Onglyza® [Saxagliptin]

ONGLIZA (ONGLIZA)

SAXAGLIPTINUM A10B H03

Astrazeneca

COMPOSITION AND FORM OF ISSUE:

tab. p / captive. 2.5 mg shell, No. 30

No. UA / 10715/01/01 from 05/18/2010 to 05/18/2015

tab. p / captive. 5 mg shell, No. 30

No. UA / 10715/01/02 from 05/18/2010 to 05/18/2015

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics. Saxagliptin is a potent selective reversible competitive dipeptidyl peptidase-4 (DPP-4) inhibitor. In patients with type II diabetes mellitus, the use of the Ongliza drug leads to inhibition of the activity of the DPP-4 enzyme for 24 hours. After oral glucose loading, this inhibition of DPP-4 leads to a 3-fold increase in the level of circulating active incretin hormones, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, a decrease in the concentration of glucagon and an increase in the glucose-dependent reaction of β-cells, which leads to an increase in the concentration of insulin and C-peptide. The release of insulin by pancreatic β-cells and a decrease in glucagon release from pancreatic α-cells is associated with a decrease in fasting glucose and a decrease in glucose after glucose loading or eating. Onglyza improves glycemic control by lowering fasting glucose and postprandial glucose in patients with type II diabetes.
When using Ongliza drug at a dose of ≥5 mg, the basal value of HbA1c was associated with a more regulated average change in HbA1c compared to the baseline level. Onglyza therapy did not cause an increase in body weight compared to the baseline, but a slight decrease in body weight was observed in the Onglyza 5 mg and placebo treatment groups.
Pharmacokinetics The pharmacokinetics of saxagliptin and its main metabolite were similar in healthy volunteers and in patients with type II diabetes mellitus. Saxagliptin is rapidly absorbed after oral administration on an empty stomach with achievement of C_max saxagliptin and its main metabolite in blood plasma within 2 and 4 hours, respectively. C_max and the AUC of saxagliptin and its main metabolite increased in proportion to an increase in the dose of saxagliptin.
After a single oral administration of 5 mg of saxagliptin by healthy volunteers, the average value of the final T_½ for saxagliptin and its main metabolite were 2.5 and 3.1 hours, respectively, and the average value of T_½ inhibition of plasma DPP-4 - 26.9 hours. Inhibition of plasma activity of DPP-4 by saxagliptin for at least 24 hours after oral administration of saxagliptin occurs due to high power, affinity and wide binding to the active site. No noticeable cumulation of saxagliptin or its main metabolite under conditions of multiple doses in the regimen 1 time per day at any dose level was not observed. There was no dose and time dependence of the clearance of saxagliptin and its main metabolite when taking saxagliptin 1 time per day within a dose of 2.5 to 400 mg for 14 days.
Absorption.Saxagliptin can be taken on an empty stomach or during meals. The amount of saxagliptin absorbed after taking an oral dose is at least 75%. Food had a relatively moderate effect on the pharmacokinetics of saxagliptin in healthy volunteers. High-fat meals did not affect C_max saxagliptin, AUC at the same time increased by 27% compared with fasting. Time to reach C_max (T_max) for saxagliptin increased by approximately 0.5 hours when taken in conjunction with food compared with fasting. These changes were not considered clinically significant.
Distribution. In vitro the binding of saxagliptin and its main metabolite to proteins in human serum is below a defined level. Thus, changes in the level of blood proteins in various pathological conditions (for example, renal or liver failure) do not affect the distribution of saxagliptin.
Metabolism.Saxagliptin metabolism is mainly mediated by cytochrome P450 3A4 / 5 (CYP 3A4 / 5). The main metabolite of saxagliptin - also a selective, reversible, competitive inhibitor of DPP-4, has 2 times less power than saxagliptin.
Breeding. Saxagliptin is secreted by the kidneys and liver. After a single dose of 50 mg ¹⁴C-saxagliptin, 24, 36 and 75% of the dose was excreted in the urine in the form of saxagliptin, its main metabolite and total radioactivity, respectively. The average renal clearance of saxagliptin (~ 230 ml / min) was greater than the average estimated value of glomerular filtration (~ 120 ml / min), which is probably associated with active renal excretion. For the main metabolite, the value of renal clearance was compared with the estimated value of glomerular filtration. A total of 22% of the administered radioactivity was detected in the feces, which corresponds to the part of saxagliptin that got into the bile and / or the part of the drug that was not absorbed in the digestive tract.
Characteristics of special patient groups
Renal failure. In patients with renal failure, which is classified by creatinine clearance of mild (> 50 to ≤80 ml / min), moderate (30≤50 ml / min) and severe (<30 ml / min), as well as in patients with terminal stage hemodialysis kidney disease; degree of renal impairment did not affect C_max saxagliptin and its main metabolite. In patients with mild renal failure, the AUC values ​​of saxagliptin and its main metabolite were respectively 1.2 and 1.7 times higher than the AUC values ​​in individuals with normal renal function, an increase in these values ​​is not clinically significant. In patients with moderate and severe renal failure or end-stage renal disease undergoing hemodialysis, the AUC values ​​of saxagliptin and its main metabolite were 2.1 and 4.5 times higher than the AUC values ​​in individuals with normal renal function.
Liver failure. There was no clinically significant difference in pharmacokinetic parameters in patients with mild, moderate and severe impaired liver function.
Elderly patients. There was no clinically significant difference in pharmacokinetic parameters in the elderly (65–80 years) compared with young patients (18–40 years).

