Fliptin

Sitagliptin.

FLIPTIN 50 mg: Light beige, round, and shallow film-coated tablet, diameter 8 mm, side I marked DEXA and side II unmarked.
Each film-coated tablet contains: Sitagliptin phosphate monohydrate equivalent to sitagliptin 50 mg.
FLIPTIN 100 mg: Beige, round, and shallow film-coated tablet, diameter 9.6 mm, side I marked DEXA and side II unmarked.
Each film-coated tablet contains: Sitagliptin phosphate monohydrate equivalent to sitagliptin 100 mg.
Excipients/Inactive Ingredients: Microcrystalline cellulose PH-102, dicalcium phosphate anhydrous, crosscarmellose sodium, magnesium stearate, opadry II 85G58977 white, iron oxide red, iron oxide yellow, purified water.

Pharmacology: Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes 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 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: FLIPTIN film-coated tablet has been studied in an open-label, randomized, single dose, two-period, two-sequence, cross-over study under fasting conditions which included 24 healthy adult male and female subjects (age between 18-55 years). The AUC_0-t and C_max of sitagliptin were defined as the main parameters in order to assess possible bioequivalence between the test drug and the comparator drug. The bioequivalence of the two products was concluded based on the 90% confidence intervals of the test/comparator geometric mean ratios of sitagliptin's AUC_0-t and C_max which were within the range of 80.00-125.00%.
Following oral administration of 100 mg FLIPTIN film-coated tablet, the mean of AUC_0-t and AUC_0-inf sitagliptin were 4,001.27 ng.hour/ml and 4,207.15 ng.hour/ml, respectively. The mean of maximum plasma concentration (C_max) of sitagliptin was 470.90 ng/ml with the median (range) of t_max was 2.00 (0.50-5.00) hours. The mean elimination half-life (t_½) of sitagliptin was 7.88 hours. The geometric mean ratios (90% confidence intervals) of sitagliptin were 100.30% (94.64%-106.29%) for AUC_0-t and 102.66% (95.63%-110.22%) for C_max.
The result of the study showed that the pharmacokinetic parameters of FLIPTIN film-coated tablet were within the acceptance range for bioequivalence, therefore, FLIPTIN film-coated tablet were similar or bioequivalent to the comparator drug.

Monotherapy: Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
Combination with metformin or PPARγ agonist: Sitagliptin is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPARγ agonist (i.e. thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control.
Combination with metformin and sulfonylurea: Sitagliptin is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin and a sulfonylurea when dual therapy with these agents, with diet and exercise does not provide adequate glycemic control.
Combination with insulin: 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 glycemic control.

The recommended dose of sitagliptin is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARγ agonist (e.g., thiazolidinediones), metformin and sulfonylurea, stable dose of insulin (with or without metformin). Sitagliptin can be taken with or without food.
When used in combination with metformin or a PPARγ agonist, the dose of metformin 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 hypoglycemia.
Special populations: 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 (eGFR ≥60 ml/minute/1.73 m² to <90 ml/minute/1.73 m²), no dosage adjustment for sitagliptin is required.
For patients with moderate renal impairment (eGFR ≥45 ml/minute/1.73 m² to <60 ml/minute/1.73 m²), no dosage adjustment for sitagliptin is required.
For patients with moderate renal impairment (eGFR ≥30 ml/minute/1.73 m² to <45 ml/minute/1.73 m²), the dose of sitagliptin is 50 mg once daily.
For patients with severe renal impairment (eGFR ≥15 ml/minute/1.73 m² to <30 ml/minute/1.73 m²) or with end-stage renal disease (ESRD) (eGFR <15 ml/minute/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.

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 as dictated by the patient's clinical status.
Sitagliptin is modestly dialyzable. 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.

Patients with known hypersensitivity to sitagliptin or any of the excipients.
Ketoacidosis.

Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: There have been reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis (see Adverse Reactions), in patients taking sitagliptin. After initiation of sitagliptin, patients should be observed carefully for signs and symptoms of 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. If pancreatitis is suspected, sitagliptin, and other potentially suspect medicinal products, should be discontinued.
Use in patients with renal impairment: A dosage adjustment is recommended in patients with eGFR <45 ml/minute/1.73 m²), as well as in ESRD patients requiring hemodialysis or peritoneal dialysis. (See Special populations: Patients with renal impairment under Dosage & Administration.)
Use with medications known to cause hypoglycemia: As is typical with other antihyperglycemic agents, hypoglycemia has been observed when sitagliptin was used in combination with insulin or a sulfonylurea. Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with sitagliptin or any other antidiabetic drug.
Bullous pemphigoid: Cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to 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 Children: Safety and effectiveness of sitagliptin in pediatric patients have not been established.
Use in the Elderly: Sitagliptin is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter.

Pregnancy: Pregnancy category: B.
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Lactation: Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sitagliptin is administered to a nursing woman.

Adverse reactions observed in the use of sitagliptin as both monotherapy and/or combination therapy with other antihyperglycemic agents (pioglitazone, glimepiride, metformin, or insulin) was: hypoglycemia, nasopharyngitis, upper respiratory tract infection, headache, infections, renal failure, a small increase in white blood cell count due to an increase in neutrophils.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome (see Precautions); hepatic enzyme elevations; acute pancreatitis, including fatal and nonfatal hemorrhagic and necrotizing pancreatitis (see Precautions); constipation; vomiting; headache, worsening renal function, including acute renal failure (sometimes requiring dialysis), bullous pemphigoid (see Precautions); arthralgia, myalgia, pain in extremity, back pain, pruritus.

Effects of sitagliptin on other drugs: Sitagliptin did not alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives.
Sitagliptin is not an inhibitor of CYP3A4, CYP2C8, CYP2C9 isozymes, and organic cationic transporter (OCT).
Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or sitagliptin.
Metformin: Coadministration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
Sulfonylurea: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in patients receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9. However, the risk of hypoglycemia from the coadministration of sitagliptin and sulfonylureas is unknown.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in patients receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Oral contraceptives: Coadministration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Effects of other drugs on sitagliptin: Metformin: Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Ciclosporin: Coadministration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin, a potent inhibitor of p-glycoprotein, increased the AUC and C_max of sitagliptin but these changes were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

Store at temperatures below 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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