Galvus Met (Galvus Met)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVildagliptin + MetforminVildagliptin + Metformin
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  • Galvus Met
    pills inwards 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active substances: vildagliptin 50.0 mg and metformin hydrochloride 500.0 mg, 850.0 mg or 1000.0 mg;

    Excipients: giprolose 49.5 mg, 84.15 mg, 99.0 mg; magnesium stearate 6.5 mg, 9.85 mg, 11.0 mg; hypromellose 12.858 mg, 18.58 mg, 20.0 mg; titanium dioxide (E 171) 2.36 mg, 2.90 mg, 2.2 mg; macrogol 4000 1.283 mg, 1.86 mg, 2.0 mg; talc 1.283 mg, 1.86 mg, 2.0 mg; iron oxide yellow (E 172) 0.21 mg, 0.82 mg, 1.8 mg.

    Tablets, film-coated, 50 mg + 500 mg, additionally contain iron oxide red (E 172) 0.006 mg.

    Description:

    Tablets, film-coated, 50 mg + 500 mg: oval tablets with beveled edges, covered with a film shell of light yellow with a faint pinkish hue of color. On one with Torone tablets labeling "NVR", on the other side - "LLO".

    Tablets, film-coated, 50 mg + 850 mg: oval tablets with beveled edges, covered with a film coating of yellow with a weak grayish shade of color. On one side tablet marking "NVR", on the other side - "SEN".

    Tablets, film-washed, 50 mg+1000 mg: oval tablets with beveled edges, covered with a film coating of dark yellow with a grayish shade of color. On one side of the tablet labeling "NVR", on the other side - "FLO".

    Pharmacotherapeutic group:A hypoglycemic agent for oral administration combined (dipeptidyl peptidase-4-inhibitor + biguanide)
    ATX: & nbsp

    A.10.B.D.08   Metformin and vildagliptin

    A.10.B.D   Combination of biguanides and sulfonylurea derivatives

    Pharmacodynamics:

    The composition of the drug Galvus Met includes two hypoglycemic agents with different mechanisms of action: vildagliptin, belonging to the class of inhibitors of dipeptidyl peptidase-4 (DPP-4), and metformin (in the form of hydrochloride), a representative of the biguanide class. The combination of these components makes it possible to more effectively control the concentration of blood glucose in patients with type 2 diabetes mellitus within 24 hours.

    Vildagliptin, a representative of the class of stimulants of the islet apparatus of the pancreas, selectively inhibits the DPP-4 enzyme that destroys the type 1 glucagon-like peptide (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP).

    Metformin reduces the production of glucose by the liver, reduces the absorption of glucose in the intestine and reduces insulin resistance by enhancing the capture and utilization of glucose by peripheral tissues.

    Metformin induces intracellular synthesis of glycogen, acting on glycogen synthetase, and enhances the transport of glucose by some membrane proteins-glucose transporter (GLUT-1 and GLUT-4).

    Vildagliptin

    Rapid and complete inhibition of DPP-4 activity after taking vildagliptin causes both basal and stimulated food intake of GLP-1 secretion and GIP from the intestine to enter the systemic bloodstream throughout the day.

    Increasing the concentration of GLP-1 and HIP, vildagliptin causes an increase in the sensitivity of β-cells of the pancreas to glucose, which leads to an improvement in the glucose-dependent secretion of insulin. The degree of improvement in the function of β-cells depends on the degree of their initial damage; so, in individuals without diabetes mellitus (with a normal concentration of glucose in the blood plasma) vildagliptin does not stimulate the secretion of insulin and does not reduce the concentration of glucose.

    Increasing the concentration of endogenous GLP-1, vildagliptin increases the sensitivity of α-cells to glucose, which leads to an improvement in glucose-dependent regulation of glucagon secretion. Reducing the increased concentration of glucagon after meals, in turn, causes a decrease in insulin resistance.

    Increasing the ratio of insulin / glucagon amid hyperglycemia due to increased concentration of GLP-1 and GIP, it causes a decrease in hepatic glucose production, both during and after the meal, leading to a decrease in plasma glucose concentration.

    Furthermore, on background of vildagliptin, a decrease lipid concentrations in plasma after ingestion of food, but this effect is not related to its action on GLP-1 or GIP and improved function of pancreatic islet cells.

    It is known that an increase in the concentration of GLP-1 can lead to a slowdown in gastric emptying, however, against the background of the use of vildagliptin, this effect is not observed.

    In the application of vildagliptin in 5759 patients with type 2 diabetes for 52 weeks as monotherapy or in combination with metformin, sulfonylureas, thiazolidinediones, or insulin had significantly prolonged decrease in glycated hemoglobin concentration (HbA1C) and fasting blood glucose.

    Metformin

    Metformin improves glucose tolerance in patients with type 2 diabetes, reducing the concentration of glucose in the plasma both before and after meals.

