Velmetiya

General characteristics. Structure:

Active ingredients: 50 mg of a sitagliptin, 500 mg, 850 mg or 1000 mg of Metforminum.

Excipients: cellulose microcrystallic, povidone, sodium lauryl sulfate, the sodium stearylfumarating.

Tablet cover: dye of Opadray II 85F94203 pink (tablets of 50 mg / 500 mg) or Opadray of II 85F94182 pink (tablets of 50 mg / 850 mg) or Opadray of II 85F15464 red (tablets of 50 mg / 1000 mg).

Composition of dye: polyvinyl alcohol, titanium dioxide (Е 171), polyethyleneglycol 3350, talc, ferrous oxide black (Е 172), ferrous oxide red (Е 172).

Pharmacological properties:

Pharmacodynamics. Velmetiya represents a combination - two hypoglycemic drugs with the complementary (complementary) mechanism of action, intended for improvement of control of a glycemia at patients with a diabetes mellitus of the II type: sitagliptina, inhibitor of a dipeptidilpeptidaza 4 (DPP-4), and Metforminum hydrochloride, representative of a class of guanyl guanidines.

Sitagliptin is active at oral administration, the high-selection inhibitor of enzyme of a dipeptidilpeptidaza 4 (DPP-4), intended for treatment of a diabetes mellitus of the II type. Pharmacological effects of a class of the drugs-inhibitors DPP-4 are mediated by activation of inkretin. Inhibiting DPP-4, ситаглиптин increases concentration of two known active hormones of family of inkretin: glyukagonopodobny peptide 1 (GPP-1) and glyukozozavisimy insulinotropny polypeptide (GIP). _nkretin are a part of internal physiological system of regulation of a homeostasis of glucose. At the normal or increased level of glucose of GPP-1 and GIP blood promote increase in synthesis and secretion of insulin pancreas beta cells. GPP-1 also oppresses secretion of a glucagon pancreas alpha cells, reducing, thus, synthesis of glucose in a liver. This mechanism of action differs from the mechanism of action of derivatives of sulphonylurea which stimulate release of insulin and at low levels of glucose of blood that causes development sulphonyl - the induced hypoglycemia not only patients on a diabetes mellitus have the II type, but also at healthy volunteers. Being the high-selection and effective inhibitor of DPP-4 enzyme, ситаглиптин in therapeutic concentration does not suppress activity of related DPP-8 or DPP-9 enzymes. Sitagliptin differs on chemical structure and pharmacological action from analogs of GPP-1, insulin, derivatives of sulphonylurea or meglitinid, guanyl guanidines, agonists of gamma receptors which are activated by a prol_ferator of peroxisomas (PPAR-), inhibitors alpha гликозидазы, received and analogs of an amilin.

Metforminum. It is hypoglycemic the means increasing tolerance to glucose at patients with a diabetes mellitus of the II type, reducing the basal and postprand_alny plasma level of glucose. Its pharmacological mechanisms of action differ from mechanisms of effect of peroral hypoglycemic drugs of other classes.

Metforminum reduces synthesis of glucose in a liver, reduces absorption of glucose in intestines and increases sensitivity to insulin by strengthening of peripheral capture and utilization of glucose. Unlike sulphonylurea derivatives, Metforminum does not cause a hypoglycemia neither in patients with a diabetes mellitus of the II type, nor in healthy volunteers (except for some circumstances, see the section of Feature of use. Metforminum a hydrochloride) also does not cause a giperinsulinemiya. During treatment by Metforminum secretion of insulin does not change, at the same time insulin level on an empty stomach and daily value of plasma level of insulin can decrease.

Pharmacokinetics. Action mechanism. Velmetiya. The combined Velmetiya's tablets (ситаглиптин / Metforminum a hydrochloride) on 50 mg / 500 mg and 50 mg / 1000 mg are bioequivalent to separate reception of the corresponding doses of a sitagliptin of phosphate (Velmetiya) and Metforminum of a hydrochloride.

Taking into account the proved bioequivalence of tablets with the smallest and greatest dose of Metforminum, a tablet with an intermediate dose of Metforminum of 850 mg bioequivalence on condition of a combination in a tablet of the fixed doses of drugs was also inherent.

