Zincretin 50: Sitagliptin.
Zincretin 100: Sitagliptin phosphate.
Zincretin 50: Each film-coated tablet contains: Sitagliptin Phosphate, USP equivalent to Sitagliptin 50 mg.
Zincretin 100: Each film coated tablet contains: Sitagliptin Phosphate, USP equivalent to Sitagliptin 100 mg.
Sitagliptin Phosphate, Dipeptidyl Peptidase 4 Inhibitor Anti-Diabetic, the chemical name 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 monohydrate.
Sitagliptin Phosphate has the molecular formula C16H15F6N5O·H3O4P·H2O and a molecular weight of 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 and isopropyl acetate.
Pharmacotherapeutic group: Drugs used in diabetes, Dipeptidyl peptidase 4 (DPP-4) inhibitors. ATC code: A10BH01.
Pharmacology: Pharmacodynamics: Mechanism of action: Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin 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. 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. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia 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.
Pharmacokinetics: Absorption: Following 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 post-dose. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Distribution: The mean volume of distribution at steady state following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Biotransformation: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79 % of sitagliptin is excreted unchanged in the urine.
CYP3A4 is the primary enzyme responsible for the limited metabolism of sitagliptin (with contribution from CYP2C8).
Elimination: Studies involving administration [14C] sitagliptin to healthy subjects showed that nearly all the radioactivity (100%) was eliminated within one week, with 87% excreted in urine and 13% in feces. The apparent terminal half-life after a 100 mg oral dose was about 12.4 hours, with minimal accumulation upon multiple dosing. Renal clearance was approximately 350 mL/min.
Sitagliptin elimination primarily involves active tubular secretion and renal excretion. It is a substrate for human organic anion transporter-3 (hOAT-3) and p-glycoprotein, but the clinical significance of hOAT-3 in sitagliptin transport remains unclear. Sitagliptin doesn't affect OCT2, OAT1, or PEPT1/2 transporters. In vitro, it didn't inhibit OAT3 or p-glycoprotein at therapeutic plasma concentrations, but it has a mild effect on plasma digoxin levels, suggesting mild p-glycoprotein inhibition.
Characteristics in patients: The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Renal impairment: Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥60 to <90 mL/min) and patients with moderate renal impairment (GFR ≥45 to <60 mL/min), respectively. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary.
Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal impairment (GFR ≥30 to <45 mL/min), and approximately 4-fold in patients with severe renal impairment (GFR <30 mL/min), including in patients with ESRD on haemodialysis. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR <45 mL/min.
Hepatic impairment: No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly: No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of sitagliptin compared to younger subjects.
Other patient characteristics: No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin.
For adult patients with type 2 diabetes mellitus, sitagliptin is indicated to improve glycaemic control: As monotherapy: in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
As dual oral therapy in combination with: metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance; a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control.
As triple oral therapy in combination with: a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control; a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.
Sitagliptin is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.
The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ agonist should be maintained, and sitagliptin administered concomitantly.
When sitagliptin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia.
If a dose of sitagliptin is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Special populations: Renal impairment: When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
For patients with mild renal impairment (glomerular filtration rate [GFR] ≥60 to <90 mL/min), no dose adjustment is required.
For patients with moderate renal impairment (GFR ≥45 to <60 mL/min), no dosage adjustment is required.
For patients with moderate renal impairment (GFR ≥30 to <45 mL/min), the dose of sitagliptin is 50 mg once daily.
For patients with severe renal impairment (GFR ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR <15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter.
Hepatic impairment: No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Sitagliptin has not been studied in patients with severe hepatic impairment and care should be exercised (see Pharmacology: Pharmacokinetics under Actions).
However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly: No dose adjustment is necessary based on age.
Paediatric population: Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Sitagliptin has not been studied in paediatric patients under 10 years of age.
Method of administration: Sitagliptin can be taken with or without food.
Symptoms: 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.
Treatment: 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 haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.
Hypersensitivity to the active substance or to any of the excipients use in formulation.
General: Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis: Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. 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 (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, sitagliptin and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, sitagliptin should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products: In clinical trials of sitagliptin as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered.
Hypersensitivity reactions: Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, sitagliptin should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, sitagliptin should be discontinued.
Renal impairment: 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 GFR <45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis.
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.
Pregnancy: There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, sitagliptin should not be used during pregnancy.
Breast-feeding: It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. Sitagliptin should not be used during breast-feeding.
Fertility: Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.
Summary of the safety profile: Occurrences of pancreatitis and hypersensitivity reactions have been reported as serious adverse events. Hypoglycemia have been reported, especially in cases where sitagliptin is co-administered with sulphonylurea (ranging from 4.7% to 13.8%) and insulin (9.6%).
Tabulated list of adverse reactions: Adverse reactions are listed as follows (see Table) by system organ class and frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). (See Table.)
Click on icon to see table/diagram/image
Description of selected adverse reactions: In addition to the drug-related adverse experiences described previously, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of >0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.
Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza [common with insulin (with or without metformin)], nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth [uncommon with insulin (with or without metformin)].
Paediatric population: In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.
Effects of other medicinal products on sitagliptin: Clinical data described as follows suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.
Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: The renal clearance of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with ciclosporin or other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products: Digoxin: No dose adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.
Store 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.
Zincretin 100 FC tab 100 mg
30's (P30/film-coated tab)
Zincretin 50 FC tab 50 mg
30's (P30/film-coated tab)
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