Sitaglix^® (Tablets) Instructions for Use

Marketing Authorization Holder

Izvarino Pharma LLC (Russia)

ATC Code

A10BH01 (Sitagliptin)

Active Substance

Sitagliptin (Rec.INN registered by WHO)

Dosage Forms

	Sitaglix^®	Film-coated tablets 25 mg: 10, 14, 20, 28, 30, 40, 42, 56, 60, 70, 84 or 98 pcs.
		Film-coated tablets 50 mg: 10, 14, 20, 28, 30, 40, 42, 56, 60, 70, 84 or 98 pcs.
		Film-coated tablets 100 mg: 10, 14, 20, 28, 30, 40, 42, 56, 60, 70, 84 or 98 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to white with a yellowish tint, round, biconvex.

	1 tab.
Sitagliptin phosphate monohydrate	32.125 mg,
Equivalent to sitagliptin	25 mg

Excipients: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, glyceryl dibehenate, croscarmellose sodium, magnesium stearate, film coating [polyvinyl alcohol, titanium dioxide (E171), macrogol, talc].

10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
10 pcs. – contour cell packaging (7) – cardboard packs.
14 pcs. – contour cell packaging (1) – cardboard packs.
14 pcs. – contour cell packaging (2) – cardboard packs.
14 pcs. – contour cell packaging (3) – cardboard packs.
14 pcs. – contour cell packaging (4) – cardboard packs.
14 pcs. – contour cell packaging (6) – cardboard packs.
14 pcs. – contour cell packaging (7) – cardboard packs.

Film-coated tablets from pink to pink with a grayish tint, round, biconvex.

	1 tab.
Sitagliptin phosphate monohydrate	64.25 mg,
Equivalent to sitagliptin	50 mg

Film-coated tablets from white to white with a yellowish tint with a score on one side, round, biconvex.

	1 tab.
Sitagliptin phosphate monohydrate	128.5 mg,
Equivalent to sitagliptin	100 mg

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; dipeptidyl peptidase-4 (DPP-4) inhibitors

Pharmacological Action

Oral hypoglycemic agent, a highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4).

Sitagliptin differs in chemical structure and pharmacological action from glucagon-like peptide-1 (GLP-1) analogues, insulin, sulfonylurea derivatives, biguanides, peroxisome proliferator-activated receptor (PPAR-γ) agonists, alpha-glucosidase inhibitors, and amylin analogues. By inhibiting DPP-4, Sitagliptin increases the concentration of two known incretin hormones: GLP-1 and glucose-dependent insulinotropic peptide (GIP). Incretin hormones are secreted in the intestine throughout the day, and their levels increase in response to food intake. Incretins are part of the internal physiological system regulating glucose homeostasis. At normal or elevated blood glucose levels, incretin hormones promote increased insulin synthesis and its secretion by pancreatic beta-cells via intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also helps suppress the elevated secretion of glucagon by pancreatic alpha-cells. The decrease in glucagon concentration against the background of increased insulin levels leads to a reduction in glucose production by the liver, ultimately resulting in decreased glycemia.

At low blood glucose concentrations, the listed effects of incretins on insulin release and decreased glucagon secretion are not observed. GLP-1 and GIP do not affect glucagon release in response to hypoglycemia. Under physiological conditions, incretin activity is limited by the enzyme DPP-4, which rapidly hydrolyzes incretins to form inactive products.

Sitagliptin prevents the hydrolysis of incretins by the DPP-4 enzyme, thereby increasing the plasma concentrations of the active forms of GLP-1 and GIP. By increasing incretin levels, Sitagliptin enhances glucose-dependent insulin release and contributes to a decrease in glucagon secretion. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in insulin and glucagon secretion lead to a decrease in the level of glycated hemoglobin HbA_1c and a reduction in plasma glucose concentration measured fasting and after a glucose tolerance test.

In patients with type 2 diabetes mellitus, a single dose of sitagliptin leads to inhibition of DPP-4 enzyme activity for 24 hours, resulting in a 2-3 fold increase in circulating incretins GLP-1 and GIP, an increase in plasma insulin and C-peptide concentration, a decrease in plasma glucagon concentration, a reduction in fasting glycemia, and a decrease in glycemia after a glucose load or food load.

Pharmacokinetics

The pharmacokinetics of sitagliptin have been studied in healthy individuals and patients with type 2 diabetes mellitus.

After oral administration of the drug at a dose of 100 mg in healthy individuals, sitagliptin is rapidly absorbed, reaching C_max in 1-4 hours. AUC increases proportionally to the dose and is 8.52 µmol × h in healthy subjects after oral administration of a 100 mg dose, C_max was 950 nmol. The absolute bioavailability of sitagliptin is approximately 87%. Intra- and interindividual coefficients of variation for sitagliptin AUC are insignificant. Concurrent intake of fatty food does not affect the pharmacokinetics of sitagliptin.

