Universal reference book for medicines
Product name: ONLLYZA ® (ONGLYZA ® )

Active substance: saxagliptin

Type: Oral hypoglycemic drug

Manufacturer: BRISTOL-MYERS SQUIBB Company (USA) in cooperation with ASTRAZENECA (Unknown)
Composition, form of production and packaging
The tablets covered with a film membrane
from pale yellow to light yellow color, round, biconcave, with the inscription "2.5" on one side and "4214" - on the other side, applied with a blue dye.

1 tab.

saxagliptin (in the form of hydrochloride) 2.5 mg

Auxiliary substances: lactose monohydrate - 99 mg *, microcrystalline cellulose - 90 mg, croscarmellose sodium - 10 mg, magnesium stearate - 1 mg **, hydrochloric acid 1 M or sodium hydroxide solution 1 M - the required amount, Opadrai II white (% weight / weight) 26 mg (polyvinyl alcohol 40%, titanium dioxide 25%, macrogol (PEG 3350) 20.2%, talc 14.8%), Opadrai II yellow (w / w) 7 mg (polyvinyl alcohol 40%, titanium dioxide 24.25%, macrogol (PEG 3350) 20.2%, talc 14.8%, dye iron oxide yellow (E172) 0.75%), Opacode Blue *** is the required amount.

10 pieces.
- blisters of aluminum foil (3) - packs of cardboard.
* - The amount of lactose can vary depending on the amount of magnesium stearate used.

** - The amount of magnesium stearate can vary within the range of 0.5-2 mg.
The optimal amount is 1 mg.
*** - Composition of Opacod blue ink (% w / w): shellac 45% in ethanol 55.4%, FD & C Blue # 2 / indigocarmine aluminum pigment (E132) 16%, n-butyl alcohol 15%, propylene glycol 10.5%, alcohol isopropyl 3%, 28% ammonium hydroxide 0.1%.
Very small amounts of shellac and FD & C Blue # 2 / indigo-carmine aluminum pigment remain on the tablets when labeling is applied. Solvents that form part of the ink are removed during the manufacturing process.
The tablets covered with a film covering of pink color, round, biconcave, with inscriptions "5" on one side and "4215" - on the other side, put by a blue dye.

1 tab.

saksagliptin (in the form of hydrochloride) 5 mg

Auxiliary substances: lactose monohydrate - 99 mg *, microcrystalline cellulose - 90 mg, croscarmellose sodium - 10 mg, magnesium stearate - 1 mg **, hydrochloric acid 1 M or sodium hydroxide solution 1 M - the required amount, Opadrai II white (% weight / weight) 26 mg (polyvinyl alcohol 40%, titanium dioxide 25%, macrogol (PEG 3350) 20.2%, talc 14.8%), Opadrai II pink (% w / w) 7 mg (polyvinyl alcohol 40%, titanium dioxide 24.25%, macrogol (PEG 3350) 20.2%, talc 14.8%, ferric oxide red oxide (E172) 0.75%), Opacode Blue *** is the required amount.

10 pieces.
- blisters of aluminum foil (3) - packs of cardboard.
* - The amount of lactose can vary depending on the amount of magnesium stearate used.

** - The amount of magnesium stearate can vary within the range of 0.5-2 mg.
The optimal amount is 1 mg.
*** - Composition of Opacod blue ink (% w / w): shellac 45% in ethanol 55.4%, FD & C Blue # 2 / indigocarmine aluminum pigment (E132) 16%, n-butyl alcohol 15%, propylene glycol 10.5%, alcohol isopropyl 3%, 28% ammonium hydroxide 0.1%.
Very small amounts of shellac and FD & C Blue # 2 / indigo-carmine aluminum pigment remain on the tablets when labeling is applied. Solvents that form part of the ink are removed during the manufacturing process.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2012.

PHARMACHOLOGIC EFFECT

Saksagliptin is a potent selective reversible competitive inhibitor of dipeptidyl peptidase-4 (DPP-4).

In patients with type 2 diabetes, the administration of saxagliptin leads to inhibition of the activity of the DPP-4 enzyme within 24 hours. After ingestion of glucose, 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 (HIP), a decrease in glucagon concentration and an increase in glucose-dependent response of beta cells, which leads to an increase in the concentration of insulin and C-peptide.

