Gliptadin

50 mg: Light peach to peach, 7 mm, round biconvex, film-coated tablet.
100 mg: Light orange to orange, 11.12 mm, round biconvex, film-coated tablet.
Each film-coated tablet contains: Sitagliptin (as Phosphate Monohydrate) 50 mg or 100 mg.

Pharmacodynamics: The Dipeptidyl Peptidase 4 inhibitors are class of agents that act as incretin enhancers. Sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), when the DPP-4 enzyme is inhibited. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. As the blood glucose 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.
General: In a study of patients with type 2 diabetes, administration of single oral dose of sitagliptin resulted to a significant reduction of glucose levels. This is the same case with those patients with type 2 diabetes who are in an inadequately controlled metformin monotherapy. In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.
Effects on blood pressure: Based on studies in hypertensive patients on one or more anti-hypertensive drugs (including angiotensin-converting enzyme inhibitors, angiotensin-II antagonists, calcium-channel blockers, beta-blockers and diuretics), co-administration of sitagliptin was generally well tolerated. Reductions in the blood pressure of subjects with normal blood pressure have not been observed.
Cardiac Electrophysiology: Healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase of the placebo-corrected mean change in QTc from baseline at 3 hours post dose was 8.0 msec. This small increase was not considered to be clinically significant. Patients with type 2 diabetes taking 100 mg or 200 mg dose of sitagliptin did not have meaningful change in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.
Pharmacokinetics: Sitagliptin was rapidly absorbed with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose after oral administration of 100 mg dose to healthy subjects. The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption: Sitagliptin has an absolute bioavailability of approximately 87% and may be administered with or without food.
Distribution: The fraction of sitagliptin reversibly bound to plasma protein is low (38%).
Metabolism: Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Elimination: Approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing following the administration of an oral [¹⁴C] sitagliptin dose to healthy subjects. The apparent terminal t_½ following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Characteristics in Patients: Renal Impairment: Compared to normal healthy control subjects, there is an approximately 1.2 fold and 1.6 fold increase in plasma AUC of sitagliptin in patients with mild renal impairment (eGFR ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²) and in moderate renal impairment (eGFR ≥45 mL/min/1.73 m² to <60 mL/min/1.73 m²). Increases of this magnitude are not clinically relevant and dosage adjustment in these patients is not necessary.
An approximately 2-fold increase in plasma AUC of sitagliptin in patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m² to <45 mL/min/1.73 m²) and approximately 4-fold increase approximately in plasma AUC of sitagliptin in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) including patients with ESRD on hemodialysis were observed.
Lower dosages are recommended in patients with eGFR <45 mL/min/1.73 m² to achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function.
Hepatic Impairment: No dosage adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment. 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 dosage adjustment is required based on age. Age has no clinically meaningful impact on the pharmacokinetics of sitagliptin.
Pediatrics: No studies with sitagliptin have been performed in pediatric patients.
Gender: No dosage adjustment is necessary based on gender.
Race: No dosage adjustment is necessary based on race.
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI.
Type 2 Diabetes: The pharmacokinetics of sitagliptin in patients with type 2 diabetes are generally similar to those in healthy subjects.

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. It can also be used in combination with metformin, sulfonylurea, PPARγ agonist, metformin and sulfonylurea, metformin and a PPARγ agonist, and insulin, to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin has a recommended dose of 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 PPARγ agonist. When it 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: Since there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter.
Patients with mild renal impairment (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m² to <90 mL/min/1.73 m²): No dosage adjustment for sitagliptin is required.
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.
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.
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: Sitagliptin recommended dose is 25 mg once daily and may be administered without regard to the timing of dialysis.
Mode of Administration: Sitagliptin can be taken orally with or without food.

In the event of overdose, it is reasonable to employ the usual supportive measures, employ clinical monitoring, and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Hypersensitivity to sitagliptin.

General: Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: Acute pancreatitis (persistent, severe abdominal pain characteristic symptom), including fatal and non-fatal hemorrhagic or necrotizing pancreatitis in patients taking sitagliptin has been reported. Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If alleged of pancreatitis, sitagliptin and other potentially suspect medicinal products should be discontinued.
Hypoglycemia in combination with a Sulfonylurea or with Insulin: Hypoglycemia has been observed. A lower dose of sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea - or insulin - induced hypoglycemia.
Hypersensitivity reactions: These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If hypersensitivity occurs, discontinue sitagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes.
Bullous Pemphigoid: Patients should report development of blisters or erosions while receiving sitagliptin. If bullous pemphigoid is suspected, sitagliptin should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Use in patients with 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 eGFR <45 mL/min/1.73 m², as well as in ESRD patients requiring hemodialysis or peritoneal dialysis.
Use in Children: Safety and effectiveness of sitagliptin in pediatric patients under 18 years have not been established.
Use in the Elderly: No dosage adjustment is required based on age. Elderly patients are more likely to have renal impairment; as with other patients, dosage adjustment may be required in the presence of significant renal impairment.

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. It is not known whether sitagliptin is secreted in human milk. Therefore, sitagliptin should not be used by a woman who is nursing.

Adverse reactions are listed in the table as follows 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

Co-administration of multiple twice-daily of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Concomitant medications did not have a clinically meaningful effect on the pharmacokinetics of sitagliptin. Medications assessed were those that are commonly administered to patients with type 2 diabetes including the following: Cholesterol lowering agents: Statins, fibrates, ezetimibe.
Anti-platelet agents: Clopidogrel.
Antihypertensives: ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide.
Analgesics and non-steroidal anti-inflammatory agents: Naproxen, diclofenac, celecoxib.
Anti-depressants: Bupropion, fluoxetine, sertraline.
Antihistamines: Cetirizine.
Proton-pump inhibitors: Omeprazole, lansoprazole.
Medications for erectile dysfunction: Sildenafil.
Digoxin: Increase in AUC (11%) is not considered to be clinically meaningful. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or sitagliptin is recommended.
Cyclosporine or other p-glycoprotein inhibitors: Ketoconazole, no dosage adjustment is recommended when co-administered with sitagliptin.

Store at temperature 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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