Expiration date: 03/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substance:

saxagliptin (in the form of saxagliptin hydrochloride) 2.5 or 5 mg

excipients: lactose monohydrate — 99 mg* ICC — 90 mg croscarmellose sodium 10 mg magnesium stearate 1 mg** hydrochloric acid solution or 1M sodium hydroxide solution 1M — necessary quantity of Opadry II white (%/weight/weight) and 26 mg (vinyl alcohol — 40% titanium dioxide — 25% macrogol (PEG 3350) — 20,2% talc — 14,8%) Opadry II yellow (%/weight/weight) 7 mg (vinyl alcohol — 40% titanium dioxide — 24,25% macrogol (PEG 3350) — 20,2% talc — 14.8% of the dye iron oxide yellow (E172) — 0,75%) — for dosage of 2.5 mg Opadry II pink (%/weight/weight) 7 mg (vinyl alcohol — 40% titanium dioxide — 24,25% macrogol (PEG 3350) — 20,2% talc — 14.8% of the colorant iron oxide red (E172) — 0,75%) — for the dose of 5.0 mg blue ink Opacode — required quantity 

* the amount of lactose can vary depending on the amount of magnesium stearate 

** the amount of magnesium stearate can vary within 0.5–2 mg. the Optimum amount of 1 mg 

ink composition blue Opacum (%/weight/weight) shellac — 45% in ethanol — 55,4% FD&C Blue#2/Indigo Carmine aluminum pigment (E132) — 16% alcohol n-butyl — 15% propylene glycol and 10.5% isopropyl alcohol — 3% of 28% ammonium hydroxide and 0.1%. Very small amounts of shellac, and FD&C Blue#2/Indigo Carmine aluminum pigment remain on the pill when marking. The solvents included in the ink are removed in the production process 

blistere in 10 PCs. in cardboard pack 3 blisters.

Description pharmaceutical form:

Tablets, film-coated, 2.5 mg: round biconvex, film-coated from light-yellow to light yellow color, with the words "to 2.5" on one side and "4214" on the other side, caused by the blue dye.

Tablets, film-coated, 5 mg: round biconvex, film-coated pink color, with inscription "5" on one side and "4215" on the other side, caused by the blue dye.

Pharmacokinetics:

In patients with diabetes mellitus type 2 and healthy volunteers noted a similar pharmacokinetic parameters of saxagliptin and its main metabolite. Saxagliptin is rapidly absorbed after ingestion on an empty stomach with the achievement of Cmax saxagliptin and its main metabolite in plasma within 2 h and 4 h, respectively. With increasing doses saxagliptin it was observed a proportional increase in Cmax and AUC values of saxagliptin and its main metabolite. After receiving a single saxagliptin oral dose of 5 mg in healthy volunteers the average values of the AUC saxagliptin and its main metabolite were 78 and 214 ng/ml·h, and the values of Cmax in the plasma of 24 and 47 ng/ml, respectively.

The average duration of the final T1/2 saxagliptin and its main metabolite was 2.5 and 3.1 hours respectively, and the average value of T1/2 of inhibition of dipeptidyl-peptidase-4 (DPP-4) plasma and 26.9 h. the Inhibition activity of DPP-4 in plasma for at least 24 h after administration of saxagliptin due to its high affinity for DPP-4 and long bondage with her. A notable accumulation of saxagliptin and its main metabolite during chronic administration of the drug 1 time per day was observed. No correlation was observed between clearance of saxagliptin and its main metabolite from a dose of the drug and duration of therapy when receiving saxagliptin 1 times a day in doses of 2.5 to 400 mg for 14 days.

Suction. Once inside absorbed no less than 75% of the dose, saxagliptin. The meal had no significant effect on the pharmacokinetics of saxagliptin in healthy volunteers.

Meal with a high fat content had no effect on saxagliptin Cmax, while AUC was increased by 27% compared to fasting. Tmax for saxagliptin grew at about 0.5 h before the drug with food compared with fasting. However, these changes are not clinically significant.

Distribution. Bondage saxagliptin and its main metabolite from serum proteins is negligible, therefore we can assume that the distribution of saxagliptin with changes in protein composition of blood serum, observed in hepatic or renal failure, will not be subject to significant changes.