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

The efficacy and safety of saxagliptin in doses of 2.5 mg, 5 mg, and 10 mg once a day were studied in six double-blind, placebo-controlled trials involving 4,148 patients with type 2 diabetes.
The administration of the drug was accompanied by a statistically significant improvement in the indices of glycosylated hemoglobin (HbA 1c ), fasting plasma glucose (GPN) and postprandial glucose (PPG) of blood plasma compared to the control.
Patients in whom the target level of glycemia could not be achieved with the administration of saxagliptin as monotherapy, metformin, glibenclamide or thiazolidinediones were additionally prescribed.
When taking saxagliptin in a dose of 5 mg, a decrease in HbA 1c was observed after 4 weeks and GPN - after 2 weeks. In the group of patients receiving saxagliptin in combination with metformin, glibenclamide or thiazolidinediones, a decrease in HbA 1c was also observed after 4 weeks and GPN after 2 weeks.
The effect of saxagliptin on the lipid profile is similar to that of placebo.
Against the background of therapy with saxagliptin, there was no increase in body weight.
PHARMACOKINETICS

Patients with type 2 diabetes mellitus and healthy volunteers have similar pharmacokinetics of saxagliptin and its main metabolite.

Saxagliptin is rapidly absorbed after ingestion with fasting to C max of saxagliptin and the main metabolite in plasma for 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 main metabolite was noted. After a single dose of saxagliptin inside at a dose of 5 mg by healthy volunteers, the mean values ​​of AUC of saxagliptin and its main metabolite were 78 ng. h / ml and 214 ng? h / ml, and C max values ​​in plasma were 24 ng / ml and 47 ng / ml, respectively.
The average duration of the final T 1/2 of saxagliptin and its main metabolite was 2.5 h and 3.1 h, respectively, and the mean inhibition of T 1/2 of the plasma DTP-4 was 26.9 h. The inhibition of DPP-4 activity in plasma for at least 24 hours after the administration of saxagliptin is due to its high affinity for DPP-4 and prolonged binding to it.
A noticeable cumulation of saxagliptin and its main metabolite with long-term administration of the drug 1 time / day was not observed. There was no dependence of the clearance of saxagliptin and its main metabolite on the dose of the drug and the duration of therapy with the administration of saxagliptin 1 time / day in doses from 2.5 mg to 400 mg for 14 days.
Suction

After ingestion, at least 75% of the dose of saxagliptin is absorbed.
The intake of food had no significant effect on the pharmacokinetics of saxagliptin in healthy volunteers. Eating high-fat foods had no effect on C max of saxagliptin, whereas AUC increased by 27% compared with fasting. The time to reach C max for saxagliptin increased by approximately 0.5 h when taken together with food as compared to fasting. However, these changes are not clinically significant.
Distribution

The binding of saxagliptin and its main metabolite to serum proteins is insignificant, so it can be assumed that the distribution of saxagliptin with changes in the protein composition of blood serum, which are noted in hepatic or renal insufficiency, will not undergo significant changes.

Metabolism

Saxagliptin is metabolized mainly with the participation of cytochrome P450 3A4 / 5 isozymes (CYP 3A4 / 5) to form an active basic metabolite, the inhibitory effect of which on DPP-4 is 2 times weaker than that of saxagliptin.

Excretion

Saksagliptin is excreted in the urine and with bile.
After a single administration of 50 mg of labeled 14 C-saxagliptin, 24% of the dose was excreted by the kidneys in the form of unchanged saksagliptin and 36% in the form of the main metabolite of saxagliptin. The total radioactivity found in urine corresponded to 75% of the dose taken. The mean renal clearance of saxagliptin was about 230 ml / min, the mean glomerular filtration was approximately 120 ml / min. For the main metabolite, the renal clearance was comparable to the mean values ​​of glomerular filtration.
About 22% of the total radioactivity was found in feces.

Pharmacokinetics in special clinical cases

In patients with mild renal insufficiency, the AUC value of saxagliptin and its main metabolite was 1.2 and 1.7 times higher, respectively, than those in persons 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 insufficiency, as well as in patients on hemodialysis, the values ​​of AUC of saxagliptin and its main metabolite were 2.1 and 4.5 times higher, respectively, than those in persons with normal renal function.
For patients with moderate and severe renal dysfunction, as well as for patients on hemodialysis, the dose of saxagliptin should be 2.5 mg 1 time / day.
In patients with mild, moderate and severe impairment of liver function, there were no clinically significant changes in the parameters of the pharmacokinetics of saxagliptin, so dose adjustments for such patients are not required.

In patients aged 65-80 years, there were no clinically significant differences in the parameters of the pharmacokinetics of saxagliptin compared with younger patients (18-40 years), so dose adjustments in elderly patients are not required.
However, it should be borne in mind that this category of patients is more likely to have decreased kidney function.
INDICATIONS

Diabetes mellitus type 2 in addition to diet and exercise to improve glycemic control as:

- monotherapy;

- starting combination therapy with metformin;

- addition to monotherapy with metformin, thiazolidinediones, derivatives of sulfonylurea, in the absence of adequate glycemic control in this therapy.

