Dixaptin^® (Tablets) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

ATC Code

A10BH03 (Saxagliptin)

Active Substance

Saxagliptin (Rec.INN registered by WHO)

Dosage Form

Dixaptin®

Film-coated tablets 5 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
8 pcs. – blister packs (4 pcs.) – cardboard packs (32 pcs.) – By prescription

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

Pharmacological Action

Hypoglycemic agent, a selective reversible competitive inhibitor of dipeptidyl peptidase-4 (DPP-4).

In patients with type 2 diabetes, taking saxagliptin leads to suppression of DPP-4 enzyme activity for 24 hours. After oral glucose intake, inhibition of DPP-4 leads to a 2-3 fold increase in the concentration of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), a decrease in glucagon concentration, and an enhancement of the glucose-dependent response of beta-cells, which leads to an increase in the concentration of insulin and C-peptide.

The release of insulin by pancreatic beta-cells and the reduction of glucagon release from pancreatic alpha-cells leads to a decrease in fasting glycemia and postprandial glycemia.

The efficacy and safety of saxagliptin at doses of 2.5 mg, 5 mg, and 10 mg once daily were studied in six double-blind, placebo-controlled trials involving 4148 patients with type 2 diabetes. Treatment with the drug was accompanied by a statistically significant improvement in glycated hemoglobin (HbA_1c), fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) compared to control.

For patients who did not achieve target glycemic levels with saxagliptin monotherapy, metformin, glibenclamide, or thiazolidinediones were additionally prescribed. When taking saxagliptin at a dose of 5 mg, a decrease in HbA_1c was noted after 4 weeks and FPG after 2 weeks. In the group of patients receiving Saxagliptin in combination with metformin, glibenclamide, or thiazolidinediones, a decrease in HbA_1c was also noted after 4 weeks and FPG after 2 weeks.

The effect of saxagliptin on the lipid profile is similar to that of placebo. No increase in body weight was observed during therapy with saxagliptin.

Pharmacokinetics

Patients with type 2 diabetes and healthy volunteers showed similar pharmacokinetic parameters for saxagliptin and its major metabolite.

Saxagliptin is rapidly absorbed after oral administration on an empty stomach, with C_max of saxagliptin and the major metabolite in plasma reached within 2 hours and 4 hours, respectively. With an increase in the dose of saxagliptin, a proportional increase in C_max and AUC of saxagliptin and its major metabolite was noted. After a single oral dose of 5 mg of saxagliptin in healthy volunteers, the mean AUC values for saxagliptin and its major metabolite were 78 ng × h/ml and 214 ng × h/ml, and the C_max values in plasma were 24 ng/ml and 47 ng/ml, respectively.

The mean terminal T_1/2 of saxagliptin and its major metabolite was 2.5 hours and 3.1 hours, respectively, and the mean plasma DPP-4 inhibition T_1/2 was 26.9 hours. Inhibition of plasma DPP-4 activity for at least 24 hours after taking saxagliptin is due to its high affinity for DPP-4 and prolonged binding to it. No noticeable accumulation of saxagliptin and its major metabolite was observed during long-term use of the drug once daily. No dependence of the clearance of saxagliptin and its major metabolite on the drug dose and duration of therapy was detected when taking saxagliptin once daily in doses from 2.5 mg to 400 mg for 14 days.

After oral administration, at least 75% of the administered saxagliptin dose is absorbed. Food intake did not have a significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. A high-fat meal did not affect the C_max of saxagliptin, while the AUC increased by 27% compared to administration on an empty stomach. The time to reach C_max for saxagliptin increased by approximately 0.5 hours when the drug was taken with food compared to administration on an empty stomach. However, these changes are not clinically significant.

The binding of saxagliptin and its major metabolite to serum proteins is negligible, so it can be assumed that the distribution of saxagliptin will not be subject to significant changes with alterations in serum protein composition observed in hepatic or renal failure.

Saxagliptin is metabolized mainly by cytochrome P450 3A4/5 (CYP3A4/5) isoenzymes to form an active major metabolite, whose inhibitory effect on DPP-4 is 2 times weaker than that of saxagliptin.

Saxagliptin is excreted in urine and bile. After a single dose of 50 mg of labeled ¹⁴C-saxagliptin, 24% of the dose was excreted by the kidneys as unchanged saxagliptin and 36% as the major metabolite of saxagliptin. The total radioactivity detected in the urine corresponded to 75% of the administered dose of the drug. The mean renal clearance of saxagliptin was about 230 ml/min, the mean glomerular filtration rate was approximately 120 ml/min. For the major metabolite, renal clearance was comparable to the mean glomerular filtration rate values.