Absorptions. Sitagliptin. Absolute bioavailability of a sitagliptin makes about 87%. Reception of a sitagliptin along with greasy food does not exert impact on drug pharmacokinetics.

Metforminum hydrochloride. Absolute bioavailability of Metforminum of a hydrochloride at use on an empty stomach in a dose of 500 mg makes 50-60%. Results of researches of a single dose of tablets of Metforminum of a hydrochloride in doses from 500 mg to 1500 mg and from 850 mg to 2550 mg demonstrate disturbance of a dozoproportsionnost with increase in a dose that is rather caused by reduced absorption, than the accelerated removal. The concomitant use of drug with food reduces the speed and quantity of the soaked-up metformin that is confirmed by decrease in value of peak plasma concentration (Cmax) approximately for 40%, decrease in value of the area under a curve concentration time (AUC) approximately for 25%, and also a 35-minute delay in achievement of peak plasma concentration (Tmax) after a single dose of Metforminum in a dose of 850 mg together with food in comparison with values of the corresponding parameters after reception of a similar dose of drug on an empty stomach. The clinical importance of decrease in values of pharmacokinetic parameters is not established.

Distribution. Sitagliptin. The average volume of distribution in an equilibrium state after single

intravenous administration of 100 mg the sitagl_ptina at healthy volunteers is made by about 198 l. The fraction to a sitagl_ptin that back contacts proteins of plasma, is rather small (38%).

Metforminum. The volume of distribution of Metforminum after single oral administration in a dose of 850 mg averaged 654 ± 358 l. Metforminum only in very insignificant proportion contacts proteins of plasma, unlike sulphonylurea derivatives (to 90%). Metforminum is partially and temporarily distributed in erythrocytes. At use of Metforminum in the recommended doses and the modes of plasma concentration of an equilibrium state (usually less than 1 mkg/ml) reach approximately in 24-48 hours. According to controlled researches, the maximum plasma concentration of drug did not exceed value of 5 mkg/ml even after reception of the maximum doses of drug.

Metabolism. Sitagliptin. About 79% of a sitagliptin are removed in not changed state with urine, metabolic transformation of drug minimum.

After introduction 14s-marked to a sitagl_ptin in about 16% of the entered radioactivity it was excreted in the form of metabolites of a sitagliptin. Were found out in insignificant concentration of 6 metabolites of a sitagliptin that have no contribution in plasma Dpp-4-Ingibiruyushchee activity of a sitagliptin. In the researches in vitro isoenzymes of system of CYP3A4 and CYP2C8 cytochrome are defined as the main, participating in limited metabolism of a sitagliptin.

Metforminum. After single intravenous administration to healthy volunteers of Metforminum practically all entered dose was removed in not changed state with urine. Metabolic transformations in a liver and excretion does not happen to bile, and no metabolites removal of not changed Metforminum are found in the person.

Conclusion. Sitagl_ptin. After reception of a 14C-mechenny sitagliptin inside practically all entered radioactivity is brought out of an organism within a week, including 13% - through intestines and 87% - with urine. The average elimination half-life of a sitagliptin at oral administration of 100 mg makes about 12,4 hours, renal clearance - about 350 ml/min.

Conclusion of a sitagliptin is carried out preferential by renal excretion on the mechanism of active canalicular secretion. Sitagliptin is substrate of the conveyor of the organic anions of the person of the third type (hOAT-3) participating in process of elimination of a sitagliptin kidneys. The clinical importance of participation of hOAT-3 in transport of a sitagliptin is not established. Participation of a r-glycoprotein in renal elimination of a sitagliptin is possible (as substrate), however r-glycoprotein inhibitor cyclosporine does not reduce renal clearance of a sitagliptin.

Metforminum. The renal clearance of Metforminum exceeds clearance of creatinine by 3,5 times, indicating active renal secretion as the main way of removal. After reception of Metforminum about 90% of drug that was absorbed, removed by kidneys within the first 24 hours at value of a plasma polkelimination about 6,2 hours. In blood this value increases till 17,6 o'clock, indicating possible participation of erythrocytes as potential component of distribution.

Pharmacokinetics in separate groups of patients. Patients with a diabetes mellitus of the II type. Sitagliptin. Pharmacokinetics of a sitagliptin at patients with a diabetes mellitus of the II type similar to pharmacokinetics of healthy volunteers.

