Si2norm

50 mg: Sitagliptin Tablets USP 50 mg (SI2NORM): White to off-white colored, round shaped, biconvex, plain on both sides, film-coated tablet.
Each Film-Coated Tablet contains: Sitagliptin (as Phosphate Monohydrate) 50 mg.
100 mg: Sitagliptin Tablets USP 100 mg (SI2NORM): Pink colored, round shaped, biconvex, plain on both sides, film-coated tablet.
Each Film-Coated Tablet contains: Sitagliptin (as Phosphate Monohydrate) 100 mg.

Pharmacology: Pharmacodynamics: Mechanism of action: Sitagliptin tablet is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement of 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 in 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 A_1C (HbA_1C) 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.
In a two-day study in healthy subjects, Sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of Sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.
Pharmacokinetics: Absorption: Following oral administration of a 100 mg dose to healthy subjects, Sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours post-dose, mean plasma AUC of Sitagliptin was 8.52 μM·hr, C_max was 950 nM. The absolute bioavailability of Sitagliptin is approximately 87%. Since co-administration of a high-fat meal with Sitagliptin tablet had no effect on the pharmacokinetics, Sitagliptin tablet may be administered with or without food.
Plasma AUC of Sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C_max and C_24hr (C_max increased in a greater than dose-proportional manner and C_24hr 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 urine.
Following a [¹⁴C] Sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of Sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of Sitagliptin. In vitro studies indicated that the primary enzyme responsible was CYP3A4, with contribution from CYP2C8.
In vitro data showed that Sitagliptin is not an inhibitor of CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination: Following administration of an oral [¹⁴C] Sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100 mg oral dose of Sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.
Elimination of Sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of Sitagliptin. The clinical relevance of hOAT-3 in Sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of Sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of Sitagliptin. Sitagliptin is not a substrate of OCT2 or OATI or PEPT1/2 transporters. In vitro, Sitagliptin did not inhibit OAT3 (IC50-160 μM) or p-glycoprotein (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study Sitagliptin had a small effect on plasma digoxin concentrations indicating that Sitagliptin may be a mild inhibitor of p-glycoprotein.
Characteristic in patients: The pharmacokinetics of Sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Renal Impairment: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of Sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal impairment on Sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.
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. Sitagliptin was modestly removed by haemodialysis (13.5% over a 3- to 4-hour haemodialysis session starting 4 hours post dose). To achieve 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 tablet 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 pharmacokinetic of Sitagliptin.
Elderly: No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of Sitagliptin compared to younger subjects.
Paediatric: No studies with Sitagliptin tablets have been performed in paediatric patients.
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 based on a composite analysis of Phase I pharmacokinetic analysis of Phase I and Phase II data.

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 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 tablet 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 recommended dose of Sitagliptin is 100 mg once daily as monotherapy or as combination therapy with metformin, a sulfonylurea, insulin (with or without metformin), a PPARγ agonist (e.g., thiazolidinediones), metformin plus a sulfonylurea, or metformin plus a PPARγ agonist.
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.
Patients with Renal Impairment: Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Sitagliptin and periodically thereafter.
For patients with mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²), no dose adjustment for Sitagliptin is required.
For patients with moderate renal impairment (eGFR >45 mL/min/1.73 m² to 60 mL/min/1.73 m²), no dosage adjustment for Sitagliptin is required.
For patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²), the dose of Sitagliptin is 50 mg once daily.
For patients with severe renal impairment (eGFR ≥15 mL/min/1.73 m² to <30 mL/min/1.73 m²) or with end-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m²), including those requiring hemodialysis or peritoneal dialysis, the dose of Sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of dialysis.
Method of Administration: 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 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 dialyzable. 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 dialyzable by peritoneal dialysis.

Hypersensitivity to the active substance or to any of the excipients of this product.

General: Sitagliptin tablets 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 necrotizing 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 started. Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents: 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.
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 <45mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis.
When considering the use of Sitagliptin in combination with another anti-diabetic product, its conditions for use in patients with renal impairment should be checked.
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.

Fertility: Animal data do not suggest an effect of treatment with Sitagliptin on male and female fertility. Human data are lacking.
Pregnancy: There are no adequate data from the use of Sitagliptin tablet 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 tablet 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 tablet should not be used during breast-feeding.

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with Sulphonylurea and Insulin.
Adverse reactions are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare <1/10000) and not known (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image

Effects of other medicinal product on Sitagliptin: Clinical data described as follows suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of Sitagliptin is CYP3A4, with contribution from CYP2C8. 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.
In vitro transport studies showed that Sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of Sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple twice-daily doses of 1000 mg metformin with 50 mg Sitagliptin did not meaningfully alter the pharmacokinetics of Sitagliptin in patients with type 2 diabetes.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of Sitagliptin. Co-administration of a single 100 mg oral dose of Sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and Cmax of Sitagliptin by approximately 29% and 68% respectively. These changes in Sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of Sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of Sitagliptin on other medicinal products: Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of Sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11% and the plasma Cmax on average by 18%. 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 mild inhibitor of p-glycoprotein in vivo.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

A10BH01 - sitagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.

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