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Active ingredients
Vildagliptin
Release form
Pills
Composition
1 tablet contains: Vildagliptin 50 mg Auxiliary substances: microcrystalline cellulose - 95.68 mg, anhydrous lactose - 47.82 mg, sodium carboxymethyl starch - 4 mg, magnesium stearate - 2.5 mg.
Pharmacological effect
Mechanism of actionVildagliptin is a member of the class of pancreatic islet apparatus stimulators that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4). Rapid and complete inhibition of DPP-4 activity (> 90%) causes an increase in both basal and food-stimulated secretion of glucagon-like type 1 peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP) from the intestine into the systemic circulation 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 glucose-dependent insulin secretion. Pharmacodynamics When using vildagliptin 50-100 mg / day in patients with aharnym type 2 diabetes (T2DM) marked improvement of pancreatic β-cells. The degree of improvement in β-cell function depends on the degree of their initial damage; so in persons without diabetes (with a normal glucose concentration in the blood plasma), vildagliptin does not stimulate insulin secretion and does not reduce the glucose concentration. By increasing the concentration of endogenous GLP-1, vildagliptin increases the sensitivity of β-cells to glucose, which leads to an improvement in glucose-dependent regulation of glucagon secretion. A decrease in elevated glucagon concentration during a meal, in turn, causes a decrease in insulin resistance. An increase in the insulin / glucagon ratio due to hyperglycemia, due to an increase in the concentration of GLP-1 and HIP, causes a decrease in glucose production by the liver both during and after meals, which leads to a decrease in the concentration of glucose in the blood plasma. In addition, when using vildagliptin, there is a decrease in the concentration of lipids in the blood plasma after a meal, but this effect is not related to its action and and GLP-1 or HIP and improved function of the islet cells of the pancreas. It is known that increasing the concentration of GLP-1 may lead to slower gastric emptying,however, this effect was not observed when using vildagliptin. When using vildagliptin, in 5795 patients with type 2 diabetes for 52 weeks in monotherapy or in combination with metformin, sulfonylurea derivatives, thiazolidinedione, or insulin, a significant decrease in the concentration of glycated hemoglobin (HbA1c) and blood glucose on an empty stomach. When using the combination of vildagliptin and metformin as initial therapy in patients with type 2 diabetes mellitus, a dose-dependent effect was observed for 24 weeks HbA1c concentration versus monotherapy with these drugs. Cases of hypoglycemia were minimal in both groups of therapy. When using vildagliptin 50 mg once a day for 6 months in patients with type 2 diabetes with impaired mean renal function (glomerular filtration rate (GFR)> 30, <50 ml / min / 1.73 m2) or severe (GFR <30 ml / min / 1.73 m2) degree showed a clinically significant decrease in the concentration of HbA1c compared with placebo. When using vildagliptin 50 mg 2 times / day in combination with / without metformin and insulin ( the average dose of 41 U / day) was shown to decrease the HbA1c by 0.77 % of the original mean 8.8% with a statistically significant difference from placebo 0.72%. The frequency of hypoglycemia in the vildagliptin group is comparable to that in the placebo group. When using vildagliptin 50 mg 2 times / day in combination with metformin (> 1500 mg / day) and glimepiride (> 4 mg / day), a statistically significant decrease in HbA1c was shown by 0.76% from the initial mean of 8.8%.
Pharmacokinetics
Absorption When ingested on an empty stomach, vildagliptin is rapidly absorbed, and its maximum plasma concentration (Cmax) is reached within 1.75 hours after ingestion. When taken simultaneously with food, the absorption rate of vildagliptin decreases slightly: there is a decrease in Cmax by 19% and an increase in the time to reach it to 2.5 hours. However, food intake does not affect the degree of absorption and the area under the concentration-time curve (AUC). Wilddagliptin is rapidly absorbed, and its absolute bioavailability after ingestion is 85%. Cmax and AUC in the therapeutic range of doses increase approximately in proportion to the dose. Distribution The degree of vildagliptin binding to plasma proteins is low (9.3%).Vildagliptin is distributed evenly between blood plasma and red blood cells. The distribution of vildagliptin occurs, presumably, in an extravascular manner, the volume of distribution in the equilibrium state after intravenous injection (Vss) is 71 l. Metabolism. The main way of removing vildagliptin is biotransformation. In humans, 69% of the drug dose is biotransformed. The main metabolite is LAY151 (57% of the dose) is pharmacologically inactive and is the product of hydrolysis of the cyano component. About 4% of the dose of the drug undergoes amide hydrolysis. In preclinical studies, DPP-4 has a positive effect on vildagliptin hydrolysis. Vildagliptin is metabolized without the participation of cytochrome P450 isoenzymes. Vildagliptin is not a substrate of P450 (CYP) isoenzymes, it does not inhibit and does not induce cytochrome P450 isoenzymes. Withdrawal After taking the drug orally, about 85% of the dose is excreted by the kidneys and 15% through the intestines. Renal excretion of unchanged vildagliptin is 23%. When i / v administration, the average half-life (T1 / 2) reaches 2 h, the total plasma clearance and renal clearance of vildagliptin are 41 l / h and 13 l / h, respectively. 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 vildagliptin pharmacokinetics. Patients with impaired liver function in patients with impaired liver function of mild and moderate degrees (6 -9 points on the Child-Pugh scale) after a single dose of the drug, bio-availability of vildagliptin is noted to decrease by 20% and 8%, respectively. In patients with severely impaired liver function (10-12 points on the Child-Pugh scale), bioavailability of vildagliptin is increased by 22%. An increase or decrease in the maximum bioavailability of vildagliptin, not exceeding 30%, is not clinically significant. There was no correlation between the severity of liver dysfunction and the bioavailability of the drug. Patients with impaired renal function In patients with impaired mild, moderate or severe AUC, vildagliptin increased in comparison with healthy volunteers by 1.4, 1.7, and 2 times, respectively. The AUC of the LAY151 metabolite increased 1.6, 3.2, and 7.3 times, and the metabolite BQS867 increased 1.4, 2.7, and 7.3 times in patients with impaired mild, moderate, and severe degrees, respectively.Limited data in patients with end-stage chronic kidney disease (CKD) indicate that the indicators in this group are similar to those in patients with severe renal impairment. The concentration of metabolite LAY151 in patients with end-stage CKD increased by 2-3 times compared with the concentration in patients with severe renal dysfunction. When using the drug in patients with impaired renal function, dose adjustment may be required. Vildagliptin withdrawal during hemodialysis is limited (after 4 h after a single dose is 3% with a duration of the procedure of more than 3-4 h). Use in patients aged ≥65 years Maximal increase in the bioavailability of the drug by 32% (increase in Cmax by 18%) in the patient in people over 70 is not clinically significant and does not affect the inhibition of DPP-4. The use of patients aged ≤18 yearsPharmacokinetic features of vildagliptin in children and adolescents under 18 years of age have not been established.