Metabolism. Saxagliptin metabolised mainly with the participation of isoenzymes of cytochrome P450 CYP3A4/5 with the formation of the active main metabolite, inhibitory action against DPP-4 is expressed in 2 times is weaker, than saxagliptin.

Excretion. Saxagliptin excreted in the urine and bile. After a single dose of 14C-labeled-saxagliptin at a dose of 50 mg of 24% of the dose was deduced by kidneys in an unchanged saxagliptin and 36% as the main metabolite of saxagliptin. The total radioactivity found in the urine corresponded to 75% of the dose of the drug. The average renal clearance of saxagliptin amounted to about 230 ml/min, the average value of glomerular filtration rate is approximately 120 ml/min.

For the main metabolite renal clearance was comparable with the average values of glomerular filtration.

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

Pharmacokinetics in special clinical cases

The impairment of renal function. In patients with mild renal insufficiency, the AUC value of saxagliptin and its main metabolite were, respectively, 1.2 and 1.7 times higher than in persons with normal renal function. The increase in AUC values was not clinically significant, therefore dose adjustment is not required.

In patients with renal insufficiency moderate and severe, and in patients on hemodialysis, the AUC values saxagliptin and its main metabolite were, respectively, 2.1 and 4.5 times higher than in persons with normal renal function. For patients with moderate and severe impaired renal function, and patients, on hemodialysis, dose saxagliptin should be 2,5 mg 1 times per day (see "Method of application and dosage" and "Special instructions").

The liver dysfunction. Patients with slight, moderate and severe hepatic impairment no clinically significant changes in pharmacokinetic parameters of saxagliptin, therefore, dose adjustment for these patients is not required.

Patients of advanced age. Patients 65-80 years no clinically significant differences in pharmacokinetic parameters of saxagliptin compared to patients of younger age (18-40 years), therefore dose adjustment in elderly patients is not required. Note, however, that this category of patients more likely to decline in renal function (see "Method of application and dosage" and "Special instructions").

Description pharmacological action:

Saxagliptin — potent, selective reversible competitive inhibitor of DPP-4. In patients with diabetes type 2 receiving saxagliptin leads to the suppression of enzyme activity of DPP-4 for 24 h. After ingestion of glucose inside the inhibition of DPP-4 leads to a 2-3 fold increase in the concentration of glucagonoma peptide-1 (GLP-1) and glukagonovykh insulinotropic polypeptide (GIP), decreased concentrations of glucagon and increased glucosidation response of the beta cells, which leads to increased concentrations of insulin and C-peptide. The release of insulin from the beta cells of the pancreas and reduced release of glucagon from pancreatic alpha-cells leads to a decrease of fasting glycemia and postprandial glycemia.

The effectiveness and safety of using saxagliptin when taken in doses of 2.5, 5 and 10 mg 1 time per day was studied in six double-blind, placebo-controlled trials involving 4148 patients with diabetes mellitus type 2. The drug was accompanied by statistically significant improvements glycosylated hemoglobin (HbAlc), fasting plasma glucose fasting (FPG) and postprandial glucose (PPG) blood plasma compared with the control.

The patients in whom the target level of glycemia failed to be achieved when taking saxagliptin as monotherapy was also prescribed Metformin, glibenclamide, or thiazolidinediones. When receiving saxagliptin at a dose of 5 mg, the reduction in HbAlc was observed after 4 weeks and GPN — 2 weeks.

In the group of patients treated with saxagliptin in combination with Metformin, glibenclamide or thiazolidinedione, the reduction in HbAlc was also noted after 4 weeks and GPN — 2 weeks.

Saxagliptin effect on the lipid profile similar to that of placebo. The therapy saxagliptin not marked increase of body weight.

Indications:

Diabetes mellitus type 2 in addition to diet and exercise to improve glycaemic control as: monotherapy starting combination therapy with Metformin added to monotherapy with Metformin, thiazolidinedione derivatives sulfanilmocevina in the absence of adequate glycemic control in the therapy.

Contraindications:

• increased individual sensitivity to any component of the drug
  
• diabetes mellitus type 1 (application not investigated)
  
• the use in combination with insulin (not studied)
  
• diabetic ketoacidosis
  
• congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption
  
• pregnancy
  
• lactation
  
• the age of 18 years (safety and effectiveness not studied).
  