About 22% of the total radioactivity was found in the feces.

In patients with mild renal impairment, the AUC values of saxagliptin and its major metabolite were 1.2 and 1.7 times higher, respectively, than the corresponding values in individuals with normal renal function. This increase in AUC values is not clinically significant, so no dose adjustment is required.

In patients with moderate and severe renal impairment, as well as in patients on hemodialysis, the AUC values of saxagliptin and its major metabolite were 2.1 and 4.5 times higher, respectively, than the corresponding values in individuals with normal renal function.

In patients with mild, moderate, and severe hepatic impairment, no clinically significant changes in the pharmacokinetic parameters of saxagliptin were detected, so no dose adjustment is required for such patients.

In patients aged 65-80 years, no clinically significant differences in the pharmacokinetic parameters of saxagliptin were found compared to younger patients.

Indications

Type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control as monotherapy; as initial combination therapy with metformin; for addition to metformin, thiazolidinediones, or sulfonylurea derivatives monotherapy, when adequate glycemic control is not achieved with this therapy.

ICD codes

Dosage Regimen

Take orally at a dose of 5 mg once daily.

For patients with mild renal impairment (CrCl >50 ml/min), no dose adjustment is required. For patients with moderate or severe renal impairment (CrCl ≤50 ml/min), as well as for patients on hemodialysis, the recommended dose is 2.5 mg once daily. It should be taken after the hemodialysis session. The use of saxagliptin in patients on peritoneal dialysis has not been studied.

When used concomitantly with potent CYP3A4/5 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin, the recommended dose of saxagliptin is 2.5 mg once daily.

Adverse Reactions

Endocrine system hypoglycemia (frequency comparable to placebo).

Respiratory system nasopharyngitis, sinusitis.

Digestive system frequently – gastroenteritis, vomiting.

Nervous system headache.

Other urinary tract infections, hypersensitivity reactions (frequency comparable to placebo), peripheral edema, slight decrease in lymphocyte count (clinical significance unknown).

Contraindications

Type 1 diabetes mellitus (use not studied); use in combination with insulin (not studied); diabetic ketoacidosis; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age (safety and efficacy not studied); hypersensitivity to saxagliptin.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Special Precautions

The drug should be used with caution in moderate and severe renal impairment, in elderly patients, and in combination with sulfonylurea derivatives.

Dose adjustment is recommended for patients with moderate and severe renal impairment, as well as for patients on hemodialysis. It is recommended to assess renal function before starting therapy and periodically during treatment with the drug.

Sulfonylurea derivatives can cause hypoglycemia, so when used concomitantly with saxagliptin, a reduction in the dose of sulfonylurea derivatives may be required to reduce the risk of hypoglycemia.

Saxagliptin should not be prescribed to patients who have experienced serious hypersensitivity reactions when using other DPP-4 inhibitors.

According to clinical studies, efficacy and safety indicators in patients aged 65 years and older did not differ from those in younger patients. However, increased individual sensitivity to saxagliptin in some elderly patients cannot be ruled out. No dose adjustment is required in elderly patients, but when choosing a dose, it should be taken into account that this category of patients is more likely to have reduced renal function.

In mild, moderate, and severe hepatic impairment, no dose adjustment is required.

Saxagliptin and its major metabolite are partially excreted by the kidneys, so it must be taken into account that elderly patients are more likely to have reduced renal function.

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of saxagliptin on the ability to drive vehicles and operate machinery. It should be taken into account that Saxagliptin may cause dizziness.

Drug Interactions

The metabolism of saxagliptin is primarily mediated by CYP3A4/5 isoenzymes. In vitro studies have shown that Saxagliptin and its major metabolite do not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes and do not induce CYP1A2, 2B6, 2C9, and 3A4 isoenzymes. In studies involving healthy volunteers, the pharmacokinetic parameters of saxagliptin and its major metabolite were not significantly altered by the influence of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, omeprazole, a combination of aluminum hydroxide, magnesium hydroxide and simethicone, or famotidine. Saxagliptin does not significantly alter the pharmacokinetic parameters of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, or ketoconazole.

Concomitant use of saxagliptin and inducers of CYP3A4/5 isoenzymes, such as carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin, may lead to a decrease in the plasma concentration of saxagliptin and an increase in the concentration of its major metabolite.

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.