Metforminum. At the kept function of kidneys pharmacokinetic parameters after single and repeated receptions of Metforminum at patients with a diabetes mellitus of the II type and healthy volunteers are identical, cumulation of drug at use in therapeutic doses does not happen.

Patients with a renal failure. Velmetiya. Patients should not appoint Velmetiya with a renal failure (see the section of the Contraindication).

Sitagliptin. At patients with a moderate renal failure noted approximately 2-times increase in a sitagliptin by plasma AUC, and at patients with heavy and an end-stage (on a hemodialysis) increase in AUC value was 4-fold in comparison with control values at healthy volunteers.

Metforminum. At patients with reduced renal function (on clearance of creatinine) the period of plasma semi-removal of drug is extended, and the renal clearance decreases in proportion to decrease in clearance of creatinine.

Patients with an abnormal liver function. Sitagliptin. At patients with a moderate liver failure (7-9 points on a scale of Chayld-Pyyu) average AUC and Cmax values to a sitagliptin after a single dose of 100 mg increase approximately by 21% and 13% respectively in comparison with healthy volunteers. The similar difference is not clinically significant.

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, proceeding from preferential renal way of removal of drug, significant changes of pharmacokinetics of a sitagliptin at patients with a heavy liver failure are not predicted.

Metforminum. Researches of pharmacokinetic parameters of Metforminum at patients with a liver failure were not conducted.

Patients of advanced age. Age changes of pharmacokinetics of drug are caused by decrease in secretory function of kidneys.

Treatment by Velmetiya's drug is not shown to elderly patients 80 years, except for persons with the kept clearance of creatinine are more senior (see the section of Feature of use. Metforminum hydrochloride).

Indications to use:

Velmetiya is shown as addition to a diet and the mode of exercise stresses for improvement of control over a glycemia at the patients with a diabetes mellitus of the II type who did not reach adequate control against the background of monotherapy by Metforminum or sitagliptiny or after the unsuccessful combined treatment by two drugs.

Velmetiya is shown in a combination with sulphonylurea derivatives (a combination of three drugs) as addition to a diet and the mode of exercise stresses for improvement of control over a glycemia at the patients with a diabetes mellitus of the II type who did not reach adequate control after treatment by two of three following drugs: Metforminum, sitagliptiny or sulphonylurea derivatives.

Velmetiya is shown in a combination with PPAR-γ agonists (for example, thiazlolidinedithis) as addition to a diet and the mode of exercise stresses for improvement of control over a glycemia at the patients with a diabetes mellitus of the II type who did not reach adequate control after treatment by two of three following drugs: Metforminum, sitagliptiny or PPAR-γ agonist.

Velmetiya is shown to patients with a diabetes mellitus of the II type (a combination of three drugs) as addition to a diet and the mode of exercise stresses for improvement of control over a glycemia in a combination with insulin.

Route of administration and doses:

General information. The mode of dosing of Velmetiya should be selected individually, proceeding from the current therapy, efficiency and portability, but without exceeding the maximum recommended daily dose of a sitagliptin – 100 mg.

Velmetiya is usually applied 2 times a day during food, with gradual increase in a dose to minimization of possible side effects from a GIT, characteristic of Metforminum.

Recommendations about a dosage. The initial dose of drug of Velmetiya depends on the current hypoglycemic therapy. Velmetiya is accepted 2 times a day during food.

The following dosages of drug are offered:

- 50 mg sitagliptina/500 hydrochloride Metforminum mg.

- 50 mg sitagliptina/850 hydrochloride Metforminum mg.

- 50 mg sitagliptina/1000 hydrochloride Metforminum mg.

For the patients who did not reach adequate control at monotherapy by Metforminum. The initial recommended Velmetiya's dose for the patients who did not reach adequate control at monotherapy by Metforminum has to provide the daily recommended dose of a sitagliptin of 100 mg, that is on 50 mg of a sitagliptin 2 times a day plus the current dose of Metforminum.

For the patients who did not reach adequate control at monotherapy sitagliptiny. The initial recommended Velmetiya's dose for the patients who did not reach adequate control at monotherapy sitagliptiny makes 50 mg sitagliptina/500 hydrochloride Metforminum mg 2 times a day. Further the dose can be increased to 50 mg sitagliptina/1 000 mg of Metforminum of a hydrochloride 2 times a day. Treatment by Velmetiya's drug is contraindicated to patients who apply the corrected dose of a sitagliptin for renal failures (see the section of the Contraindication).

