Onglyza, 5 mg 30 pcs.

Onglyza has hypoglycemic action.

Pharmacodynamics

Saxagliptin is a potent selective reversible competitive inhibitor of dipeptidyl peptidase-4 (DPP-4). In patients with type 2 diabetes mellitus (DM2) administration of saxagliptin leads to suppression of DPP-4 enzyme activity within 24 hours. After glucose ingestion, inhibition of DPP-4 leads to 2-3 times increased concentration of glucagon-like peptide-1 (GFP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased concentration of glucagon and increased glucose-dependent response of beta-cells, which leads to increased concentration of insulin and C-peptide. Insulin release by pancreatic beta-cells and decrease of glucagon release from pancreatic alpha-cells leads to decrease of fasting and postprandial glycemia.
The efficacy and safety of saxagliptin at doses of 2.5 mg, 5 mg, and 10 mg once daily have been studied in six double-blind, placebo-controlled studies involving 4148 patients with DM2. Administration of the drug was accompanied by statistically significant improvement of glycosylated hemoglobin (HbAlc), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) compared to controls.

Patients in whom the target glycemic level could not be achieved when receiving saxagliptin as monotherapy were additionally prescribed metformin, glibenclamide or thiazolidinediones. When receiving saxagliptin in a dose of 5 mg, a decrease in HbAlc was observed after 4 weeks and in HbAlc after 2 weeks.

In the group of patients receiving saxagliptin in combination with metformin, glibenclamide, or thiazolidinedione, a decrease in HbAlc was also noted after 4 weeks and HbA at 2 weeks.

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

Pharmacokinetics

The pharmacokinetics parameters of saxagliptin and its main metabolite are similar in patients with DM2 and healthy volunteers. Saxagliptin is rapidly absorbed after oral administration on an empty stomach with reaching the maximum concentration of saxagliptin and the main metabolite in plasma (Cmax) within 2 h and 4 h, respectively. When the dose of saxagliptin was increased, there was a proportional increase in Cmax and the area under the curve “concentration-time” (AUC) of saxagliptin and its main metabolite. After a single oral dose of 5 mg of saxagliptin in healthy volunteers, the mean AUC values of saxagliptin and its major metabolite were 78 ng/h/mL and 214 ng/h/mL, and plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.

The mean duration of the final half-life (t½) of saxagliptin and its major metabolite was 2.5 h and 3.1 h, respectively, and the mean t½ plasma inhibition of DPP-4 was 26.9 h. Inhibition of plasma DPP-4 activity for at least 24 h after administration of saxagliptin is due to its high affinity for and prolonged binding to DPP-4. No appreciable cumulation of saxagliptin and its major metabolite was observed with long-term administration of the drug once daily. No dependence of clearance of saxagliptin and its main metabolite was revealed depending on the dose of preparation and duration of therapy when saxagliptin was taken once daily in doses from 2.5 mg to 400 mg for 14 days.

Absorption

At least 75% of the administered dose of saxagliptin is absorbed after oral administration. Food intake had no significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. High-fat meal had no effect on saxagliptin Cmax, whereas AUC was increased by 27% compared to fasting meal. The time to reach Cmax (Tmax) for saxagliptin was increased by approximately 0.5 h when the drug was taken with food compared with fasting food intake. However, these changes are not clinically significant.

Distribution

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

Metabolism

Saxagliptin is metabolized mainly with the participation of cytochrome P450 isoenzymes ZA4/5 (CYP3A4/5) to form the active main metabolite, whose inhibitory effect against DPP-4 is 2 times weaker than that of saxagliptin.

Elimation

Saxagliptin is excreted with urine and bile. After a single dose of 50 mg of 14C-labeled saxagliptin, 24% of the dose was excreted by the kidneys as unchanged saxagliptin and 36% as the major metabolite saxagliptin. Total radioactivity detected in the urine corresponded to 75% of the dose taken. Mean renal clearance of saxagliptin was approximately 230 ml/min, and mean glomerular filtration was approximately 120 ml/min.

For the main metabolite, renal clearance was comparable to the mean glomerular filtration values.
About 22% of the total radioactivity was detected in the feces.