DOSING MODE

The drug is administered orally, regardless of food intake.

With monotherapy, the recommended dose of saxagliptin is 5 mg 1 time / day.

When
combination therapy, the recommended dose of saxagliptin is 5 mg 1 time / day in combination with metformin, thiazolidinedione or sulfonylurea derivatives.
With the initial combination therapy with metformin, the recommended dose of saxagliptin is 5 mg 1 time / day, the initial dose of metformin is 500 mg / day.
In case of an inadequate response, the dose of metformin can be increased.
If you miss a dose of Onglys ®, the missed tablet should be taken as soon as the patient remembers it, but do not take a double dose of the drug for one day.

For patients with mild renal insufficiency ( CK> 50 ml / min ), dose adjustment is not required.
For patients with moderate or severe renal insufficiency ( KK≥50 ml / min ), as well as for patients on hemodialysis, the recommended dose of Onglis ® is 2.5 mg 1 time / day. The drug should be taken at the end of the hemodialysis session. The use of saxagliptin in patients on peritoneal dialysis has not been studied. Before starting therapy with saxagliptin and during treatment, it is recommended that the kidney function be assessed.
If the liver function is mild, moderate and severe, dose adjustment is not required.

Dose adjustments in elderly patients are not required.
However, when choosing a dose, it should be borne in mind that this category of patients is more likely to have decreased kidney function.
The safety and efficacy of the drug in patients under the age of 18 years has not been studied.

When used simultaneously with potent CYP 3A4 / 5 inhibitors such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin, the recommended dose of Onglysa ® is 2.5 mg 1 time / day.

SIDE EFFECT

The overall incidence of adverse events with the administration of Onglys ® 5 mg in
monotherapy and in the mode of addition to therapy with metformin, thiazolidinedione or glibenclamide was comparable to that in the placebo group.
Scale of adverse reactions frequency: very often (? 1/10);
often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000).
The table shows the side effects found in patients with type 2 diabetes mellitus when taking Ongliza ® in a dose of 5 mg during clinical trials.
Side effects are presented by the data of the combined analysis of five placebo-controlled clinical trials of the drug Ongliza ® .
Upper respiratory tract infections

Urinary tract infection

Gastroenteritis Often

Sinusitis Often

Vomiting Often

Headache Often

The incidence of hypersensitivity reactions noted by the 24th week of therapy was 1.5% in patients receiving Onglis® 5 mg and 0.4% in patients receiving placebo.Hypersensitivity reactions that occurred in patients taking the drug Ongliza ® did not require hospitalization and were regarded by the treating physicians as not posing a life threat.

Side effects of the drug Ongliza ® with combined therapy

In a study of the combined use of saxagliptin and glibenclamide, the incidence of confirmed hypoglycemia in the 5 mg group (0.8%) and placebo (0.7%) was not statistically different.
The incidence of confirmed episodes of hypoglycemia in patients treated with Onglysis® 5 mg in two studies of saxagliptin in monotherapy regimen, a study on combined therapy with saxagliptin and metformin, and in a study on the combined use of saxagliptin and thiazolidinediones was comparable to that of placebo.
In a study on the use of saxagliptin in combination with thiazolidinediones, the incidence of peripheral edema was higher in the 5 mg group of saxagliptin than in the placebo group (8.1% and 4.3%, respectively).
Peripheral edema was mild or moderate and did not lead to discontinuation of treatment. The incidence of peripheral edema in patients taking the Onglysis ® 5 mg preparation in clinical studies of monotherapy with saxagliptin and combination therapy with metformin or glibenclamide was comparable to that of placebo (1.7% and 2.4%, respectively).
With starting combination therapy with saxagliptin at a dose of 5 mg and metformin , cases of nasopharyngitis and headache were often noted.
The incidence of nasopharyngitis was higher with combined therapy (6.9%) compared with monotherapy with saxagliptin 10 mg (4.2%) and metformin (4%). Headache was more frequent in the group of patients on combined therapy with metformin and saxagliptin 5 mg (7.5%) compared with the groups of monotherapy with saxagliptin 10 mg (6.3%) and metformin (5.2%).
Laboratory studies: in clinical trials, the frequency of changes in laboratory parameters when taking saxagliptin at a dose of 5 mg and placebo was comparable.
There was a slight decrease in the number of lymphocytes, with the average absolute number of lymphocytes remaining stable and within the normal range with daily intake of saxagliptin for up to 102 weeks. The decrease in the number of lymphocytes was not accompanied by clinically significant undesirable reactions. The clinical importance of reducing the number of lymphocytes on the background of therapy with saxagliptin is not known.
CONTRAINDICATIONS

- type 1 diabetes mellitus (the application has not been studied);

- application together with insulin (not studied);

- diabetic ketoacidosis;

- congenital intolerance to galactose, lactase deficiency and glucose galactose malabsorption;

- Pregnancy;

- lactation;

- age under 18 years (safety and efficacy not studied);

- increased individual sensitivity to any component of the drug.