For the patients accepting a combination of drugs of a sitagliptin with Metforminum. Upon transition from the combined treatment sitagliptiny and Metforminum the initial dose of drug of Velmetiya can be to an equivalent dose in which they applied ситаглиптин and Metforminum.

For the patients accepting two of the listed three hypoglycemic drugs - ситаглиптин, Metforminum or derivative sulphonylurea. The initial recommended drug dose Velmetiya has to provide a daily therapeutic dose of a sitagliptin of 100 mg (50 mg of a sitagliptin 2 times a day). The initial dose of Metforminum is defined on the basis of the level of glycemic control and flowing (if the patient accepts this drug) by Metforminum doses. Increase in a dose of Metforminum has to be gradual for minimization of the related side effects from a GIT. To patients who accept derivative sulphonylurea will be reasonable to lower the current dose for decrease in risk of development of a sulfonilindukovanny hypoglycemia.

For the patients accepting two of the listed three hypoglycemic drugs - ситаглиптин, Metforminum or an agonist of PPAR-γ (for example, тиазолидиндион). The initial recommended drug dose Velmetiya has to provide a daily therapeutic dose of a sitagliptin of 100 mg (50 mg of a sitagliptin 2 times a day). The initial dose of Metforminum is defined on the basis of the level of glycemic control and flowing (if the patient accepts this drug) by Metforminum doses. Increase in a dose of Metforminum has to be gradual for minimization of the related side effects from a GIT.

For the patients accepting two of the listed three hypoglycemic drugs - ситаглиптин, metformin or insulin. The initial recommended drug dose Velmetiya has to provide a daily therapeutic dose of a sitagliptin of 100 mg (50 mg of a sitagliptin 2 times a day). The initial dose of Metforminum is defined on the basis of the level of glycemic control and flowing (if the patient accepts this drug) by Metforminum doses. Increase in a dose of Metforminum has to be gradual for minimization of the related side effects from a GIT. Or begin to apply insulin to patients who apply, there can be necessary an insulin dose decline for decrease in risk of development of a hypoglycemia.

Special researches of safety and efficiency of transition from treatment by other hypoglycemic drugs on treatment by the combined Velmetiya's drug were not conducted. Any changes of treatment of a diabetes mellitus of the II type have to be carried out with care and under control, taking into account possible changes of level of control over a glycemia.

Features of use:

Use during pregnancy or feeding by a breast. Velmetiya, as well as other peroral hypoglycemic drugs, is not recommended for use during pregnancy.

Pilot studies from definition of secretion of components of the combined Velmetiya's drug in breast milk were not conducted therefore it is not necessary to appoint drug during feeding a breast. As a rule, during pregnancy and feeding груддю apply only insulin.

Children. Safety and efficiency of drug of Velmetiya at children were not studied therefore drug is not used to patients of this age category.

Features of use. Velmetiya. Velmetiya's drug is not used for treatment of a diabetes mellitus of 1 type or diabetic ketoacidosis.

Velmetiya's use needs to be stopped for the period of carrying out radiological researches with intravascular administration of yodosoderzhashchy contrast mediums as use of such drugs can provoke an acute disorder of function of kidneys.

Monitoring of function of kidneys. An overwhelming way of removal of Metforminum and a sitagliptin - renal excretion. The risk of cumulation of Metforminum and development of a lactacidemia increases in proportion to degree of a renal failure. Thus, with clearance of creatinine above a veozrastny limit of norm of treatment by Velmetiya's drug it is not recommended to patients. At elderly patients it is necessary to try to reach adequate control on the minimum dose of drug of Velmetiya through age depression of function of kidneys. At elderly patients, 80 years are especially aged more senior, carry out careful monitoring of function of kidneys.

Before an initiation of treatment Velmetiya's drug, and also at least once a year after an initiation of treatment carry out monitoring of function of kidneys. At the increased probability of development of renal dysfunction control inspections are carried out more often, and at its identification cancel Velmetiya's reception.