INDICATIONS:

Monotherapy
Onglyza is indicated for patients with type II diabetes mellitus as a supplement to diet and exercise to improve glycemic control.
Supplement to ongoing therapy
Onglyza is indicated for patients with type II diabetes mellitus to improve glycemic control as an adjunct to metformin, thiazolidinedione (TZD) or sulfonylurea therapy, when monotherapy with these drugs in combination with diet and exercise does not provide adequate glycemic control.
Initial combination therapy
Onglis is indicated for patients with type II diabetes mellitus as an initial combination therapy combined with metformin, in addition to diet and exercise to improve glycemic control.

APPLICATION:

Monotherapy
The recommended dose of the drug as monotherapy is 5 mg 1 time per day.
Supplement to ongoing therapy
The recommended dose of the drug Onglyza as an addition to therapy with metformin, PPAR-γ agonists (thiazolidinediones) or sulfonylurea is 5 mg once a day.
Initial combination therapy
The recommended doses of the drug Onglyza and metformin when prescribing the initial combination therapy are 5 mg of Onglyza once a day and 500 mg of metformin per day.
For patients who cannot achieve glycemic control using the initial dose, the dose of metformin should be increased according to the approved dosage recommendations.
If the patient missed a dose, it should be taken immediately, as soon as he remembered about it. Do not double the dose.
The drug Onglyza can be taken regardless of the meal.
Patients with renal failure. There are no recommendations regarding dose adjustment of Onglyza for patients with mild renal failure (creatinine clearance> 50 ml / min, which approximately corresponds to creatinine levels <150 μmol / L (<1.7 mg / dL) in men and <133 μmol / L ( <1.5 mg / dl) in women), therefore, the dose should not be adjusted.
For patients with moderate to severe renal failure or with a terminal stage of kidney disease requiring hemodialysis (creatinine clearance ≤50 ml / min, which approximately corresponds to creatinine levels of 1.7 mg / dl in men and 1.5 mg / dl in women) , the dose of Onglyza is 2.5 mg / day. The drug Onglyza should be used after hemodialysis. The use of the drug in patients undergoing peritoneal dialysis has not been studied.
Since there is a need for dose adjustment taking into account renal function, it is recommended that an assessment of renal function be performed before treatment and periodically during treatment with Onglyza. CC can be estimated by the level of creatinine in blood serum using the Cockcroft-Gault formula.
Patients with liver failure. Patients with mild, moderate, and severe liver failure do not need dose adjustment.
Patients taking potent CYP 3A4 / 5 inhibitors. In the case of simultaneous use with powerful CYP 3A4 / 5 inhibitors (such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), the dose of Ongliz should be limited to 2.5 mg / day.
Elderly patients. There are no recommendations for dose adjustment depending on age. Since elderly patients are more likely to have decreased renal function, the dose for them must be selected taking into account renal function.

CONTRAINDICATIONS:

hypersensitivity to the active substance or any of the components of the drug; During pregnancy and breastfeeding; childhood.

SIDE EFFECTS:

adverse reactions in organ systems according to a combined analysis of five placebo-controlled clinical trials using Onglyza were grouped by frequency of occurrence and were rated as: very often (> 1/10), often (> 1/100, <1/10), sometimes (> 1/1000, <1/100), rarely (> 1/10 000, <1/1000), very rarely (<1/10 000), including single messages.
Infections and infestations: often - infections of the upper respiratory tract, urinary tract, gastroenteritis, sinusitis.
From the digestive tract: often - vomiting.
From the side of the central nervous system: often - a headache.
Adverse reactions associated with taking the drug Onglyza and combination therapy. In a study examining the inclusion of Ongliza in glibenclamide therapy, episodes of confirmed hypoglycemia were rated as uncommon (0.8%) for Ongliza 5 mg and (0.7%) for placebo. The difference was not statistically significant. In two studies on monotherapy, one study examining the inclusion of Onglyza in metformin therapy and a study examining the inclusion of Onglyza in the treatment of TZD, the incidence of confirmed hypoglycemia in patients who received Onglyza 5 mg was the same as in patients receiving placebo. In a study examining the inclusion of Onglyza in the treatment of TZD, cases of peripheral edema were considered frequent and their frequency was higher with 5 mg Onglyza therapy compared with placebo (8.1 and 4.3%, respectively). All reported cases of peripheral edema were mild or moderate and did not lead to discontinuation of the drug. In a generalized analysis of two studies on monotherapy, one study on the inclusion of Onglyza in metformin therapy and a study on the inclusion of Onglyza in glibenclamide therapy, the overall incidence of peripheral edema observed in patients who took Onglyza 5 mg was the same as with placebo (1.7 and 2.4%, respectively).
In combination therapy with Onglyza 5 mg with metformin, cases of nasopharyngitis were evaluated as frequent and their frequency was higher with the combination of Onglis + metformin (6.9%) compared with monotherapy with saxagliptin 10 mg (4.2%) or metformin (4.0 %).Cases of headache were assessed as frequent and their frequency was higher with the combination of Onglyza 5 mg + metformin (7.5%) compared with monotherapy with saxagliptin 10 mg (6.3%) or metformin (5.2%).
During treatment with saxagliptin, cases of dizziness were reported.
Laboratory indicators. In clinical trials, the frequency of changes in laboratory parameters was similar in patients receiving Onglyza 5 mg and placebo. Among people taking Ongliza, there was a slight decrease in the absolute number of lymphocytes. According to a pooled analysis of five placebo-controlled clinical trials, an average decrease in lymphocyte count of approximately 100 cells / μl from the initial mean absolute lymphocyte count was observed, which was approximately 2200 cells / μl compared to placebo. The average absolute number of lymphocytes remained stable and within normal values ​​with daily use of the drug for 102 weeks. The decrease in the number of lymphocytes was not accompanied by any clinically significant adverse reactions. The clinical significance of a decrease in lymphocyte count compared with placebo is unknown.

SPECIAL INSTRUCTIONS:

Are common. The drug Onglyza should not be used in patients with type I diabetes mellitus or for the treatment of diabetic ketoacidosis. The use of Onglyza has not been studied in combination with insulin.
Patients with renal failure. For patients with moderate and severe renal failure or end-stage renal disease requiring hemodialysis, dose adjustment of the Ongliza drug is recommended. Before starting therapy and periodically during treatment with the drug, it is recommended to monitor renal function.
Patients with liver failure.Saxagliptin should be prescribed with caution to patients with moderate hepatic insufficiency, and patients with severe hepatic insufficiency should not be prescribed saxagliptin.
Use with drugs that can cause hypoglycemia.Drugs of the sulfonylurea class from the group of antihyperglycemic agents can cause hypoglycemia. Therefore, to reduce the risk of hypoglycemia when used in combination with Onglyza, it may be necessary to reduce the dose of sulfonylurea.
Hypersensitivity reactions. The drug Onglyza should not be used in patients who have had serious hypersensitivity reactions to DPP-4 inhibitors.
Elderly patients. There were no differences in safety or efficacy between individuals 65 years of age and older and those of a younger age. Clinical experience did not show differences in the reaction to the drug between elderly patients and younger patients, however, the likelihood that some elderly patients may be more sensitive to the drug cannot be ruled out.
Saxagliptin and its main metabolite are excreted in part by the kidneys. Since elderly patients are more likely to have decreased renal function, it is necessary to select a dose for the elderly taking into account renal function (see APPLICATION).
Immunocompromised patients. Immunocompromised patients, after organ transplantation or HIV-infected patients, did not participate in the Onglyza clinical research program. Therefore, the efficacy and safety of the use of the drug Onglyza in this category of patients have not been established.
Excipients. The tablet of the drug contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
During pregnancy and breastfeeding. There are no adequate data on the use of Onglyza during pregnancy.Therefore, the drug Onglyza should not be used during pregnancy.
It is not known whether saxagliptin passes into breast milk. During treatment with saxagliptin, breast-feeding should be discontinued.
Children. The safety and effectiveness of the drug in children have not been established, so Onglizu is not used in pediatric practice.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms.Studies of the impact on the ability to drive vehicles and work with mechanisms have not been conducted. Given the presence of dizziness as an adverse reaction, during treatment with saxagliptin, it is necessary to refrain from driving vehicles or working with other mechanisms.

INTERACTIONS:

the clinical data described below indicate a low risk of clinically significant drug interactions with drugs that are prescribed in combination.
Saxagliptin is metabolized mainly with the participation of cytochrome P450 3A4 / 5 (CYP 3A4 / 5).
In studies in vitro saxagliptin and its active metabolite did not inhibit CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 and did not induce CYP 1A2, 2B6, 2C9 or 3A4. In clinical trials involving healthy volunteers, the pharmacokinetics of saxagliptin and its main metabolite did not change with the administration of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, anticides, or famotidine. In addition, saxagliptin did not alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.
Powerful CYP 3A4 / 5 inhibitors. Simultaneous administration of saxagliptin with a potent inhibitor of CYP 3A4 / 5 ketoconazole led to an increase in C_max saxagliptin by 62% and an increase in AUC of saxagliptin by 2.5 times, these indicators for the active metabolite decreased by 95 and 88%, respectively.
When using saxagliptin in combination with potent CYP 3A4 / 5 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin), a similar increase in plasma concentration of saxagliptin can also be expected. In the case of simultaneous use with powerful CYP 3A4 / 5 inhibitors, the dose of Onglyza should be limited to 2.5 mg / day.
Moderate CYP 3A4 / 5 inhibitors. Concomitant administration of saxagliptin with a moderate CYP 3A4 / 5 inhibitor diltiazem led to an increase in C_max saxagliptin by 63% and an increase in AUC of saxagliptin by 2.1 times, these indicators for the active metabolite decreased by 44 and 34%, respectively. Diltiazem increases the exposure of saxagliptin. A similar increase in the concentration of saxagliptin in blood plasma can be expected in the presence of other moderate CYP 3A4 / 5 inhibitors (such as amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil), however, a dose reduction of Onglyza is not required.
Inducers of CYP 3A4 / 5 enzymes. Rifampicin significantly reduces the systemic exposure of saxagliptin and does not affect the AUC of its active metabolite, hydroxysaxagliptin. In this case, rifampicin does not affect the degree of inhibition of the activity of DPP-4 in blood plasma over a 24-hour dose interval. Dose adjustment of the drug Onglyza is not required.
The simultaneous use of saxagliptin and other CYP 3A4 / 5 inducers, such as carbamazepine, dexamethasone, phenobarbital and phenytoin, has not been studied and can lead to a decrease in the concentration of saxagliptin in the blood plasma and an increase in the concentration of its main metabolite. It is necessary to carry out strict glycemic control with the simultaneous use of saxagliptin and powerful CYP 3A4 / 5 inducers.
The effects of smoking, diet, herbal products, and alcohol on the pharmacokinetics of saxagliptin have not been specifically studied.

OVERDOSE:

with oral administration of Onglyza once a day, the drug was safe and well tolerated without a clinically significant effect on the interval Q – Tc or on heart rate at doses up to 400 mg / day for 2 weeks (exceeds the maximum recommended dose by 80 times). In case of overdose, carry out symptomatic treatment according to the clinical condition of the patient. Saxagliptin and its main metabolite are excreted by hemodialysis (23% of the dose in 4 hours).

STORAGE CONDITIONS:

at a temperature below 30 ° C.