    In contrast to the sulfonylurea derivatives, metformin does not cause hypoglycemia in either patients with type 2 diabetes, nor in healthy individuals (except in special cases). The drug therapy does not lead to the development of hyperinsulinemia. When metformin is used, the secretion of insulin does not change, while the concentration of insulin in the blood plasma on an empty stomach and during the day can decrease.

    When metformin is used, there is a favorable effect on the metabolism of lipoproteins: a decrease in the concentration of total cholesterol, low density lipoprotein cholesterol and triglycerides, not related to the effect of the drug on the concentration of glucose in the blood plasma.

    Vildagliptin + Metformin

    When combined therapy with vildagliptin and metformin at daily doses of 1500-3000 mg of metformin and 50 mg of vildagliptin 2 times a day for 1 year, a statistically significant persistent decrease in blood glucose concentration was observed (determined by a decrease in the HbA1C) and an increase in the proportion of patients in whom a decrease in the concentration of HbA1C was at least 0.6-0.7% (compared to the group of patients who continued to receive only metformin).

    In patients who received a combination of vildagliptin and metformin, there was no statistically significant change in body weight compared with the baseline. 24 weeks after the start of treatment in the groups of patients receiving vildagliptin in combination with metformin, there was a decrease in systolic and diastolic blood pressure in patients with arterial hypertension.

    When a combination of vildagliptin and metformin was used as an initial therapy for patients with type 2 diabetes mellitus, a dose-dependent decrease in HbA1C in comparison with the monotherapy of these drugs. The incidence of hypoglycemia was minimal in both treatment groups.

    When using vildagliptin (50 mg twice a day) simultaneously with / without metformin in combination with insulin (mean dose 41 V) in patients in the clinical study, the HbA1C statistically significantly decreased by 0.72% (the initial rate, on average, 8.8%). The incidence of hypoglycemia in patients treated was comparable to the incidence of hypoglycemia in the placebo group.

    When vildagliptin is used (50 mg twice a day) concomitantly with metformin (≥ 1500 mg) in combination with glimepiride (≥4 mg per day) in patients in the clinical trial the HbA1C statistically significantly decreased by 0.76% (from the average level of 8.8%).

    Pharmacokinetics:

    Vildagliptin

    Suction

    When administered on an empty stomach vildagliptin quickly absorbed, and its maximum concentration in the blood plasma (CmOh) is achieved after 1.75 hours after administration. With simultaneous intake with food, the rate of absorption of vildagliptin decreases slightly: a decrease in CmOh by 19% and an increase in the time it takes to reach 2.5 hours. However, eating does not affect the degree of absorption and the area under the concentration-time curve (AUC).

    Vildagliptin is rapidly absorbed, and its absolute bioavailability after oral administration is 85%. FROMmOh and AUC in the therapeutic range of doses increase approximately in proportion to the dose.

    Distribution

    The degree of binding of vildagliptin to plasma proteins is low (9.3%). The drug is distributed evenly between the plasma and erythrocytes. The distribution of vildagliptin is presumed to be extravascular, the volume of distribution in the equilibrium state after intravenous administration (Vss) is 71 liters.

    Metabolism

    Biotransformation is the main way of removing vildagliptin. In the human body, a 69% dose of the drug is converted. The main metabolite - LAY151 (57% of the dose) is pharmacologically inactive and is a product of hydrolysis of the cyano component. About 4% of the dose of the drug is subjected to amide hydrolysis.

    In experimental studies, there is a positive effect of DPP-4 on the hydrolysis of the drug. Vildagliptin It is not metabolized with the participation of isoenzymes of the cytochrome P system450. According to research in vitro, vildagliptin is not a substrate of isoenzymes P (CYP)450, Does not inhibit or induce isoenzymes of the cytochrome system CYP450.

    Excretion

    After ingestion, about 85% of the dose is excreted by the kidneys and 15% through the intestine, while renal excretion of unchanged vildagliptin is 23%. With intravenous administration, the average half-life reaches 2 hours, the total plasma clearance and renal clearance of vildagliptin are 41 l / h and 13 l / h, respectively. The half-life (T1/2) after oral administration is about 3 hours regardless of the dose.

    Pharmacokinetics in special cases

    Sex, body mass index and ethnicity do not affect the pharmacokinetics of vildagliptin.

    Patients with impaired hepatic function

    In patients with impaired hepatic and mild liver functionseverity (6-10 points according to the Child-Pugh classification) after a single application of the drug, a decrease in the bioavailability of vildagliptin by 8% and 20%, respectively. In patients with severe hepatic dysfunction (Child-Pugh grade 12), the bioavailability of vildagliptin is increased by 22%. The maximum change in the bioavailability of vildagliptin, an increase or decrease on average to 30%, is not clinically significant. Correlations between the degree of severity of violations of the liver and the bioavailability of the drug is not revealed.