Development of a hypoglycemia at Velmetiya's combination with derivatives to sulphonylurea or with insulin. As well as in case of a combination of other hypoglycemic means with derivatives to sulphonylurea, the concomitant use of Velmetiya with derivatives to sulphonylurea or insulin (group of drugs which cause a hypoglycemia) causes the hypoglycemia induced by use to sulphonylurea or insulin more often; frequency of emergence of a hypoglycemia is higher compared with placebo in a combination with metformin, sulphonylurea or insulin. Therefore for decrease in risk of emergence of a hypoglycemia can be necessary to lower doses to sulphonylurea or insulin.

Lactacidemia. At Metforminum cumulation the lactacidemia very seldom develops that is a serious state in a type of a high rate of mortality in the absence of urgent treatment. Most often about development of a lactacidemia at use of Metforminum it was reported at patients with diabetes and the accompanying renal failure or any other morbid condition which is followed by the expressed hypoperfusion and an anoxemia of fabrics and bodies, with heart failure, at unstable stenocardia / acute heart failure that are followed by the expressed hypoperfusion and a hypoxia. For the prevention of development of a lactacidemia it is necessary to estimate risk factors, such as badly controlled diabetes, a ketosis, long starvation, overconsumption of alcohol, an abnormal liver function and state which are followed by a hypoxia.

The lactacidemia is characterized atsidozny диспноэ, abdominal pain and a hypothermia then the coma develops. The lactacidemia develops more often gradually, initial symptoms nonspecific and include an indisposition, mialgiya, a respiratory distress, the increased drowsiness and abdominal symptoms. With increase in acidosis the hypothermia, arterial hypotension and a resistant bradyarrhythmia join above-mentioned symptoms.

Laboratory indicators - determine plasma concentration of electrolytes, ketones, glucose, and also (by indicators) PH value of blood, lactate level, plasma concentration of Metforminum. If against the background of treatment Metforminum defined plasma concentration of a lactate in a venous blood exceeds an upper limit of norm, remaining not higher than 5 mmol/l, it is not characteristic of a lactacidemia and can be caused by such states as badly controlled diabetes mellitus or obesity, either an excessive exercise stress, or a technical error of measurements.

At patients with a diabetes mellitus with a metabolic acidosis in the absence of confirmation of ketoacidosis (the ketonuria and a ketonemiya) should think of development of a lactacidemia.

At suspicion on development of a lactacidemia treatment by Metforminum is cancelled and carry urgently out the necessary supporting measures. Possible emergency carrying out a hemodialysis (Metforminum is dialyzed with a speed up to 170 ml/min. in the conditions of a good hemodynamics) for bystry correction of acidosis and removal of Metforminum.

The listed actions most often lead to bystry disappearance of all symptoms of a lactacidemia and recovery of the patient.

Hypoglycemia. The hypoglycemia does not develop at treatment only by Velmetiya under usual circumstances, however is possible against the background of starvation, after a considerable exercise stress without the following compensation of the spent calories or at a concomitant use of other hypoglycemic drugs (derivative sulphonylurea and insulin) or alcohol. More development of a hypoglycemia is experienced by the summer and exhausted persons who abuse alcohol, and patients with nadpochechnikozavisimy or pituitary insufficiency. It is difficult to distinguish a hypoglycemia in summer and patients who accept beta adrenoblockers.

Hypersensitivity reactions. In the post-marketing period it was reported about the following reactions of hypersensitivity at patients who applied ситаглиптин: anaphylaxis, Quincke's disease, exfoliative conditions of skin and Stiyensa-Johnson's syndrome. Such reactions arose within the first three months of use of a sitagliptin and sometimes - after use of the first dose. If there are suspicions concerning development of reactions and to appoint alternative treatment of diabetes.

The accompanying medicamentous therapy which can negatively influence secretory function of kidneys or distribution of Metforminum. It is necessary to appoint the accompanying drugs which negatively influence functions of kidneys either a hemodynamics, or Metforminum distribution, in particular cationic drugs which are brought out of an organism by canalicular secretion with care.

