Onglyza^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca UK Limited (United Kingdom)

Manufactured By

AstraZeneca Pharmaceuticals LP (USA)

Packaging and Quality Control Release

ASTRAZENECA UK, Limited (United Kingdom)

ATC Code

A10BH03 (Saxagliptin)

Active Substance

Saxagliptin (Rec.INN registered by WHO)

Dosage Forms

	Onglyza®	Film-coated tablets, 2.5 mg: 30 pcs.
		Film-coated tablets, 5 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from pale yellow to light yellow, round, biconvex, with inscriptions “2.5” on one side and “4214” on the other side, printed in blue dye.

Excipients : lactose monohydrate – 99 mg*, microcrystalline cellulose – 90 mg, croscarmellose sodium – 10 mg, magnesium stearate – 1 mg**, Opadry II white (% w/w) – 26 mg (polyvinyl alcohol 40%, titanium dioxide 25%, macrogol/PEG 3350 20.2%, talc 14.8 %), Opadry II yellow (% w/w) – 7 mg (polyvinyl alcohol 40%, titanium dioxide 24.25%, macrogol/PEG 3350) 20.2%, talc 14.8%, dye yellow iron oxide (E172) 0.75%), hydrochloric acid solution 1 M – required quantity***, Opacode blue ink**** – required quantity.

10 pcs. – blisters made of aluminum foil (3) – cardboard packs.

* The amount of lactose may vary depending on the amount of magnesium stearate used.
** The amount of magnesium stearate may vary within 0.5-2 mg. The optimal amount is 1 mg.
***If necessary, sodium hydroxide solution 1M may be used to adjust the pH.
**** Composition of Opacode blue ink (% w/w): shellac 45% in ethyl alcohol 55.4%, FD&C Blue #2/indigo carmine aluminum pigment (E132) 16%, n-butyl alcohol 15%, propylene glycol 10.5%, isopropyl alcohol 3%, 28% ammonium hydroxide 0.1%. Very small amounts of shellac and FD&C Blue #2/indigo carmine aluminum pigment remain on the tablets during marking. The solvents included in the ink are removed during the manufacturing process.

Film-coated tablets pink, round, biconvex, with inscriptions “5” on one side and “4215” on the other side, printed in blue dye.

Excipients : lactose monohydrate – 99 mg*, microcrystalline cellulose – 90 mg, croscarmellose sodium – 10 mg, magnesium stearate – 1 mg**, Opadry II white (% w/w) – 26 mg (polyvinyl alcohol 40%, titanium dioxide 25%, macrogol/PEG 3350 20.2%, talc 14.8 %), Opadry II pink (% w/w) – 7 mg (polyvinyl alcohol 40%, titanium dioxide 24.25%, macrogol/PEG 3350 20.2%, talc 14.8%, dye red iron oxide (E172) 0.75%), hydrochloric acid solution 1 M – required quantity***, Opacode blue ink**** – required quantity.

10 pcs. – blisters made of aluminum foil (3) – cardboard packs.

* The amount of lactose may vary depending on the amount of magnesium stearate used.
** The amount of magnesium stearate may vary within 0.5-2 mg. The optimal amount is 1 mg.
***If necessary, sodium hydroxide solution 1M may be used to adjust the pH.
**** Composition of Opacode blue ink (% w/w): shellac 45% in ethyl alcohol 55.4%, FD&C Blue #2/indigo carmine aluminum pigment (E132) 16%, n-butyl alcohol 15%, propylene glycol 10.5%, isopropyl alcohol 3%, 28% ammonium hydroxide 0.1%. Very small amounts of shellac and FD&C Blue #2/indigo carmine aluminum pigment remain on the tablets during marking. The solvents included in the ink are removed during the manufacturing process.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor

Pharmacological Action

Hypoglycemic agent, 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 results in 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 when taken in doses of 2.5 mg, 5 mg, and 10 mg once daily were studied in six double-blind, placebo-controlled studies involving 4148 patients with type 2 diabetes. Taking the drug was accompanied by a statistically significant improvement in the parameters of glycated hemoglobin (HbA_1c), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) compared to control.

For patients who did not achieve the target glycemic level 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

In patients with type 2 diabetes and in healthy volunteers, similar pharmacokinetic parameters of saxagliptin and its major metabolite were noted.

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 saxagliptin 5 mg 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 dose of the drug and the 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 taken dose of saxagliptin 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 taking it on an empty stomach. The time to reach C_max for saxagliptin increased by approximately 0.5 hours when taking the drug with food compared to taking it on an empty stomach. However, these changes are not clinically significant.

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

Saxagliptin is metabolized mainly by the cytochrome P4503A4/5 (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 taken 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 rates.

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 dose adjustment is not 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 dose adjustment for such patients is not required.

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 in addition to diet and physical exercise to improve glycemic control as monotherapy; as initial combination therapy with metformin; for addition to monotherapy with metformin, thiazolidinediones, sulfonylurea derivatives, in the absence of adequate glycemic control on 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. 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

From the endocrine system hypoglycemia (frequency comparable to placebo).

From the respiratory system nasopharyngitis, sinusitis.

From the digestive system often – gastroenteritis, vomiting.

From the 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 period (breastfeeding); children and adolescents under 18 years of age (safety and efficacy not studied); hypersensitivity to saxagliptin.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during the lactation period (breastfeeding).

Special Precautions

The drug should be prescribed with caution in cases of moderate and severe renal failure, in elderly patients, and also 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 similar indicators in younger patients. However, increased individual sensitivity to saxagliptin in some elderly patients cannot be ruled out. Dose adjustment in elderly patients is not required, 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 cases of mild, moderate, and severe hepatic impairment, dose adjustment is not 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 to study 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 predominantly mediated by the CYP3A4/5 isoenzymes. In vitro studies have shown that Saxagliptin and its major metabolite do not inhibit the CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes and do not induce the 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, as well as 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 30°C (86°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.