Caution should be given to the drug when
renal insufficiency of moderate and severe degree, elderly patients, and also together with derivatives of sulfonylurea.
PREGNANCY AND LACTATION

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

It is not known whether saksagliptin penetrates into breast milk.
Due to the fact that the possibility of saxagliptin penetration into breast milk is not ruled out, breastfeeding should be terminated for the duration of saxagliptin treatment or treatment can be canceled, taking into account the risk ratio for the child and the benefits for the mother.
APPLICATION FOR FUNCTIONS OF THE LIVER

For patients with mild renal insufficiency ( CK> 50 ml / min ), dose adjustment is not required.
For patients with moderate or severe renal insufficiency ( CK <50 ml / min ), as well as for patients on hemodialysis, the recommended dose of Onglis ® is 2.5 mg 1 time / day. The drug should be taken at the end of the hemodialysis session. The use of saxagliptin in patients on peritoneal dialysis has not been studied. Before starting therapy with saxagliptin and during treatment, it is recommended that the kidney function be assessed.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

If the liver function is mild, moderate and severe, dose adjustment is not required.

APPLICATION FOR CHILDREN

Contraindicated in children and adolescents under 18 years.

APPLICATION IN ELDERLY PATIENTS

Caution should be given to elderly patients.

SPECIAL INSTRUCTIONS

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

Patients with impaired renal function

A dose adjustment is recommended for patients with moderate to severe degree of renal insufficiency, as well as for patients on hemodialysis.
Before the start of therapy and periodically during treatment with recommended to assess renal function.
The use in combination with drugs that may induce hypoglycemia
Sulfonylureas can induce hypoglycemia, therefore reducing the risk of hypoglycemia, while the use of the drug Ongliza ® may require a reduction in the dose of sulfonylurea derivatives.
Hypersensitivity
drug should not be administered to patients who have severe hypersensitivity reactions were observed when applying other inhibitors of DPP-4.
Elderly patients

According to clinical studies, the efficacy and safety profile in patients aged 65 years and older did not differ from similar parameters in younger patients. However, we can not exclude an increased individual sensitivity to saxagliptin in some elderly patients.
Saxagliptin and its major metabolite partly excreted by the kidneys, therefore it is necessary to take into account that elderly patients are more likely to decline in renal function.
Preparation Ongliza ® contains lactose. Patients with congenital galactose intolerance, lactase deficiency and glucose-galactose malabsorption should not take this drug.
Impact on the ability to drive vehicles and manage mechanisms

Studies on the effect of saxagliptin on ability to drive vehicles and management mechanisms are not carried out.
Note that saxagliptin may cause dizziness.
OVERDOSE

Symptoms of toxicity are not described with chronic administration of the drug in doses to 80 times higher than recommended.
Treatment: In case of overdose should be used symptomatically. Saxagliptin and its major metabolite excreted by hemodialysis (removal rate 23% dose in 4 hours).
DRUG INTERACTION

Analysis of the clinical data suggests that the risk of clinically significant interactions saxagliptin with other drugs at their joint use is small.
Metabolism saxagliptin system predominantly mediated cytochrome P450 isoenzymes 3A4 / 5 (CYP3A4 / 5). In studies in vitro it was shown that saxagliptin and its major metabolite do not inhibit isozymes CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 and does not induce isozymes CYP 1A2, 2B6, 2C9, and ZA4. In studies in healthy volunteers the pharmacokinetic parameters 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 did not significantly alter the pharmacokinetic parameters of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.
Influence of inducers isozymes CYP 3A4 / 5 on the pharmacokinetics of saxagliptin unknown. However, the combined use of inductors and saxagliptin isozymes CYP 3A4 / 5, such as carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampin may lead to a decrease in the plasma concentration of saxagliptin and increased concentration of its main metabolite.
Study the effect of smoking, diet food, herbal preparations and reception of alcohol on saxagliptin therapy was conducted.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be kept out of reach of children at a temperature not higher than 30 ° C.
Shelf life - 3 years.
Do not use after the expiry date printed on the package.

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