Radiological researches with intravascular administration of yodosoderzhashchy contrast agents (for example, intravenous Urogramum, an intravenous holangiografiya, a computer tomography with intravenous administration of contrast agents). Intravascular administration of contrast mediums on the basis of iodine can cause an acute disorder of function of kidneys, in particular in patients who accepted Metforminum for the period of the research, took place cases of development of a lactacidemia. Thus, Velmetiya's reception is temporarily stopped on the eve of the research and within 48 hours later, updating of treatment is admissible only after laboratory confirmation of normal function of kidneys.

Hypoxemic states. The vascular collapse (shock) of any etiology, an acute heart failure, an acute myocardial infarction and other states which are followed by development of an anoxemia can provoke development of a lactacidemia and epinephral azotemia. If the listed states develop at the patient against the background of treatment by Velmetiya's drug, administration of drug should be stopped immediately.

Surgical interventions. Administration of drug of Velmetiya should be stopped the 48th hours prior to carrying out any surgical intervention (except for small manipulations which do not demand restrictions of the drinking mode and hunger), carrying out spinal or epidural anesthesia, and up to resuming of the usual mode of reception of food, on condition of laboratory confirmation of normal function of kidneys.

Alcohol use. Alcohol exponentiates influence of Metforminum on metabolism of lactic acid. The patient should be warned that it is necessary to avoid consumption of alkogolsoderzhashchy drinks during treatment by Velmetiya's drug.

Dysfunction of a liver. As the known cases of development to a lactacidemia at patients with dysfunction of a liver, it is not recommended to appoint Velmetiya's drug to patients with liver disease symptoms.

B12 vitamin levels. Decrease in normal plasma concentration of B12 vitamin without development of clinical symptoms of deficit can be observed. Decrease in content of B12 vitamin (as a result of decrease in intestinal absorption) in rare instances can become complicated anemia. However, then Velmetiya's cancellations or after purpose of vitamin therapy concentration of B12 vitamin quickly renews to norm. At treatment Velmetiya's drug recommends to make annually a check analysis of blood, any deviations are subject to adequate interpretation and correction.

To the persons inclined to development of deficit of B12 (as a result of reduced consumption or absorption of B12 vitamin or to calcium), it is recommended to define concentration of B12 vitamin in bucketed blood serum in 2-3 years.

Change of the clinical status of the patient from adequately controlled diabetes mellitus of the II type. If the patient from earlier adequately controlled diabetes mellitus of the II type at administration of drug of Velmetiya has laboratory deviations or clinical symptoms of a disease, especially unspecified and those which do not give in to accurate identification), it is necessary to exclude immediately first of all ketoacidosis or a lactacidemia by results of the analysis of blood serum on electrolytes and ketone, glucose level, and also (behind indications) рН blood, concentration of a lactate, pyruvate and Metforminum. At development of acidosis of any etiology further administration of drug of Velmetiya is cancelled and actions concerning correction of acidosis get used.

Loss of control over a glycemia. In situations of a physiologic stress (a hyperthermia, an injury, an infection or surgical intervention) at once stable patient temporary loss of control over a glycemia is possible. During such periods admissible temporary replacement for drug of Velmet_ya on insulin, and after decrease in an acute episode the patient can resume the former treatment.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Researches were not conducted, but it is necessary to consider that at use of a sitagliptin dizziness and drowsiness therefore it is necessary to be careful at control of motor transport or work with mechanisms were noted.

Side effects:

Side reactions in the table are placed on classes of systems of bodies and for frequency which is determined as  are very widespread (≥1/10), extended (≥1/100, <1/10), not widespread (> 1/1 000, <1/100), are seldom widespread (> 1/10 000, < 1/1 000) and  are very seldom widespread (< 1/10 000).

Side reaction	Frequency of emergence of side reactions, depending on the scheme of treatment
	Sitagliptin and Metforminum	Sitagliptin, metformin and sulphonylurea	Sitagliptin, Metforminum and розиглитазон	Sitagliptin, metformin and insulin
	24 weeks	24 weeks	18 weeks	24 weeks
From laboratory researches
Decrease in level of glucose in blood	not widespread
From a nervous system
Headache			widespread	not widespread
Drowsiness	not widespread
From a GIT
Diarrhea	not widespread
Nausea	widespread
Lock		widespread
Pain at an upper part of a stomach	not widespread
Vomiting			widespread
Dryness in a mouth				not widespread
From metabolism and food
Hypoglycemia		strongly widespread	widespread	strongly widespread
General state
Peripheral hypostases			widespread

It was reported about the following side reactions when using a sitagliptin with other drugs.