With caution:

• renal failure moderate and severe
  
• old age
  
• concomitant use with sulfonylureas.
  

Application of pregnancy and breast-feeding:

Due to the fact that the use of saxagliptin during pregnancy have not been studied, it should appoint a drug during pregnancy.

It is unknown whether saxagliptin penetrates in breast milk. Due to the fact that there is a possibility of penetration of saxagliptin in breast milk, you should stop breast-feeding during treatment saxagliptin or cancel the therapy, taking into account the ratio of risk to the child and benefit to the mother.

Side effects:

The table shows side effects, identified patients with diabetes type 2 diabetes while taking the drug Onglyza at a dose of 5 mg during clinical studies. The overall incidence of adverse events while taking the drug Onglyza at a dose of 5 mg as monotherapy and in add mode to Metformin therapy, thiazolidindiones or glibenclamide were comparable in the placebo group.

Scale frequency of adverse reactions: very often — &ge1/10 often — &ge1/100 but <1/10 rare — &ge1/1000 and <1/100 rare &ge1/10000, but <1/1000 very rare <1/10000.

Table

Side effects according to the joint analysis of 5 placebo-controlled clinical studies of the drug Onglyza

Organs and systems	??????? ??????? ???????? ???????? ????????
Infections and infestations
Infections of the upper respiratory tract	Often
Urinary tract infection	Often
Gastroenteritis	Often
Sinusitis	Often
From the digestive tract
Vomiting	Often
From the nervous system
Headache	Often

The frequency of hypersensitivity reactions, marked to the 24th week of treatment was 1.5% in patients receiving the drug Onglyza 5 mg, and 0.4% in patients receiving placebo. Hypersensitivity reactions that occurred in patients taking the drug Onglyza, did not require hospitalization and were regarded by doctors as not representing a threat to life.

Side effects of the drug Onglyza in combination therapy

In the study on the combined use of glibenclamide and saxagliptin the frequency of confirmed hypoglycemia in the group saxagliptin 5 mg (0.8%) and placebo (0.7 percent) was not statistically different. The frequency of confirmed hypoglycemia in patients treated with the drug Onglyza 5 mg in two studies, saxagliptin as monotherapy, the study on combination therapy with Metformin and saxagliptin, as well as in the study on the combined use of saxagliptin and tiazolidindionov, was comparable to the background placebo.

In a study on the use of saxagliptin together with thiazolidinedione frequency of peripheral edema was higher in the group saxagliptin 5 mg compared with the placebo group (8.1 and 4.3% respectively). Peripheral edema were mild or moderate and did not lead to treatment cessation. Frequency of peripheral edema in patients taking the drug Onglyza at a dose of 5 mg during clinical studies saxagliptin monotherapy and combination therapy with Metformin or glibenclamide were comparable to the background placebo (1.7 and 2.4%, respectively).

When starting combination therapy saxagliptin at a dose of 5 mg and Metformin are often mentioned cases of nasopharyngitis and headache. The frequency of nasopharyngitis was higher on the background of combination therapy (6.9 percent) compared with the monotherapy saxagliptin 10 mg (up 4.2%) and Metformin (4.0 per cent). Headache was more common in the group of patients on combination therapy with Metformin and saxagliptin 5 mg (7,5%) compared with the monotherapy groups saxagliptin 10 mg (6.3%) and Metformin (5.2 percent).

Laboratory studies

In clinical studies, the incidence of changes in laboratory values while receiving saxagliptin at a dose of 5 mg and placebo was comparable. There has been a slight decrease in the number of lymphocytes, while the mean absolute number of lymphocytes remained stable and within the normal range with daily administration of saxagliptin for up to 102 weeks. The decrease in the number of lymphocytes was not accompanied by clinically significant adverse reactions. The clinical significance of a reduction in the number of lymphocytes during therapy saxagliptin unknown.

Drug interactions:

Data analysis of clinical studies suggests that the risk of clinically significant interactions with other drugs saxagliptin in their joint application is small.

