Asiglia^® (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

ATC Code

A10BH01 (Sitagliptin)

Active Substance

Sitagliptin (Rec.INN registered by WHO)

Dosage Forms

	Asiglia®	Film-coated tablets 25 mg: 14, 28, 30, 56, 60, 84 or 98 pcs.
		Film-coated tablets 50 mg: 14, 28, 30, 56, 60, 84 or 98 pcs.
		Film-coated tablets 100 mg: 14, 28, 30, 56, 60, 84 or 98 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets round, slightly biconvex, film-coated pink, with an engraving “K25” on one side of the tablet.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate.

Film coating
Film-forming mixture¹, colorant iron oxide red (E172), colorant iron oxide yellow (E172)
¹ film-forming mixture: polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc.

14 pcs. – blisters (1, 2, 4, 6 or 7) – cardboard packs.
15 pcs. – blisters (2, 4 or 6) – cardboard packs.

Film-coated tablets round, biconvex, film-coated light orange, with a score on one side of the tablet, with an engraving “K” on one side of the score and an engraving “50” on the other side of the score; the tablet can be divided into equal doses.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate.

Film coating
Film-forming mixture¹, colorant iron oxide red (E172), colorant iron oxide yellow (E172)
¹ film-forming mixture: polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc.

14 pcs. – blisters (1, 2, 4, 6 or 7) – cardboard packs.
15 pcs. – blisters (2, 4 or 6) – cardboard packs.

Film-coated tablets round, biconvex, film-coated brownish-orange, with a score on one side of the tablet, with an engraving “K” on one side of the score and an engraving “100” on the other side of the score; the tablet can be divided into equal doses.

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, sodium stearyl fumarate, magnesium stearate.

Film coating:
Film-forming mixture¹, colorant iron oxide red (E172), colorant iron oxide yellow (E172)
¹ film-forming mixture: polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc.

14 pcs. – blisters (1, 2, 4, 6 or 7) – cardboard packs.
15 pcs. – blisters (2, 4 or 6) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

Pharmacological Action

Oral hypoglycemic drug, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor.

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 hormones of the incretin family: 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 for regulating glucose homeostasis.

At normal or elevated blood glucose levels, incretin hormones contribute to an increase in insulin synthesis, as well as its secretion by pancreatic β-cells through intracellular signaling mechanisms associated with cyclic AMP.

GLP-1 also contributes to the suppression of increased glucagon secretion by pancreatic α-cells. The decrease in glucagon concentration against the background of an increase in insulin levels contributes to a decrease in glucose production by the liver, which ultimately leads to a decrease in glycemia.

At low blood glucose concentrations, the listed effects of incretins on insulin release and reduction of 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 increases 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 decrease in plasma glucose concentration, determined fasting and after a stress test.

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

Pharmacokinetics

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

After oral administration of the drug at a dose of 100 mg in healthy subjects, rapid absorption of sitagliptin is noted with C_max reached in 1-4 hours. AUC increases proportionally to the dose and in healthy subjects is 8.52 µmol × h when taken orally at a dose of 100 mg, C_max was 950 nmol. The absolute bioavailability of sitagliptin is approximately 87%. Intra- and interindividual coefficients of variability of sitagliptin AUC are insignificant. Simultaneous intake of fatty food does not affect the pharmacokinetics of sitagliptin.

Plasma AUC of sitagliptin increased by approximately 14% after the next dose of the drug at a dose of 100 mg upon reaching steady state after the first dose. After a single dose of the drug at a 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 drug that enters the body is metabolized. After administration of ¹⁴C-labeled sitagliptin orally, approximately 16% of the radioactive drug was excreted in the form of its metabolites. Traces of 6 metabolites of sitagliptin were found, probably not possessing DPP-4 inhibitory activity. In vitro studies have revealed 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 taking the drug by healthy volunteers, ¹⁴C-labeled Sitagliptin was excreted: in urine – 87% and in feces -13%. T_1/2 of sitagliptin when taken orally at a dose of 100 mg is approximately 12.4 hours. Renal clearance is approximately 350 ml/min.

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

Indications

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

Combination therapy: type 2 diabetes 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

Take orally once daily.

The recommended dose is 100 mg.

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

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

Administer the 25 mg dose without regard to the timing of hemodialysis.

Assess renal function before initiating therapy and periodically thereafter to determine if dosage adjustment is necessary.

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

No dose adjustment is recommended based on age, body mass index, gender, or race.

For combination therapy with metformin, initiate sitagliptin at the recommended dose of 100 mg once daily.

When used in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.

The tablets may be taken with or without food.

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 – an 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 have been 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 during the lactation period (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 failure. Accordingly, as in other age groups, dose adjustment is necessary in patients with severe renal failure.

Special Precautions

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

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

Drug Interactions

A slight increase in AUC (11%), as well as mean C_max (18%) of digoxin was noted when used concomitantly 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 concomitant use of sitagliptin at a single dose of 100 mg and cyclosporine (a potent P-glycoprotein inhibitor) at a single dose of 600 mg. 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.