From metabolism and food: not widespread - an anorksiya.

From laboratory indicators: not widespread - decrease in body weight.

Besides, it was reported about side reactions: extended - a headache, cough, vomiting, a hypoglycemia, fungal infections, upper respiratory tract infections.

Interaction with other medicines:

Sitagliptin and Metforminum. The concomitant use of several doses of a sitagliptin (50 mg 2 times a day) and Metforminum (1000 mg twice a day) is not followed by considerable changes in pharmacokinetic parameters of a sitagliptin or Metforminum at patients with diabetes of the II type.

Research of influence of interactions with other drugs on pharmacokinetic parameters of drug of Velmetiya it is not conducted, however, to carry out enough such researches for each of drug components.

Sitagliptin. Interaction researches with other drugs ситаглиптин have no clinically significant impact on pharmacokinetics from the following drugs: Metforminum, roziglitazon, Glibenclamidum, simvastatin, warfarin, oral contraceptives. Based on these data, ситаглиптин does not inhibit CYP system CYRZA4 cytochrome isoenzymes, 2S8 or 2S9. These in vitro specify what ситаглиптин also does not connect isoenzymes 1A2, CYP2D6, 2S19 and 2U6 and does not cause SYRZA4.

The accompanying therapy is lower than the listed drugs, is often used by patients with type of diabetes II, did not exert clinically significant impact on pharmacokinetics of a sitagliptin: gipokholesterinemichesky drugs (statines, fibrata, эзетемиб), antiagregant (klopidogret), anti-hypertensive drugs (APF inhibitors, blockers of receptors angiotenzinovy, beta-blockers, blockers of calcium channels, Hydrochlorthiazidum), analgetics and non-steroidal anti-inflammatory drugs (diclofenac, Naproxenum, Tselekoksib), antidepressants (бупропион, fluoxetine, sertraline), anti-histamine (цетиризин), inhibitor of a proton pomp (омепразол, ланзопразол) and drugs for treatment of erectile dysfunction (Sildenafil).

Insignificant increase in AUC (11%), and also secondary Smax (18%) of digoxin in case of use with sitagliptiny is noted. This increase is not clinically significant, however while accepting digoxin it is recommended for monitoring of a condition of the patient. Noticeable increase in AUC and Smax of a sitagliptin of 29% and 68% respectively, one-time oral administration of drug of Anuviya (ситаглиптин) in a dose on 100 mg and one-time peroral, accepting cyclosporine (a powerful ingiitor of a r-glycoprotein) in a dose of 600 mg. These changes in pharmacokinetic parameters of a sitagliptin are not clinically significant.

Metforminum. Glyburidum. Any changes of pharmacokinetic and pharmakodinamichesky parameters of Metforminum were not observed. Changes of AUC and Cmax values of Glibenclamidum were visokovariabelnima. Insufficient information (single dose) and discrepancy of plasma concentration of Glibenclamidum to observed pharmakodinamichesky effects call into question into the clinical importance of this interaction.

Furosemide. Change of pharmacokinetic parameters of both drugs is observed. Furosemide increases value of concentration Cmax of Metforminum in plasma and whole blood by 22%, AUC value of Metforminum in whole blood - for 15%, without changing at the same time renal clearance. Cmax and AUC value of furosemide, in turn, decrease by 31% and 12% respectively, and the elimination half-life decreases by 32% without essential changes of renal clearance of furosemide. There is no information on interaction with other medicines of two drugs at prolonged combined use.

Nifedipine. At an interaction research with other medicines of nifedipine and Metforminum after a single dose of drugs found increase in plasma Cmax and AUC metformin by 20% and 9% respectively, and also increase in quantity of the metformin allocated with urine. Tmax and an elimination half-life of Metforminum did not change. In a basis - increase in absorption of Metforminum in the presence of nifedipine. Influence of Metforminum on nifedipine pharmacokinetics minimum.