Metabolic saxagliptin predominantly mediated by the system of cytochrome P450 isoenzymes CYP3A4/5. In vitro studies have shown that saxagliptin and its principal active metabolite do not inhibit CYP1A2 isoenzymes, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and ZA4 and does not induce isoenzymes CYP1A2, 2B6, 2C9 and ZA4.

In studies involving healthy volunteers the pharmacokinetic parameters of saxagliptin and its main metabolite were not significantly changed under the influence of Metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, omeprazole, a combination of aluminum hydroxide, magnesium hydroxide and simethicone and famotidine. Saxagliptin not significantly alter the pharmacokinetic parameters of Metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.

The effect of inducers of cytochrome P450 isoenzymes CYP3A4/5 on the pharmacokinetics of saxagliptin not been studied.

However, the combined use of saxagliptin and inducers of cytochrome P450 isoenzymes CYP3A4/5, such as carbamazepine, dexamethasone, phenobarbital, phenytoin and rifampicin can lead to reduction in the concentration of saxagliptin in the plasma and increases the concentration of its main metabolite.

The study of the influence of Smoking, diet, plant-based drugs and alcohol to therapy saxagliptin was conducted.

Method of application and dose:

Inside, regardless of meals.

Monotherapy: the recommended dose of saxagliptin is 5 mg 1 times per day.

Combination therapy: the recommended dose of saxagliptin is 5 mg 1 times / day in combination with Metformin, thiazolidinediones or sulfonylureas.

With a starting combined therapy with Metformin the recommended dose of saxagliptin is 5 mg 1 times per day, initial dose of Metformin is 500 mg/day. In case of inadequate response, the dose of Metformin can be increased.

When skipping taking the drug Onglyza the missed pill should be taken as soon as the patient remembers about it, but we should not take a double dose of the drug for one day.

Use in special patient groups

Patients with impaired renal function. For patients with renal insufficiency, mild (creatinine Cl >50 ml/min) dose adjustment is not required. For patients with moderate or severe renal insufficiency (Cl creatinine <50 ml/min) and patients on hemodialysis, the recommended dose Onglyza is 2.5 mg 1 times per day. The drug should be taken after hemodialysis session.

Application saxagliptin in patients on peritoneal dialysis have not been studied.

Before therapy saxagliptin and during treatment is recommended to assess renal function.

Patients with impaired liver function. When liver dysfunction mild, moderate and severe, dose adjustment is not required.

Patients of advanced age. Dose adjustment in elderly patients is not required. However, the choice of dose should take into account that this category of patients more likely to decline in kidney function.

Children. The safety and efficacy of the drug in patients under 18 years has not been studied.

Overdose:

Symptoms not described chronic administration of the drug at doses up to 80 times higher than recommended.

Treatment: in case of overdose you should apply symptomatic therapy. Saxagliptin and its main metabolite are excreted from the body by hemodialysis (speed out: 23% of dose over 4 hours).

Special instructions:

The use of the drug Onglyza in combination with insulin, as well as in triple therapy with Metformin and thiazolidinedione or Metformin and sulfonylureas has not been studied.

Patients with impaired renal function. Recommended dose adjustment for patients with moderate to severe renal insufficiency and patients undergoing hemodialysis. Before therapy and periodically during treatment with the drug it is recommended to evaluate renal function.

Use in combination with drugs that can cause hypoglycemia. Sulfonylureas can cause hypoglycaemia, therefore, to reduce the risk of hypoglycemia with concomitant use with the drug Onglyza may require lower doses of sulfonylureas.

Hypersensitivity reactions. The drug should not be prescribed to patients who have had serious hypersensitivity reactions with the use of other DPP-4 inhibitors.

Patients of advanced age. According to clinical studies, indicators of efficacy and safety in patients aged 65 years and older did not differ from similar parameters in patients of younger age. However, we cannot exclude an increased individual sensitivity to saxagliptin some elderly patients. Saxagliptin and its main metabolite partially eliminated by the kidneys, so you should consider that elderly patients are more likely to decline in renal function.

Onglyza the drug contains lactose. Patients with congenital lactose galactose, lactase deficiency and glucose-galactose malabsorption should not take this drug.

Effects on ability to drive vehicles and management mechanisms. Studies have been conducted. Note that saxagliptin may cause dizziness.