    Patients with impaired renal function

    In patients with impaired renal function of mild, moderate or severe AUC vildagliptin increased in comparison with healthy volunteers in 1,4, 1,7 and 2 times, respectively. AUC metabolite LAY151 increased in 1.6, 3.2, and 7.3 times, and the metabolite BQS867 in 1,4, 2,7, and 7,3 times in patients with impaired renal function of mild, moderate and severe degree, respectively. Limited data in patients with terminal stage of chronic kidney disease (CKD) indicate that the indicators of this group are similar to those in patients with impaired renal function of severe severity.Concentration of metabolite LAY151 patients with terminal CKD increased by 2-3 times compared with the concentration in patients with impaired renal function of severe severity. Excretion of vildagliptin in hemodialysis is limited (3% for a procedure lasting more than 3-4 hours 4 hours after a single dose of the drug).

    Use in patients aged ≥65 years

    The maximum increase in bioavailability of the drug by 32% (increase in CmOh on 18%) in patients older than 70 years is not clinically significant and does not affect the inhibition of DPP-4.

    Use in patients under the age of 18 years

    Pharmacokinetic features of vildagliptin in children and adolescents under the age of 18 years have not been established.

    Metformin

    Suction

    Absolute bioavailability of metformin when ingested at a dose of 500 mg on an empty stomach was 50-60%. The maximum concentration in plasma (CmOh) is achieved after 1.81-2.69 hours after administration. With an increase in the dose from 500 mg to 1500 mg, or at doses of 850 mg to 2250 mg orally, there was a slower increase in pharmacokinetic parameters (than would be expected for linear dependence). This effect is caused not so much by the change in the excretion of the drug, as by the slowing of its absorption.Against the background of food intake, the degree and rate of absorption of metformin also decreased somewhat. Thus, with a single dose of 850 mg with food, there was a decrease in CmOh and AUC by about 40% and 25%, and an increase in the time to reach the maximum concentration (TmOh) for 35 minutes. The clinical significance of these facts is not established.

    Distribution

    With a single oral dose of 850 mg, the apparent volume of metformin distribution is 654 ± 358 liters. The preparation practically does not bind to plasma proteins, while sulfonylureas compounds bind to them more than 90%. Metformin penetrates into erythrocytes (probably the amplification of this process with time). When using metformin according to the standard scheme (standard dose and frequency of admission), the equilibrium concentration of the drug in the blood plasma is reached within 24-48 hours and, as a rule, does not exceed 1 μg / ml. During controlled clinical trials, CmOh metformin in the blood plasma did not exceed 5 mcg / ml (even when taken in high doses).

    Metabolism

    With a single intravenous injection of metformin to healthy volunteers, it is excreted by the kidneys unchanged.In this case, the drug is not metabolized in the liver (the person does not have any metabolites) and is not excreted with bile.

    Excretion

    Since the renal clearance of metformin is approximately 3.5 times greater than the creatinine clearance (CC), the main way of excretion is tubular secretion. If ingested, approximately 90% of the absorbed dose is excreted by the kidneys within the first 24 hours; here T1/2 from the blood plasma is about 6.2 hours. T1/2 metformin from whole blood is about 17.6 hours, which indicates the accumulation of a significant part of the drug in erythrocytes.

    Pharmacokinetics in special cases

    Floor patients does not affect the pharmacokinetics of metformin.

    Patients with impaired hepatic function

    Patients with hepatic insufficiency did not study the pharmacokinetic features of metformin.

    Patients with impaired renal function

    In patients with impaired renal function (assessed by CC), T1/2 Metformin from plasma and whole blood increases, and its renal clearance decreases in proportion to the decrease in CK.

    Use in patients aged ≥ 65 years old

    According to limited data from pharmacokinetic studies, in healthy people ≥65 years of age there was a decrease in total plasma clearance of metformin and an increase in T1/2 and Cmax compared with young people. These features of the pharmacokinetics of metformin in persons over 65 years are probably primarily associated with a change in renal function, and therefore in patients older than 80 years, the use of Galvus Met is possible only with normal QC.

    Use in patients under the age of 18 years

    Pharmacokinetic features of metformin in children and adolescents under the age of 18 years have not been established.

    Use in patients of different ethnicity

    There is no evidence of the influence of ethnicity of patients on the pharmacokinetic features of metformin.

    In controlled clinical studies of metformin in patients with type 2 diabetes of different ethnicity, the hypoglycemic effect of the drug was manifested to the same extent.

    Vildagliptin + Metformin

    The studies show bioequivalence in terms of indicators AUC and Cmax of Galvus Met in three different dosages (50 mg + 500 mg, 50 mg + 850 mg and 50 mg + 1000 mg) and vildagliptin and metformin taken at appropriate doses as separate tablets.

