Xelevia^® (Tablets) Instructions for Use

Marketing Authorization Holder

Berlin-Chemie, AG (Germany)

Manufactured By

Berlin-Pharma CJS (Russia)

ATC Code

A10BH01 (Sitagliptin)

Active Substance

Sitagliptin (Rec.INN registered by WHO)

Dosage Form

Xelevia®

Film-coated tablets, 100 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets beige in color, round, biconvex, with an engraving “277” on one side and smooth on the other.

Excipients: microcrystalline cellulose – 123.8 mg, calcium hydrogen phosphate unground – 123.8 mg, croscarmellose sodium – 8 mg, magnesium stearate – 4 mg, sodium stearyl fumarate – 12 mg.

Coating composition: opadry^® II beige, 85F17438 – 16 mg (polyvinyl alcohol – 40%, titanium dioxide (E171) – 21.56%, macrogol 3350 (polyethylene glycol) – 20.2%, talc – 14.8%, iron oxide yellow (E172) – 3.07%, iron oxide red (E172) – 0.37%).

14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

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, γ-receptor agonists activated by peroxisome proliferator (PPAR-γ), alpha-glucosidase inhibitors, amylin analogues. By inhibiting DPP-4, Sitagliptin increases the concentration of 2 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 contribute to increased insulin synthesis and its secretion by pancreatic beta-cells via intracellular signaling mechanisms associated with cyclic AMP. GLP-1 also contributes to the suppression of elevated glucagon secretion 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, which ultimately results 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 plasma concentrations of the active forms of GLP-1 and GIP. By increasing incretin levels, Sitagliptin enhances glucose-dependent insulin release and contributes to decreased 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 or meal.

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 concentration of insulin and C-peptide, a decrease in plasma glucagon concentration, a reduction in fasting glycemia, and a decrease in glycemia after a glucose load or meal.

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, rapid absorption of sitagliptin is observed with C_max reached in 1-4 hours. AUC increases proportionally to the dose and in healthy subjects is 8.52 µmol × h 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 variability 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 oral dose of 100 mg, 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 part of the administered drug is metabolized. After administration of ¹⁴C-labeled sitagliptin orally, approximately 16% of the radioactive drug was excreted as its 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 to healthy volunteers, ¹⁴C-labeled Sitagliptin 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 via renal excretion through 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

Dosage Regimen

Administer orally as a single 100 mg dose once daily.

Take the tablet with or without food.

Assess renal function before initiating therapy and periodically thereafter.

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

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

Administer the 25 mg dose to patients with ESRD without regard to the timing of hemodialysis sessions.

No dose adjustment is required for patients with mild renal impairment (CrCl ≥50 mL/min).

No dose adjustment is recommended based solely on age or for patients with hepatic impairment.

Adverse Reactions

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%).

Central nervous system: headache (100 mg – 3.6%, 200 mg – 3.9%, placebo – 3.6%).

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%).

Musculoskeletal system: arthralgia (100 mg – 2.1%, 200 mg – 3.3%, placebo – 1.8%).

Endocrine system: hypoglycemia (100 mg – 1.2%, 200 mg – 0.9%, placebo – 0.9%).

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 development were reported.

Contraindications

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

Use in Pregnancy and Lactation

Contraindicated for use 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 with concurrent use 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 concurrent use 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.