Indications

Type 2 diabetes in addition to diet and exercise to improve glycemic control as:

Active ingredient

Composition

Active ingredient:

saxagliptin in the form of saxagliptin hydrochloride;

Excipients:

lactose monohydrate,

microcrystalline cellulose,

croscarmellose sodium,

magnesium stearate,

1 M hydrochloric acid solution or 1 M sodium hydroxide solution,

Opadray II white [polyvinyl alcohol, titanium dioxide, macrogol (PEG 3350), talcum],

Opadray II yellow [polyvinyl alcohol, titanium dioxide, macrogol (PEG 3350),
talcum, iron oxide yellow dye (E172)] (for 2.5 mg dosage),

Photo Opadray II pink [polyvinyl alcohol, titanium dioxide, macrogoal (PEG 3350), talcum, iron oxide dye red (E172)] (for 5.0 mg dosage), Opacode blue ink

How to take, the dosage

The recommended dose of Onglisa is 5 mg once daily as part of combination therapy.

Interaction

The analysis of clinical trial data suggests that the risk of clinically significant interactions of saxagliptin with other drugs when used together is low.

The metabolism of saxagliptin is mainly mediated by the cytochrome Р450 3A4/5 isoenzyme system (CYP3A4/5). In in vitro studies, saxagliptin and its main metabolite have been shown not to inhibit CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes and not to induce CYP 1A2, 2B6, 2C9, and WA4 isoenzymes. In studies involving healthy volunteers, the pharmacokinetic parameters of saxagliptin and its main metabolite were not significantly changed by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, omeprazole, a combination of aluminum hydroxide, magnesium hydroxide and simethicone, and famotidine. Saxagliptin does not significantly alter the pharmacokinetic parameters of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.

The effect of CYP 3A4/5 isoenzyme inducers on the pharmacokinetics of saxagliptin has not been studied. However, co-administration of saxagliptin and inducers of CYP 3A4/5 isoenzymes, such as carbamazepine, dexamethasone, phenobarbital, phenytoin and rifampicin, may lead to decreased plasma concentration of saxagliptin and increased concentration of its main metabolite. There have been no studies of the effects of smoking, dietary intake, intake of herbal medicines and alcohol consumption on saxagliptin therapy.

Special Instructions

The use of Onglyza® in combination with insulin, as well as in triple therapy with metformin and thiazolidinediones or metformin and sulfonylurea derivatives, has not been studied.

Patients with impaired renal function.

Dose adjustment is recommended for patients with moderate to severe renal impairment and for patients on hemodialysis. Renal function assessment is recommended before initiating therapy and periodically during treatment with the drug.

The use in combination with drugs that may cause hypoglycemia.

Sulfonylurea derivatives may cause hypoglycemia; therefore, reduction of the dose of sulfonylurea derivatives may be required to reduce the risk of hypoglycemia when used concomitantly with Onglyza®.

Hypersensitivity reactions.

The drug should not be administered to patients in whom serious hypersensitivity reactions have been noted with other DPP-4 inhibitors.

Patients of advanced age.

According to data of clinical trials, efficacy and safety parameters in patients aged 65 years and older did not differ from those in younger patients. However, individual hypersensitivity to saxagliptin in some elderly patients cannot be excluded.

Saxagliptin and its main metabolite are partially excreted by the kidneys, so it should be taken into account that in elderly patients renal function is more likely to decrease. Onglyza® contains lactose. Patients with congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption should not take this drug.

Impact on the ability to drive and operate machinery.

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

Contraindications

With caution: moderate to severe renal failure; elderly patients; co-administration with sulfonylurea derivatives.

Overdose

Symptoms of intoxication have not been described with long-term administration of the drug in doses up to 80 times higher than recommended.

Treatment:

In case of overdose, symptomatic therapy should be used. Saxagliptin and its main metabolite are excreted by hemodialysis (excretion rate: 23% of the dose in 4 hours).

Pregnancy use

Due to the fact that the use of saxagliptin in pregnancy has not been studied, the drug should not be prescribed during this period.

It is unknown whether saxagliptin penetrates into the breast milk.

Because it is possible that saxagliptin may penetrate into breast milk, breastfeeding should be stopped during treatment with saxagliptin or therapy should be discontinued, considering the risk-benefit ratio for the child versus the benefit to the mother.