    The intake of food does not affect the extent and rate of absorption of vildagliptin in the composition Galvus Met.The values ​​of CmOh and AUC metformin in the composition Galvus Met with simultaneous intake with food decreased by 26% and 7%, respectively. In addition, against the background of food intake, metformin absorption was slowed, which led to an increase in T1/2 (from 2.0 to 4.0 hours). A similar change in Cmax and AUC on the background of food intake was noted in the case of metformin separately, but in the latter case the changes were less significant. The effect of food on the pharmacokinetics of vildagliptin and metformin in the composition Galvus Met did not differ from that for both drugs alone.

    Indications:

    Diabetes mellitus type 2 (in combination with diet and exercise):

    - with insufficient effectiveness of monotherapy with vildagliptin or metformin;

    - in patients previously receiving combination therapy with vildagliptin and metformin in the form of monopreparations;

    - in combination with sulfonylurea derivatives (triple combination therapy) in patients previously treated with sulfonylurea derivatives and metformin without achieving adequate glycemic control;

    - in triple combination therapy with insulin in patients who had previously received insulin therapy at a stable dose and metformin without achieving adequate glycemic control;

    - as an initial therapy in patients with type 2 diabetes mellitus with insufficient effectiveness of diet therapy, exercise and if necessary improve glycemic control.

    Contraindications:

    - Hypersensitivity to vildagliptin or metformin or any other components of the drug;

    - renal failure or renal dysfunction (at a serum creatinine concentration ≥ 1.5 mg% (> 135 μmol / L) for men and ≥1.4 mg% (> 110 μmol / L for women);

    - acute conditions, with the risk of developing renal dysfunction: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxia conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);

    - acute and chronic heart failure, acute myocardial infarction, acute cardiovascular insufficiency (shock), respiratory failure;

    - impaired liver function;

    - Acute or chronic metabolic acidosis (including diabetic ketoacidosis in combination with or without coma). Diabetic ketoacidosis should be corrected by insulin therapy. Lactoacidosis (including in the anamnesis);

    - the drug should not be used 48 hours before surgery, radioisotope, radiologic studies with the introduction of contrast media and within 48 hours after their conduct;

    - pregnancy and the period of breastfeeding;

    - type 1 diabetes mellitus;

    - chronic alcoholism, acute alcohol poisoning;

    - compliance with a low-calorie diet (less than 1000 kcal / day);

    The effectiveness and safety of the drug in children under 18 years of age is not established.

    Since patients with impaired hepatic function in some cases had lactic acidosis, possibly one of the side effects of metformin, Galvus Met should not be used in patients with liver disease or liver biochemical function impairment.

    Carefully:

    Preparations containing metformin, it is recommended to use with caution in patients over 60 years of age when performing heavy physical work, due to the increased risk of developing lactic acidosis.

    Pregnancy and lactation:

    Pregnancy

    In experimental studies in animals using vildagliptin at doses 200 times higher than recommended, the drug did not cause disturbance of the early development of the embryo and did not have a teratogenic effect.When using vildagliptin in combination with metformin at a ratio of 1:10, there was also no teratogenic effect.

    Since there is no sufficient data on the use of Galvus Met during pregnancy, the use of the drug in pregnancy is contraindicated.

    Breast-feeding

    Metformin penetrates into breast milk. It is not known whether vildagliptin with breast milk. The use of Galvus Met in the period of breastfeeding is contraindicated.

    Dosing and Administration:

    The drug is used inside. Dosage regimen Galvus Met must be selected individually, depending on the effectiveness and tolerability of therapy. When using Galvus Met, do not exceed the recommended maximum daily dose of vildagliptin (100 mg).

    The recommended initial dose of Galvus Met should be selected, taking into account the duration of the course of diabetes mellitus and the level of glycemia, the patient's condition and already used in the patient's regimens for treatment with vildagliptin and / or metformin. To reduce the severity of side effects from the gastrointestinal tract, characteristic of metformin,preparation Galvus Met take with food.

    Initial dose of Galvus Met with ineffectiveness of monotherapy with vildaglyptin

    Treatment with Galvus Met can be started with a single tablet with a dosage of 50 mg + 500 mg twice a day; After evaluating the therapeutic effect, the dose can be gradually increased.

    The initial dose of Galvus Met with ineffective monotherapy with metformin

    Depending on the dose already received metformin, treatment with Galvus Met can begin with a dosage of one tablet of 50 mg + 500 mg, 50 mg or 850 mg + 50 mg + 1000 mg 2 times a day.

    The initial dose of Galvus Met in patients who had previously received combination therapy with vildagliptin and metformin in separate tablets

    Depending on the dose already taken vildagliptin or metformin, treatment with Galvus Met should start with the tablets as close dosage to the existing treatment, 50 mg + 500 mg, 50 mg + 850 mg or 50 mg + 1000 mg, and adjust the dose depending from efficiency.

    The starting dose of the drug Galvus Met as initial therapy in patients with type 2 diabetes mellitus with inadequate efficiency of diet therapy and exercise

    As starting therapy, the drug Galvus The metric should be applied at the initial dose of 50 mg + 500 mg once a day and after evaluating the therapeutic effect, gradually increase the dose to 50 mg + 1000 mg twice a day.

    Combination therapy with Galvus Meth and sulfonylureas or insulin derivatives

    The dose of Galvus Meth is calculated based on a dose of vildagliptin 50 mg x 2 times a day (100 mg per day) and metformin at a dose equal to that previously taken as a mono drug.

    Patients with impaired renal function

    Patients with impaired renal function may need to adjust the dose of the drug in the clearance of creatinine (CK, calculated by the Cockcroft-Gault formula) in the range of 60 to 90 ml / min. The use of Galvus Met in patients with CC <60 ml / min is contraindicated.

    Use in patients ≥65 years of age

    Metformin is excreted by the kidneys. Because patients with over 65 years of age are often noted to have impaired renal function, the dose of Galvus Meth in these patients should be adjusted based on the indicators of kidney function. When using the drug in patients older than 65 years, it is necessary to regularly monitor the kidney function.

    Use in patients under the age of 18 years

    Since the safety and efficacy of Galvus Meth in children and adolescents under the age of 18 have not been studied, the use of the drug is contraindicated in this category of patients.

    Side effects:

    The data presented below relate to the use of vildagliptin and metformin in monotherapy and in combination.

    Against the background of vildagliptin therapy, hepatic dysfunction (including hepatitis) was rarely seen in the asymptomatic course. In most cases, these abnormalities and abnormalities of liver function parameters from the norm were resolved independently without complications after discontinuation of therapy with the drug. When vildagliptin is used at a dose of 50 mg 1 or 2 times a day, the frequency of increase in the activity of "hepatic" enzymes (alanine aminotransferase (ALT) or aspartate aminotransferaseACT) was 3 times higher than the upper limit of the norm (VGN)) was 0.2% or 0.3%, respectively (compared with 0.2% in the control group). The increase in activity of "liver" enzymes in most cases was asymptomatic, did not progress and was not accompanied by cholestasis or jaundice.

    To assess the incidence of adverse events (AEs), the following criteria were used: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely ≥1 / 10,000, <1 / 1,000), very rarely (<1 / 10,000), including individual cases.

    Undesirable reactions, possibly associated with the use of combination therapy with vildagliptin and metformin (the incidence of which in the vildagliptin and metformin group differed from that with placebo and metformin by more than 2%) are presented below.

    Impaired nervous system: often - headache, dizziness, tremor.

    When vildagliptin was used in combination with metformin in various doses, hypoglycemia was noted in 0.9% of cases (for comparison in the placebo group in combination with metformin - in 0.4%). The frequency of AEs from the gastrointestinal tract against the combined therapy with vildagliptin and metformin was 12.9%. In the use of metformin, similar AEs were observed in 18.1% of patients.

    In the groups of patients who received metformin in combination with vildagliptin, disorders of the gastrointestinal tract were noted with a frequency of 10-15%, and in the group of patients who received metformin in combination with placebo, with a frequency of 18%.

    Long-term clinical trials of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin in monotherapy.

    Study of the application of combination vildagliptin and metformin as a starting therapy for type 2 diabetes mellitus did not reveal risks and additional data on safety of use.

    When application of vildagliptin simultaneously with insulin

    In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin in combination with or without metformin, the frequency of discontinuation of therapy due to the development of adverse reactions was 0.3% in the vildagliptin group, while in the placebo group cases of cancellation of therapy was not. The incidence of hypoglycemia was comparable in both groups (14.0% in the vildagliptin group and 16.4% in the placebo group).

    In the vildagliptin group, severe cases of hypoglycemia in two patients were noted, and in the placebo group in 6 patients.

    At the time of completion of the study vildagliptin had no effect on the average body weight (body weight increased by +0.6 kg compared with the initial weight in the vildagliptin group, there was no change in the placebo group).

    NL in patients who received vildagliptin 50 mg 2 times a day in combination with insulin (with or without metformin) are presented below.

    Disturbances from the nervous system: often a headache.

    Disorders from the gastrointestinal tract: often - nausea, gastroesophageal reflux; infrequent - diarrhea, flatulence.

    Disorders from the metabolism and nutrition: often - hypoglycemia.

    General disorders and disorders at the site of administration: often - chills.

    PWhen vildagliptin is used in combinations from drugs sulfonylureas

    There were no cases of drug withdrawal associated with the development of AE in the combination therapy group with vildagliptin, metformin and glimepiride. In the placebo, metformin and glimepiride combination therapy, the incidence of AH was 0.6%.

    Hypoglycemia was noted frequently in both groups (5.1% in the combination group of vildagliptin, metformin and glimepiride and 1.9% in the placebo, metformin and glimepiride combination therapy group). In the vildagliptin group, one episode of severe hypoglycemia was noted.

    At the time of completion of the study, no significant effect on body weight was detected (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

    NL in patients who received vildagliptin 50 mg 1 or 2 times a day in combination with drugs sulfonylureas, are presented below (with or without metformin).

    Infectious and parasitic diseases: rarely - nasopharyngitis.

    Impaired nervous system: often - dizziness, tremor, asthenia.

    Disorders from the gastrointestinal tract: infrequently - constipation.

    Disorders from the metabolism and nutrition: often - hypoglycemia.

    Disturbances from the skin and subcutaneous tissues: often hyperhidrosis.

    When vildagliptin is used in monotherapy

    Infectious and parasitic diseases: very rarely - infections of the upper respiratory tract, nasopharyngitis.

    Impaired nervous system: often - dizziness; infrequently a headache.

    Disorders from the gastrointestinal tract: infrequently - constipation.

    Disturbances from the skin and subcutaneous tissues: infrequently - a skin rash.

    Disturbances from the musculoskeletal and connective tissue: often - arthralgia.

    Vascular disorders: infrequent - peripheral edema.

    When combined therapy with vildagliptin and metformin was used, there was no clinically significant increase in the frequency of the above AEs observed with vildagliptin.Against the background of monotherapy with vildagliptin or metformin, the incidence of hypoglycemia was 0.4% (infrequently).

    Monotherapy with vildagliptin and combined treatment vildagliptin + metformin did not affect the patient's body weight. Long-term clinical trials of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin in monotherapy.

    Post-marketing research

    AT post-registration the following adverse reactions were identified (since the data are voluntarily reported from a population of undetermined size, it is not possible to reliably determine the frequency of development of AE data, and therefore they are classified as frequency unknown): hepatitis (reversible at discontinuation of therapy), increased activity of "hepatic" enzymes, myalgia, urticaria, pancreatitis, bullous and exfoliative skin lesions, arthralgia, rarely expressed.

    When using metformin in monotherapy

    Disorders from the metabolism and nutrition: very often - decrease appetite; very rarely - lactic acidosis.

    Disorders from the gastrointestinal tract: very often - flatulence, nausea, vomiting, diarrhea, abdominal pain; often - dysgeusia.

    Disorders from the liver and bile ducts: very rarely - hepatitis.

    Disturbances from the skin and subcutaneous tissues: very rarely - skin reactions (in particular, erythema, pruritus, urticaria).

    Laboratory and instrumental data: very rarely - decrease absorption of the vitamin AT12, changes in liver function.

    Decreased absorption of vitamin B12 and a decrease in serum concentration in the serum with metformin was very rare in patients who received the drug for a long time and, as a rule, did not represent a clinical significance. You should consider the possibility of reducing the absorption of vitamin A AT12 in patients with megaloblastic anemia. Individual cases of hepatitis, which were observed against metformin, were resolved after its elimination.

    If there is a worsening of the typical course of any of the side effects indicated in the manual or you notice any other side effects not listed in the instructions, inform the doctor about it.

    Overdose:

    Vildagliptin

    Vildagliptin is well tolerated in a dose up to 200 mg / day.

    When using the drug at a dose of 400 mg / day, pain in the muscles can be observed, rarely - light transient paresthesia, fever, swelling and transient increase in lipase activity (twice the VGN). With an increase in vildagliptin vine to 600 mg / day, it is possible to develop limb edema accompanied by paresthesia and an increase in the concentration of creatinine phosphokinase, C-reactive protein and myoglobin, activity ACT. All symptoms of overdose and changes in laboratory parameters disappear after discontinuation of the drug.

    Removing the drug from the body with dialysis is unlikely. but main hydrolysed metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.

    Metformin

    There have been several cases of metformin overdose, including as a result of ingestion of the drug in excess of 50 g. Metronin overdose in about 10% of cases was accompanied by hypoglycemia (however, its association with the drug was not established); in 32% of cases lactoacidosis was noted. The early symptoms of lactic acidosis are nausea, vomiting, diarrhea,a decrease in body temperature, abdominal pain, muscle pain, there may be more rapid breathing, dizziness, impaired consciousness and coma development. Metformin is excreted from the blood by hemodialysis (with a clearance of up to 170 ml / min) without the development of hemodynamic disorders. Thus, hemodialysis can be used to remove metformin from the blood in an overdose of the drug.

    In case of an overdose, appropriate symptomatic treatment should be performed, based on the patient's condition and clinical manifestations.

    Interaction:

    Vildagliptin and Metformin

    With the simultaneous use of vildagliptin (100 mg once a day) and metformin (1000 mg once a day) there were no clinically significant pharmacokinetic interactions between them. Neither during clinical trials nor during the extensive clinical use of the Galvus Met drug in patients who simultaneously received other drugs and substances, there were no unforeseen interactions.

    Vildagliptin

    Vildagliptin has a low potential for drug interaction.

    Because the vildagliptin is not a substrate of enzymes of the cytochrome P450 system (CYP), and also does not inhibit or induce these isoenzymes, its interaction with drugs that are substrates, inhibitors or inducers of P450 (CYP) is unlikely. With simultaneous application vildagliptin does not affect the metabolic rate of drugs that are substrates of enzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

    Clinical significant interaction between vildagliptin and the drugs most often used in the treatment of type 2 diabetes mellitus (glibenclamide, pioglitazone, metformin) or having a narrow therapeutic range (amlodipine, digoxin, ramipril, simvastatin, valsartan, warfarin) has not been established.

    Metformin

    Furosemide increases CmOh and AUC metformin, but does not affect its renal clearance. Metformin reduces CmOh and AUC furosemide and also does not affect its renal clearance.

    Nifedipine increases absorption, CmOh and AUC metformin; in addition, it increases the excretion of it by the kidneys. Metformin practically does not affect the pharmacokinetic parameters of nifedipine.

    Glibenclamide does not affect the pharmacokinetic / pharmacodynamic parameters of metformin. Metformin, as a whole, reduces Cmax and AUC glibenclamide, however, the magnitude of the effect varies greatly. For this reason, the clinical significance of this interaction remains unclear.

    Organic cations, for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin and others, excreted by the kidneys through tubular secretion, can theoretically interact with metformin due to competition for common kidney canal transport systems; So, cimetidine increases both the concentration of metformin in the blood plasma, and its AUC by 60% and 40% respectively. Metformin does not affect the pharmacokinetic parameters of cimetidine. Care should be taken when using Galvus Met along with drugs that affect kidney function or the distribution of metformin in the body.

    Other drugs - some drugs can cause hyperglycemia and contribute to a decrease in the effectiveness of hypoglycemic agents. Such drugs include thiazides and other diuretics, glucocorticosteroids, phenothiazines, thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, a nicotinic acid, sympathomimetics, calcium antagonists and isoniazid. With the simultaneous use of such drugs or, on the contrary, in the event of their withdrawal, it is recommended to carefully monitor the effectiveness of metformin (its hypoglycemic effect) and, if necessary, adjust the dose of the drug. We do not recommend simultaneous reception danazol to avoid hyperglycemic action of the latter. If you need treatment with danazol, and after stopping the latter, you need a correction of metformin dose under control of blood glucose concentration.

    Chlorpromazine when used in high doses (100 mg per day) increases glycemia, reducing the release of insulin. In the treatment of neuroleptics and after discontinuation of the latter, a dose adjustment of Galvus Met is required under the control of blood glucose concentration.

    Iodine-containing radiopaque agents: radiological examination with the use of iodine-containing radiocontrast agents can cause the development of lactic acidosis in patients with diabetes mellitus on the background of functional renal failure.

    Used in the form of injections of β-2 sympathomimetics: increase glycemia due to stimulation of β-2-adrenergic receptors. In this case, it is necessary to control glycemia. If necessary, the use of insulin is recommended. With the simultaneous use of metformin with derivatives of sulfonylurea, insulin, acarbose, salicylates, hypoglycemic action may be increased.

    Since the use of metformin in patients with acute alcohol intoxication increases the risk of developing lactic acidosis (especially when fasting, exhaustion or liver failure), with the Galvus Meth preparation, one should refrain from using alcohol and drugs containing ethyl alcohol.

    Special instructions:

    In patients receiving insulin treatment, the Galvus Met preparation can not replace insulin therapy.

    Vildagliptin

    Impaired liver function

    Since the increase in aminotransferase activity (usually without clinical manifestations) was observed slightly more frequently than in the control group, when using vildagliptin, it is recommended to determine the biochemical parameters of liver function before applying Galvus Met, and also regularly during drug treatment.When detecting an increase in the activity of aminotransferases, a second study should be conducted to confirm the result, and then regularly to determine the biochemical parameters of liver function before normalizing them. If the activity is exceeded ACT or ALT in 3 or more times higher than ULN is confirmed by repeated research, it is recommended to cancel the drug.

    Metformin

    Lactic acidosis

    Lactic acidosis is a very rare but severe metabolic complication arising from the accumulation of metformin in the body. Lactic acidosis in patients with metformin was observed mainly in patients with diabetes mellitus with impaired renal function of severe severity. The risk of developing lactic acidosis increases in patients with diabetes mellitus, which is difficult to treat, with ketoacidosis, prolonged starvation, prolonged alcohol abuse, impaired liver function, and diseases that cause hypoxia.

    With the development of lactic acidosis, dyspnea, abdominal pain and hypothermia are noted, followed by coma. The following laboratory indicators are of diagnostic value: blood pH reduction, serum lactate concentration above 5 nmol / l, as well as an increased anion interval and an increase in the lactate / pyruvate ratio.If suspected of lactic acidosis, the drug should be withdrawn and the patient immediately hospitalized.

    Control of kidney function

    Because the metformin is largely excreted by the kidneys, the risk of its accumulation with the development of lactic acidosis increases in proportion to the severity of impaired renal function. When Galvus Met is used, renal function should be evaluated regularly, especially in conditions that contribute to its disruption, such as the initial phase of treatment with antihypertensive drugs, hypoglycemic agents, or NSAIDs. The kidney function should be assessed before starting treatment with Galvus Meth and then at least 1 time per year in patients with normal renal function and at least 2-4 times per year in patients with QC at the lower limit of the norm, as well as in elderly patients. In patients with a high risk of developing a disorder of the function of the lobes, control should be performed more often 2-4 times a year. If signs of impaired kidney function appear, Galvus Met should be discarded.

    The use of iodine-containing radiopaque agents for intravascular administration

    When conducting X-ray studies,requiring the intravascular introduction of iodine-containing radiopaque agents, the Galvus Met preparation should be temporarily discontinued (no later than 48 hours before, and within 48 hours after the study), as intravascular injection of iodine-containing radiopaque agents can lead to a sharp deterioration in kidney function and increase the risk development of lactic acidosis. Renewal of Galvus Met should only be performed after a reassessment of renal function.

    Hypoxia

    In acute cardiovascular insufficiency (shock), acute heart failure, acute myocardial infarction and other conditions for which hypoxia is characteristic, lactoacidosis and prerenal acute renal failure may develop. If the above conditions occur, the drug should be immediately discontinued.

    Surgical interventions

    For the duration of surgical interventions (except for small operations not related to the restriction of consumption of food and liquids), the Galvus Met drug should be discarded. Renewal of the drug is possible after the restoration of oral intake of food in patients with a significantly excluded violation of the functionkidney.

    Alcohol consumption

    Determined that ethanol enhances the effect of metformin on the metabolism of lactate. Patients should be warned about the inadmissibility of alcohol abuse when using Galvus Met.

    Vitamin content AT12

    Determined that metformin approximately 7% of cases cause an asymptomatic decrease in the concentration of the vitamin AT12 in the blood serum. Such a decrease in very rare cases leads to the development of anemia. After withdrawal of metformin and / or replacement therapy with vitamin AT12 serum vitamin concentration AT12 quickly normalizes. In patients receiving Galvus Met, at least 1 time per year should monitor the general clinical analysis of blood. If hematological abnormalities are determined from the norm, the etiology of such disorders should be clarified and appropriate treatment should be carried out. In some patients (eg, patients with insufficient intake or impaired absorption of the vitamin AT12 or calcium) there is a predisposition to reduce the concentration of the vitamin AT12 in the blood serum. In such patients, the determination of the concentration of vitamin B12 in the blood serum, at least once every 2-3 years, can have diagnostic value.

    Deterioration of the condition of patients with type 2 diabetes mellitus who had previously responded to therapy

    If laboratory abnormalities are found to be abnormal, or when clinical symptoms appear to worsen the general condition (especially in unclear and lubricated symptoms), patients with a prior adequate response to therapy should immediately be diagnosed laboratory-based to detect ketoacidosis and / or lactic acidosis. If acidosis is detected, immediately stop using the drug and take the necessary measures to correct the patient's condition.

    Hypoglycaemia

    As a rule, hypoglycemia is not observed in patients receiving Galvus Met only, but it can occur against a low calorie diet (when intensive exercise is not compensated by caloric intake of food) or against the background of alcohol consumption. The development of hypoglycemia is most likely in elderly, debilitated or depleted patients, as well as against hypopituitarism, adrenal insufficiency or alcohol intoxication.In elderly patients and in persons receiving beta-blockers, the diagnosis of hypoglycemia can be difficult.

    Decreased efficiency hypoglycemic means

    With stress (fever, trauma, infection, surgery, etc.) developing in patients receiving hypoglycemic drugs according to the standard scheme, a sharp decrease in the effectiveness of the latter for a while is possible. In this case, it may be necessary to temporarily stop the Galvus Met and the insulin therapy. Renewal of treatment with Galvus Met is possible after the end of the acute period.

    Fertility

    In experimental studies in animals, the use of vildagliptin at doses 200 times higher than recommended did not cause impairment of fertility.

    There was no adverse effect on fertility in males and females when metformin was used at doses of 600 mg / kg per day, which is approximately 3 times the recommended human dose (when calculating the body surface area).

    There were no studies of the effect on fertility in humans.

    Effect on the ability to drive transp. cf. and fur:

    The effect of Galvus Met on the ability to drive vehicles and mechanisms has not been studied. When developing dizziness against the background of the drug should be refrained from the management of vehicles and mechanisms.

    Form release / dosage:Film-coated tablets are 50 mg + 500 mg, 50 mg + 850 mg or 50 mg + 1000 mg.
    Packaging:

    For 6 or 10 tablets in a blister pack.

    By 1, 3, 5, 6, 12, 18 or 36 blisters together with instructions for medical use in a cardboard bundle.

    Storage conditions:

    In a dry place, at a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    The drug should not be used after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-001749/09
    Date of registration:10.03.2009 / 31.08.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp04.04.2017
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