Cationic drugs. Cationic drugs (that is Cimetidinum, amiloride, digoxin, morphine, procaineamide, quinidine, quinine, ranitidine, Triamterenum, Trimethoprimum or Vancomycinum) which are removed by canalicular secretion, can theoretically enter interaction with Metforminum, competing for joint renal canalicular transport system. The similar competition was observed at a concomitant use of Metforminum and Cimetidinum in researches of single and reusable doses, from 60% increase in concentration of Cmax of Metforminum in plasma and whole blood and 40% increase in AUC value of Metforminum in plasma and whole blood. In a research of single doses the elimination half-life of Metforminum did not change. Metforminum does not influence Cimetidinum pharmacokinetics. And though the specified interactions with medicines have, generally theoretical value (except for Cimetidinum), careful observation of the patient and dose adjustment of drug of Velmetiya and/or the above-stated cationic drugs which are excreted proximal department of renal tubules, in cases of their concomitant use is recommended.

Other drugs. Some drugs have hyper glycemic potential and can influence on control over a glycemia is adjusted. Thiazide and other diuretics, corticosteroids (systemic and local action), beta-2 agonists, fenotiazina, drugs of a thyroid gland concern to them, are oestrogenic, oral contraceptives, Phenytoinum, niacin, sympathomimetics, blockers of calcium channels and an isoniazid. At purpose of the listed drugs that uses Velmetiya's drug, is recommended to the patient careful observation of parameters of glycemic control.

APF inhibitors can reduce glucose level in blood. If it is necessary, the dose gipoglikemiziruyushchy drug should be adjusted during simultaneous use with other drugs. At a concomitant use of Metforminum and propranolol or Metforminum and an ibuprofen did not observe change of pharmacokinetic parameters of these drugs.

Only insignificant part of Metforminum contacts proteins of a blood plasma, therefore interactions of Metforminum with medicines are improbable, actively contact proteins of plasma, such as salicylates, streptocides, chloramphenicol and пробенецид, unlike sulphonylurea derivatives which also actively свя contact proteins of plasma.

Contraindications:

• The known hypersensitivity to a sitagliptin of phosphate, Metforminum to a hydrochloride or to any other component of drug.
• Acute states which can influence function of kidneys: dehydration, heavy infections, shock.
• Acute or chronic diseases which can lead to a hypoxia of fabrics, such as heart or respiratory failure, recently postponed myocardial infarction, shock.
• Moderate or heavy renal failures (clearance of creatinine less than 60 ml/min.).
• Abnormal liver function.
• Acute drunkenness, alcoholism.
• Feeding period breast.
• Diabetes mellitus of the I type.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with a coma or without).
• Radiological researches (intravascular administration of iodinated contrast mediums) (see the section "Features of Use").

Overdose:

Velmetiya. There are no data on drug overdose. 

Sitagliptin. At healthy volunteers single doses to 800 mg were, as a rule, transferred well. At use in clinical trial of a dose of 800 mg insignificant lengthening of Qtc which was not considered as clinically significant was observed. There is no experience of use of doses which exceed 800 mg. In researches side reactions, povjjyazany with a drug dose were not observed at use of 600 mg for days within 10 days and 400 mg within 28 days.

Sitagliptin is poorly dialyzed: according to clinical trials, during the 3-4-hour session of a hemodialysis only 13,5% of a dose were removed. In case of clinical need appoint the prolonged hemodialysis. There are no data on efficiency of peritoneal dialysis of a sitagliptin.

Metforminum. Metforminum overdose cases, including reception in quantities which exceed 50 g took place. The hypoglycemia was observed approximately in 10% of all cases of overdose, however a causal relationship with overdose of Metforminum it was not established. About development of a laktatsidoz it was reported approximately in 32% of all cases of overdose of Metforminum. Perhaps emergency carrying out a hemodialysis (Metforminum is dialyzed with a speed up to 170 ml/min. in the conditions of a good hemodynamics) for the accelerated removal of excess of metformin at suspicion of its peredozrovka.

In case of overdose of drug of Velmetiya it is necessary to begin the standard supporting actions: removal from an intestinal path of the rest of drug which was not soaked up yet, control of vital signs, including an ECG, a hemodialysis, and also purpose of a maintenance therapy, if necessary.

Storage conditions:

Period of validity - 2 years. Not to use after the termination of the period of validity specified on packaging. To store at a temperature of not Vichy of 25 °C in the dry, protected from light and unavailable to children place.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in blistery on 2 or 4 blisters at cardboard to a box.