Indications

Monotherapy and Combination Therapy: Siglita is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: Siglita should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Siglita has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Siglita.

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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.

Dosage & Administration

The recommended dose of sitagliptin is 50 mg twice a day and 100 mg once daily. Sitagliptin can be taken with or without food.

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Interaction

Effects of Siglita on other Drugs: Siglita did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptive.

Digoxin: Siglita slightly increases the mean of Digoxin concentration. However, no dose adjustment of either drug is required.

Contraindications

History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

Side Effects

The most common adverse reactions include headache, upper respiratory tract infection and nasopharyngitis. Hypoglycemia may occur in patients treated with the combination to Siglita and sulfonylurea and add on to insulin.

Pregnancy & Lactation

Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Sitagliptin is secreted in the milk of lactating rats at 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.

Precautions & Warnings

If pancreatitis is suspected, Siglita should promptly be discontinued and appropriate management should be initiated.

Use in Patients with Renal Insufficiency: Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis.

Use with medications known to cause Hypoglycemia: When Siglita is used in combination therapy dosage adjustment of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with Siglita. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. If a hypersensitivity reaction is suspected, discontinue Siglita, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Use in Special Populations

Pediatric Use: Safety and effectiveness of Siglita in pediatric patients under 18 years of age have not been established.

Geriatric Use: Siglita 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.

For patients with mild renal insufciency: (CrCl <50 ml/min or serum creatinine levels of <1.7 mg/DL in men and <1.5 mg/DL in women), no dosage adjustment for Siglita is required.

For patients with moderate renal insufciency: (CrCl <30 to <50 mL/min, or serum creatinine levels of >1.7 to <3.0 mg/dL in men and >1.5 to <2.5 mg/dL in women), the dose of Siglita is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min or serum creatinine levels of >3.0 mg/dL in men and 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Siglita is 25 mg once daily. Siglita may be administered without regard to the limiting of hemodialysis.

Overdose Effects

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Siglita were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Siglita, a mean effect that is not considered clinically important. 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 Siglita with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for 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 as dictated by the patient's clinical status. Siglita is modestly 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 Siglita is dialyzable by peritoneal dialysis.

Therapeutic Class

Dipeptidyl Peptidase-4 (DPP-4) inhibitor

Storage Conditions

Store below 25°C in a dry place away from light. Keep the medicines in a safe place, out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician