected, Sitagliptin phosphate and other potentially suspect medicinal products should be discontinued.
Use in Patients with Renal Insufficiency: Sitagliptin is renally excreted. To achieve plasma concentrations of Sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring hemodialysis or peritoneal dialysis.
Hypoglycemia in Combination with a Sulfonylurea or Insulin: Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Sitagliptin and periodically thereafter.
As is typical with other antihyperglycemic agents, when Sitagliptin was used in combination with a sulfonylurea or with insulin, a medication known to cause hypoglycemia, the incidence of sulfonylurea- or insulin-induced hypoglycemia was increased over that of placebo. Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered.
Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with Sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with Sitagliptin, with some reports occurring after the 1st dose. If a hypersensitivity reaction is suspected, discontinue Sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.
Use in Children: Safety and effectiveness of Sitagliptin in pediatric patients <18 years have not been established.
Use in Elderly: In clinical studies, the safety and effectiveness of Sitagliptin in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years). No dosage adjustment is required based on age. Elderly patients are more likely to have renal insufficiency; as with other patients, dosage adjustment may be required in the presence of significant renal insufficiency.
Metformin Hydrochloride: Metformin Hydrochloride should be used in non-insulin dependent diabetes mellitus. Metformin Hydrochloride should not be used in patients with heart failure, dehydration, acute or chronic alcoholism, or any other condition likely to predispose to lactic acidosis.
Use in Pregnancy: Sitagliptin was not teratogenic in rats at oral doses up to 250 mg/kg or in rabbits given up to 125 mg/kg during organogenesis (up to 32 and 22 times, respectively, the human exposure based on the recommended daily adult human dose of 100 mg/day). In rats, a slight increase in the incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) was observed at oral doses of 1000 mg/kg/day (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decreases in mean pre-weaning body weights of both sexes and post-weaning body weight gains of males were observed in the offspring of rats given oral dose of 1000 mg/kg/day. However, animal reproduction studies are not always predictive of the human response.
There are no adequate and well-controlled studies in pregnant women; therefore, the safety of Sitagliptin in pregnant women is not known. Like other oral antihyperglycemic agents, it is not recommended for use in pregnancy.
Use in Lactation: Sitagliptin is secreted in the milk of lactating rats. It is not known whether Sitagliptin is secreted in human milk. Therefore, Sitagliptin should not be used by a woman who is nursing.
Hypoglycemia (based on all reports of symptomatic hypoglycemia, concurrent glucose measurement was not required); abdominal pain, nausea, vomiting, diarrhea, dyspepsia, flatulence; hypersensitivity reactions; exfoliative skin conditions including Stevens-Johnson syndrome; influenza, headache, cutaneous vasculitis, acute pancreatitis. Worsening renal function. Upper respiratory tract infection, nasopharyngitis, constipation, headache.
Metformin Hydrochloride causes gastrointestinal adverse effects with anorexia, nausea, and vomiting; absorption of various substances including Vitamin B12 may be impaired. Patients may experience a metallic taste and there may be weight loss, which in some diabetics could be an advantage. Hypoglycemia is less of a problem with Metformin Hydrochloride. Lactic acidosis, sometimes fatal, has occurred but to a lesser extent than with Phenformin and it is generally accepted that the lactic acidosis usually occurred in patients whose condition contraindicated the use of Metformin Hydrochloride.
Sitagliptin: DIGOXIN: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of Digoxin with the coadministration of 100 mg Sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or sitagliptin is recommended.
Metformin Hydrochloride: Use of biguanide concomitantly with other drugs that lower blood-glucose concentrations increases the risk of hypoglycaemia, while drugs that increase blood-glucose concentrations may reduce the effect of biguanide therapy. In general, fewer drug interactions have been reported with biguanides than with sulfonylureas. Alcohol may increase the risk of lactic acidosis as well as of hypoglycaemia. Care should be taken if biguanides are given concomitantly with drugs that may impair renal function.
Store at temperatures not exceeding 30°C.
A10BD07 - metformin and sitagliptin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
50/500 mg combipack 1's. 100/500 mg combipack 1's.