Plasma AUC of sitagliptin increased by approximately 14% after the next dose of 100 mg upon reaching steady state after the first dose. After a single 100 mg dose, the mean V_d of sitagliptin in healthy volunteers was approximately 198 L. The binding of sitagliptin to plasma proteins is 38%.

Only a small portion of the administered drug is metabolized. After oral administration of ¹⁴C-labeled sitagliptin, approximately 16% of the radioactive drug was excreted as metabolites. Traces of 6 metabolites of sitagliptin were detected, likely lacking DPP-4 inhibitory activity. In vitro studies have shown that the primary enzyme involved in the limited metabolism of sitagliptin is CYP3A4 with the participation of CYP2C8.

Approximately 79% of sitagliptin is excreted unchanged in the urine. Within 1 week after administration of ¹⁴C-labeled Sitagliptin to healthy volunteers, it was excreted: in urine – 87% and in feces – 13%. T_1/2 of sitagliptin after oral administration of a 100 mg dose is approximately 12.4 hours. Renal clearance is approximately 350 ml/min.

Elimination of sitagliptin occurs primarily by renal excretion via the mechanism of active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter type 3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. Sitagliptin is also a substrate for P-glycoprotein, which may also participate in the renal elimination process of sitagliptin.

Indications

Monotherapy: as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus;

Combination therapy: type 2 diabetes mellitus to improve glycemic control in combination with metformin or PPAR-γ agonists (e.g., thiazolidinedione), when diet and exercise in combination with monotherapy with the listed agents do not lead to adequate glycemic control.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
E11	Type 2 diabetes mellitus

ICD-11 code	Indication
5A11	Type 2 diabetes mellitus

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Administer Sitaglix^®orally once daily.

The recommended adult dose is 100 mg.

Take the tablet with or without food.

For patients with renal impairment, adjust the dose based on creatinine clearance.

For patients with moderate renal impairment (CrCl ≥30 to <50 mL/min), administer 50 mg once daily.

For patients with severe renal impairment (CrCl <30 mL/min) or with end-stage renal disease requiring hemodialysis, administer 25 mg once daily.

Administer the 25 mg dose following a hemodialysis session.

Do not split the 100 mg or 50 mg tablets to achieve the 25 mg dose; use the specific 25 mg strength tablet.

Assess renal function prior to initiation and periodically during treatment.

No dose adjustment is required for patients with hepatic impairment.

No dose adjustment is recommended based solely on age; however, consider age-related declines in renal function.

Adverse Reactions

From the respiratory system: upper respiratory tract infections (100 mg – 6.8%, 200 mg – 6.1%, placebo – 6.7%), nasopharyngitis (100 mg – 4.5%, 200 mg – 4.4%, placebo – 3.3%).

From the CNS headache (100 mg – 3.6%, 200 mg – 3.9%, placebo – 3.6%).

From the digestive system diarrhea (100 mg – 3%, 200 mg – 2.6%, placebo – 2.3%), abdominal pain (100 mg – 2.3%, 200 mg – 1.3%, placebo – 2.1%), nausea (100 mg – 1.4%, 200 mg – 2.9%, placebo – 0.6%), vomiting (100 mg – 0.8%, 200 mg – 0.7%, placebo – 0.9%), diarrhea (100 mg – 3%, 200 mg – 2.6%, placebo – 2.3%).

From the musculoskeletal system arthralgia (100 mg – 2.1%, 200 mg – 3.3%, placebo – 1.8%).

From the endocrine system hypoglycemia (100 mg – 1.2%, 200 mg – 0.9%, placebo – 0.9%).

From laboratory parameters at doses of 100 mg/day and 200 mg/day – increase in uric acid by approximately 0.2 mg/dl compared to placebo (mean level 5-5.5 mg/dl) in patients receiving the drug at a dose of 100 mg/day and 200 mg/day. No cases of gout were reported.

Contraindications

Type 1 diabetes mellitus; diabetic ketoacidosis; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to sitagliptin.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients are more prone to developing renal insufficiency. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency.

Special Precautions

Use with caution in patients with renal insufficiency. In moderate and severe renal insufficiency, as well as in patients with end-stage renal disease requiring hemodialysis, dose adjustment is required.

Elderly patients are more prone to developing renal insufficiency. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal insufficiency.

Drug Interactions

A slight increase in AUC (11%), as well as mean C_max (18%) of digoxin was noted when co-administered with sitagliptin. This increase is not considered clinically significant.

An increase in AUC and C_max of sitagliptin by 29% and 68%, respectively, was noted in patients with co-administration of a single 100 mg dose of sitagliptin and a single 600 mg dose of cyclosporine (a potent P-glycoprotein inhibitor). These changes in the pharmacokinetic parameters of sitagliptin are not considered clinically significant.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer