Yanuviya

General characteristics. Structure:

Active agent: a sitagliptina of phosphate hydrate 25 mg, 50 mg, 100 mg of a sitagliptin are equivalent.

Excipients: cellulose microcrystallic; calcium the hydrophosphate which is not crushed; croscarmellose sodium; magnesium stearate; the sodium stearylfumarating.
Tablet cover (Opadray® of II: Pink 85 F97191 for a dosage of 25 mg; Light-beige 85 F 17498 for a dosage of 50 mg; Beige 85 F 17438 for a dosage of 100 mg) contains polyvinyl alcohol, titanium dioxide, a macrogoal (polyethyleneglycol) 3350, talc, ferrous oxide yellow, ferrous oxide red.

Pharmacological properties:

Pharmacodynamics. YaNUVIYa (ситаглиптин) is active at oral administration, high the selection inhibitor of enzyme of a dipeptidilpeptidaza 4 (DPP-4) intended for treatment of a diabetes mellitus 2 types. Sitagliptin differs on chemical structure and pharmacological action from analogs of glyukagonopodobny peptide-1 (GPP-1), insulin, derivatives of sulphonylurea, guanyl guanidines, agonists of the gamma receptors activated by a proliferator of peroxisomas (PPAR-γ), inhibitors alpha гликозидазы, analogs of an amilin. Inhibiting DPP-4, ситаглиптин increases concentration of two known hormones of family of inkretin: GPP-1 and glyukozo-dependent insulinotropny peptide (GIP). Hormones of family of inkretin cosecrete in intestines within a day, their level increases in response to meal. Inkretina are a part of internal physiological system of regulation of a homeostasis of glucose. At the normal or increased blood glucose level hormones of family of inkretin promote increase in synthesis of insulin, and also its secretion by pancreas beta cells at the expense of the alarm intracellular mechanisms associated with cyclic AMF.
GPP-1 also promotes suppression of hypersecretion of a glucagon pancreas alpha cells. Decrease in concentration of a glucagon against the background of increase in level of insulin promotes reduction of products of glucose a liver that as a result leads to reduction of a glycemia.
At low concentration of glucose of blood the listed effects of inkretin on emission of insulin and reduction of secretion of a glucagon are not observed. GPP-1 and GIP do not influence emission of a glucagon in response to a hypoglycemia. In physiological conditions activity of inkretin is limited to DPP-4 enzyme which quickly hydrolyzes inkretina with formation of inactive products.
Sitagliptin prevents hydrolysis of inkretin DPP-4 enzyme, thereby increasing plasma concentration of the active GPP-1 and GIP forms. Increasing the level of inkretin, ситаглиптин increases glyukozo-dependent emission of insulin and promotes reduction of secretion of a glucagon. Patients with a diabetes mellitus have 2 types with a hyperglycemia these changes of secretion of insulin and a glucagon lead to decrease in level of glikozilirovanny HbA1C hemoglobin and reduction of plasma concentration of the glucose defined on an empty stomach and after load test.
At patients with a diabetes mellitus reception of one dose of drug YaNUVIYa leads 2 types to inhibition of activity of DPP-4 enzyme within 24 hours that leads to increase in level of the circulating inkretin of GPP-1 and GIP by 2-3 times, to increase of plasma concentration of insulin and S-peptide, decrease in concentration of a glucagon in a blood plasma, to reduction of a glycemia on an empty stomach, and also to reduction of a glycemia after loading glucose or food loading.

Pharmacokinetics. The pharmacokinetics of a sitagliptin is comprehensively characterized at healthy faces and patients with a diabetes mellitus 2 types. At healthy faces after oral administration of 100 mg of a sitagliptin bystry absorption of drug with achievement of the maximum concentration (Cmax) in the range from 1 is noted till 4 o'clock from the moment of reception. The area under a curve "concentration – time" (AUC) increases in proportion to a dose, and makes at healthy subjects 8,52 μМхчас at reception 100 mg inside, Cmax made 950 nM, the average elimination half-life made 12,4 hours. Plasma AUC of a sitagliptin increased approximately by 14% after the following reception of a dose of 100 mg of drug on achievement of an equilibrium state after reception of the first dose. Inside - and inter-subject coefficients of variation of AUC of a sitagliptin were insignificant.

Absorption. Absolute bioavailability of a sitagliptin makes about 87%. As joint administration of drug of YaNUVIYa and greasy food does not render effect on pharmacokinetics, drug YaNUVIYa can be appointed regardless of meal.
Distribution
The average volume of distribution in an equilibrium state after a single dose of 100 mg of a sitagliptin at healthy volunteers makes about 198 l. The fraction of a sitagliptin contacting plasma proteins is rather low and makes 38%.

Metabolism. About 79% of a sitagliptin are excreted in not changed view with urine.
Only insignificant part of the drug which came to an organism is metabolized.
After introduction of a 14C-mechenny sitagliptin in about 16% of radioactive drug it was excreted in the form of its metabolites. The traces of 6 metabolites of a sitagliptin which possibly do not have DPP-4-ingibiruyushchey activity were found. In the researches in vitro it was revealed that primary enzyme, participating in limited metabolism of a sitagliptin, CYP3A4 with participation of CYP2C8 is.

Removal. After introduction of a 14C-mechenny sitagliptin inside to healthy volunteers about 100% of the administered drug it was removed: 13% through intestines, 87% kidneys – within one week after administration of drug. The average elimination half-life of a sitagliptin at oral administration of 100 mg makes about 12,4 hours; the renal clearance makes about 350 ml/min.
Removal of a sitagliptin is carried out initially by excretion by kidneys on the mechanism of active canalicular secretion. Sitagliptin is substrate for the conveyor of organic anions of the person of the third type (hOAT-3) which can be involved in process of removal of a sitagliptin by kidneys. Clinically hOAT-3 involvement into transport of a sitagliptin was not studied. Sitagliptin is also substrate of a r-glycoprotein which can also participate in process of renal elimination of a sitagliptin. However, the cyclosporine which is r-glycoprotein inhibitor did not reduce renal clearance of a sitagliptin.

Pharmacokinetics at separate groups of patients.
- Patients with a renal failure
The open research of drug YaNUVIYa in a dosage of 50 mg a day was conducted for the purpose of studying of its pharmacokinetics at patients with varying severity of a chronic renal failure. The patients included in a research were divided into groups of the soft renal failure (clearance of creatinine from 50 to 80 ml/min.) moderated (clearance of creatinine from 30 to 50 ml/min.) and a heavy renal failure (clearance of creatinine less than 30 ml/min.), and also the patients with an end-stage of pathology of kidneys needing dialysis.
- At patients with a soft renal failure clinically significant change of concentration of a sitagliptin in plasma in comparison with control group of healthy volunteers was not noted.
Increase in AUC of a sitagliptin approximately twice in comparison with control group was noted at patients with a moderate renal failure, approximately quadruple increase in AUC was noted at patients with a heavy renal failure, and also patients with an end-stage have pathologies of kidneys in comparison with control group. Sitagliptin in weak degree left from circulation by means of a hemodialysis: only 13,5% of a dose were removed from an organism during 3-4 sentries of a session of dialysis.
Thus, achievement of therapeutic concentration of drug in a blood plasma (similar to that at patients with normal function of kidneys) at patients with a moderate and heavy renal failure requires correction of a dosage (see the Route of administration and doses).
- Patients with a liver failure
At patients with a moderate liver failure (7-9 points on a scale of Chayld-Pyyu) average AUC and Cmax of a sitagliptin at a single dose of 100 mg increase approximately by 21% and 13% respectively. Thus, correction of a dosage of drug at a soft and moderate liver failure is not required.
There are no clinical data on use of a sitagliptin for patients with a heavy liver failure (more than 9 points on a scale of Chayld-Pyyu). However in the investigation of the fact that drug is initially removed by kidneys it is not necessary to expect significant change of pharmacokinetics of a sitagliptin at patients with a heavy liver failure.
Elderly patients
- The age of patients did not make clinically significant impact on pharmacokinetic parameters of a sitagliptin. In comparison with young patients at elderly patients (65-80 years) concentration of a sitagliptin is about 19% higher. Dose adjustment of drug depending on age is not required.

Indications to use:

Monotherapy. Drug YaNUVIYa is shown as addition to a diet and exercise stresses for improvement of control over a glycemia at patients with a diabetes mellitus 2 types.

Combination therapy. Drug YaNUVIYa is also shown to patients with a diabetes mellitus 2 types for improvement of control over a glycemia in a combination with Metforminum or agonists of PPARγ (for example, thiazlolidinedithis) when the diet and an exercise stress in combination with monotherapy by the transferred funds do not lead to adequate control over a glycemia.

Route of administration and doses:

The recommended dosage of drug YaNUVIYa makes 100 mg as monotherapy or in a combination with Metforminum or an agonist of PPARγ once a day (for example, thiazlolidinedithis).
YaNUVIYa can be accepted is not dependent on meal.
If the patient missed administration of drug of YaNUVIYa, it has to be accepted as soon as possible after the patient remembers the missed administration of drug. Let's not allow reception of a double dose of drug YaNUVIYa.

Patients with a renal failure. Correction of a dosage of drug YaNUVIYa is not required to patients with a slight renal failure (≤1,5 mg/dl women have a clearance of creatinine of ≥50 ml/min. which is approximately corresponding to the level of creatinine of plasma of ≤1,7 mg/dl at men).
For patients with a moderate renal failure (clearance of creatinine of ≥30 ml/min., but <50 ml/min., approximately corresponding to plasma creatinine level> 1,7 mg/dl, but ≤3 mg/dl are at men,> 1,5 mg/dl, but women have ≤2,5 mg/dl) the dose of drug YaNUVIYa makes 50 mg once a day.

For patients with a heavy renal failure (clearance of creatinine <30 ml/min., approximately corresponding to plasma creatinine level> 3 mg/dl at men,> 2,5 mg/dl at women), and also with an end-stage of pathology of the kidneys needing a hemodialysis, the dose of drug YaNUVIYa makes 25 mg once a day. Drug YaNUVIYa can be used regardless of the schedule of the procedure of a hemodialysis.

Patients with a liver failure. Correction of a dosage of drug YaNUVIYa is not required from patients with a slight and moderate liver failure. Drug was not investigated at patients with a heavy liver failure.

Elderly patients. Correction of a dosage of drug YaNUVIYa is not required from elderly patients.

Features of use:

Hypoglycemia. In clinical trials of drug YaNUVIYa as monotherapy or as parts of a combination therapy with Metforminum or pioglitazony, the frequency of development of a hypoglycemia when using drug YaNUVIYa was similar to the frequency of development of a hypoglycemia when using placebo. Combined use of drug YaNUVIYa in a combination with the drugs, capable to cause a hypoglycemia, such as insulin, sulphonylurea derivatives, was not investigated.

Use for elderly people. In clinical trials efficiency and safety of drug YaNUVIYa at elderly (≥65 years, 409 patients) were comparable with these indicators at patients more young than 65 years.
Correction of a dosage on age is not required. Elderly patients are more often inclined to development of a renal failure. Respectively, as well as in other age groups correction of a dosage at patients with the expressed renal failure is necessary (see the Route of administration and doses).

Influence on ability of control of motor transport and works with mechanisms. Researches on studying of influence of drug YaNUVIYa on ability to manage motor transport were not conducted. Nevertheless, negative influence of drug YaNUVIYa on ability of driving or difficult mechanisms is not expected.

Side effects:

Drug YaNUVIYa in general is well transferred both as monotherapy, and to combinations with other hypoglycemic drugs. In clinical trials the general frequency of occurrence of side effects, and also drug withdrawal frequency because of the collateral undesirable phenomena, were similar to placebos, those at reception.
The by-effects meeting without causal relationship with administration of drug of YaNUVIYa in a dose of 100 mg and 200 mg a day, but are more often than at placebo reception, with a frequency of 3%: an upper respiratory tract infection (YaNUVIYa of 100 mg – 6,8%, YaNUVIYa of 200 mg – 6,1%, placebo – 6,7%), a nasopharyngitis (YaNUVIYa of 100 mg – 4,5%, YaNUVIYa of 200 mg – 4,4%, placebo – 3,3%), a headache (YaNUVIYa of 100 mg – 3,6%, YaNUVIYa of 200 mg – 3,9%, placebo – 3,6%), diarrhea (YaNUVIYa of 100 mg – 3,0%, YaNUVIYa of 200 mg – 2,6%, placebo – 2,3%), an arthralgia (YaNUVIYa of 100 mg – 2,1%, YaNUVIYa of 200 mg – 3,3%, placebo – 1,8%).
The general frequency of development of a hypoglycemia in the patients receiving drug YaNUVIYa was similar to that at placebo reception (YaNUVIYa of 100 mg – 1,2%, YaNUVIYa of 200 mg – 0,9%, placebo – 0,9%).
Frequency of occurrence of some side effects from digestive tract at administration of drug of YaNUVIYa in both dosages was similar to that at placebo reception, except for more frequent nausea at administration of drug of YaNUVIYa in a dose of 200 mg a day: an abdominal pain (YaNUVIYa of 100 mg – 2,3%, YaNUVIYa of 200 mg – 1,3%, placebo – 2,1%), nausea (YaNUVIYa of 100 mg – 1,4%, YaNUVIYa of 200 mg – 2,9%, placebo – 0,6%), vomiting (YaNUVIYa of 100 mg – 0,8%, YaNUVIYa of 200 mg – 0,7%, placebo – 0,9%), diarrhea (YaNUVIYa of 100 mg – 3,0%, YaNUVIYa of 200 mg – 2,6%, placebo – 2,3%).

Changes of laboratory indicators. The analysis of clinical trials of drug showed small increase in uric acid (approximately on 0,2 mg/dl in comparison with placebo, the average level of 5-5,5 mg/dl) at the patients receiving drug YaNUVIYa in a dose of 100 and 200 mg a day. Cases of development of gout were not registered.
The small reduction of concentration of the general alkaline phosphatase (approximately on 5 ME/l in comparison with placebo, the average level of 56-62 ME/l) which is partially connected with small reduction of bone fraction of an alkaline phosphatase was observed.
The small increase in maintenance of leukocytes (approximately on 200/mkl in comparison with placebo, the average level 6600/mkl) caused by increase in quantity of neutrophils was noted. This observation was noted in the majority, but not in all researches.
The listed changes of laboratory indicators are not considered as clinically significant.
During treatment drug YaNUVIYa did not note clinically significant changes of vital indicators and an ECG (including QTc interval).

Interaction with other medicines:

In researches on interaction with other medicines, ситаглиптин did not render clinically significant effect on pharmacokinetics of the following drugs: Metforminum, roziglitazon, Glibenclamidum, simvastatin, warfarin, oral contraceptives. Based on these data, ситаглиптин does not inhibit CYP CYP3A4, 2C8 or 2C9 isoenzymes. Based on the data obtained by in vitro ситаглиптин also possibly does not inhibit CYP2D6, 1A2, 2S19 or 2V6, and also does not induce CYP3A4.
Easy increase in AUC (11%), and also average Cmax (18%) of digoxin was noted at combined use with sitagliptiny. This increase is not considered clinically significant. Change of a dose neither digoxin, nor drug YaNUVIYa at their combined use is not recommended.
Increase in AUC and Cmax of drug YaNUVIYa by 29% and 68% respectively at patients was noted at combined use of a single peroral dose of 100 mg of drug YaNUVIYa and a single peroral dose of 600 mg of cyclosporine, powerful inhibitor of a r-glycoprotein.
Observed changes of pharmacokinetic characteristics of a sitagliptin are not considered as clinically significant. Change of a dose of drug YaNUVIYa at combined use with cyclosporine and other inhibitors of a r-glycoprotein is not recommended (for example, ketokonazoly).
The population pharmacokinetic analysis of patients and healthy volunteers (N=858) on a wide range of the accompanying drugs (N=83, about a half out of which is brought by kidneys) did not reveal any clinically significant effects of these substances on pharmacokinetics of a sitagliptin.

Contraindications:

- hypersensitivity to any of drug components;
- pregnancy, breastfeeding period;
- diabetes mellitus of 1 type;
- diabetic ketoacidosis.
- In pediatric practice patients more young have than 18 years no data on use of drug YaNUVIYa. Thus, use of drug YaNUVIYa at this category of patients is not recommended.

With care. Renal failure.
Correction of a dosage of drug YaNUVIYa is required from patients with a moderate and heavy renal failure, and also from the patients with an end-stage of renal pathology needing a hemodialysis (see the Route of administration and doses).

Use at pregnancy and in the period of a lactation. Controlled researches of drug YaNUVIYa at pregnant women were not conducted, therefore there are no data on safety of its use for pregnant women. Drug YaNUVIYa, as well as other peroral hypoglycemic drugs, is not recommended for use during pregnancy. There are no data on excretion of a sitagliptin with milk. Therefore, drug YaNUVIYa should not be appointed in the period of a lactation.

Overdose:

During clinical trials on healthy volunteers, the single dose of 800 mg of drug YaNUVIYa in general was well transferred. The minimum changes of an interval of QTc which are not considered as clinically significant were noted in one of drug YaNUVIYa researches in a dose of 800 mg a day. The dose over 800 mg a day at people was not studied.
In case of overdose it is necessary to begin the standard supporting actions: removal of not absorbed drug from digestive tract, implementation of monitoring of vital signs, including an ECG, and also purpose of a maintenance therapy if it is required.
Sitagliptin is poorly dialyzed. In clinical trials only 13,5% of a dose were removed from an organism during 3-4 sentries of a session of dialysis. The prolonged dialysis can be appointed in case of clinical need. There are no data on efficiency of peritoneal dialysis of a sitagliptin.

Storage conditions:

To store at a temperature not above 30 °C.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in PVC / the blister Is scarlet. 1, 2, 4, 6 or 7 blisters place in a cardboard pack together with the application instruction.