Sitagliptin phosphate monohydrate.
Each film-coated tablet contains: Sitagliptin (as phosphate monohydrate) 50 mg or 100 mg.
SITAGLIPTIN is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. 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, glucagonlike 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 gucose 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 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogues, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-glucosidase inhibitors, and amylin analogues.
SITAGLIPTIN tablets contain sitagliptin phosphate, an orally-active, potent, and selective inhibitor of dipeptidyl peptidase 4 (DPP-4), which is described chemically as: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo (4,3-a)pyrazine phosphate (1:1) monohydrate.
The empirical formula is C18H35F6N6O•H4PO4•H2O and the molecular weight is 523.32.
Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol acetate.
Pharmacology: Mechanism of Action: 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 coefficient 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.
as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
As monotherapy or as combination therapy with metformin, a sulfonylurea, insulin (with or without metformin), a Peroxisome Proliferator-Activated (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 (Creatinine Clearance [CrCl] ≥50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 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.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were generally well tolerated. Minimal increase 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 moderately dialyzable, in clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session.
Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
Type 1 diabetes mellitus, diabetic ketoacidosis.
Patients who are hypersensitive to Sitagliptin or to any components of the
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: Sitaglipin 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.
Use in Pregnancy & Lactation: Sitagliptin was not teratogenic in rats at oral dose 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/da (approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Slight decreases in mean preweaning body weights of both sexes and postweaning 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.
Sitagliptin like other oral antihyperglycemic agents, is not recommended for use in pregnancy.
Sitagliptin is secreted in the milk of lactating rats, it is not known whether sitagliptin is secreted in human milk, Therefore, Sitaglipin should not be used by a woman who is nursing.
(based on all reports of symptomatic hypoglycemia, concurrent glucose
measurement was not required); abdominal pain, nausea, vomiting, diarrhea,
dyspepsia, flatulence; hypersensitivity reactions; exfoliative skin
conditionsincluding Stevens-Johnson syndrome; influenza, headache, cutaneous
vasculitis, acute pancreatitis. Worsening renal function. Upper respiratory
tract infection, nasopharyngitis, constipation, headache.
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 administration of 100 mg Sitagliptin for 10 days. Patients receiving
digoxin should be monitored appropriately. No dosage adjustment of digoxin or
sitagliptin is recommended.
at temperatures not exceeding 30°C.
A10BH01 - sitagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.
FC tab 50 mg x 30's. 100 mg x 30's.