Indications
Type 2 diabetes mellitus (in combination with diet therapy and exercise): - as monotherapy in case of ineffectiveness of diet therapy and exercise in patients with contraindication to metformin or in case of inefficiency of metformin; - in combination with metformin as initial drug therapy in case of insufficient the effectiveness of diet therapy and exercise; - as part of a two-component combination therapy with metformin, a sulfonylurea derivative, thiazolidinedione or insulin m in the case of ineffectiveness of diet therapy, exercise and monotherapy with these drugs; - as part of a triple combination therapy: in combination with sulfonylurea derivatives and metformin, in patients who have previously received therapy with sulfonylurea derivatives and metformin against dietary and physical exercises and have not achieved adequate glycemic control - as part of a triple combination therapy: in combination with insulin and metformin, in patients who have previously received insulin and metformin on the background of diet therapy and physical FIR exercise and have not reached an adequate glycemic control.
Contraindications
- hypersensitivity to vildagliptin and any other components of the drug; - hereditary intolerance to galactose, lactase deficiency,glucose-galactose malabsorption; - pregnancy, breastfeeding (due to lack of relevant data); - type 1 diabetes; - acute or chronic metabolic acidosis (including diabetic ketoacidosis, with or without coma). Diabetic ketoacidosis should be adjusted by insulin therapy. Lactic acidosis (including and in history); - liver dysfunction, including patients with increased liver enzyme activity (ALT or AST 3 or more times the upper limit of the normal 3хVGN); - chronic heart failure (CHF) IV functional class (FC) according to the functional classification of the New York Heart Association (NYHA) (due to the lack of data from clinical studies on the use of vildagliptin in this group of patients) - children under 18 years of age (efficacy and safety of using the drug have not been established). It is recommended to use Galvus with caution in patients with acute pancreatitis in history. Because the experience of using Galvus in patients with end-stage CKD who are on hemodialysis or undergoing hemodialysis is limited, it is recommended that the drug be used with caution in this category of patients. vildagliptin in patients with CHF III FC according to the NYHA classification are limited and do not allow to make a final conclusion, it is recommended to use the drug with caution Galvus in patients of this category.
Precautionary measures
It is recommended to use the drug Galvus with caution in patients with an acute history of acute pancreatitis. Since the experience with Galvus in patients with end-stage CKD who are on hemodialysis or undergoing hemodialysis, is recommended to be used with caution in this category of patients. vildagliptin patients with CHF III FC according to the NYHA classification are limited and do not allow to make a final conclusion, it is recommended to use the drug Galvus with caution in patients of this category.
Use during pregnancy and lactation
There are no sufficient data on the use of Galvus in pregnant women, and therefore the drug is contraindicated during pregnancy. In preclinical studies, reproductive toxicity was found when used in high doses,the potential risk to the person is unknown. The Galvus preparation is contraindicated during breastfeeding, since it is not known whether vildagliptin penetrates human breast milk.
Dosage and administration
The dose of Galvus should be selected individually, depending on the effectiveness and tolerability. The recommended dose of Galvus is 50 mg 1 or 2 times / day. The maximum daily dose of the drug is 100 mg. The dose of 50 mg / day should be taken once a day in the morning, the dose of 100 mg / day should be divided into 2 doses - 50 mg in the morning and evening. If you miss taking the drug, you should take the missed dose as soon as possible. At the same time, it is necessary to avoid taking the doubled dose in one day. The Galvus preparation is taken orally regardless of the meal. The recommended dose of the drug in monotherapy or in combination therapy with metformin, thiazolidinedione or insulin (in combination with metformin or without metformin) is 50 mg or 100 mg per day. The recommended dose of Galvus as part of a dual combination therapy with sulfonylureas is 50 mg 1 time per day in the morning. In this patient population, the effectiveness of Galvus at a dose of 100 mg / day was similar to that at a dose of 50 mg / day. The recommended dose of Galvus as part of a triple combination therapy (vildagliptin + sulfonylurea derivatives + metformin) is 100 mg / day. If the glycemic targets are control was not achieved with the use of a maximum daily dose of 100 mg; consideration should be given to adding other hypoglycemic drugs to Galvus therapy, such as metformin, sulfonylurea derivatives, thiazo Lindinedone or insulin. Patients with impaired renal function In patients with impaired mild renal function (GFR> 60 ml / min / 1.73 m2) and moderate with GFR 50-60 ml / min / 1.73 m2, no correction of the dosage regimen is required. In patients with impaired moderate renal function with GFR 30-50 ml / min / 1.73 m2 and severe (GFR <30 ml / min / 1.73 m2), including the terminal stage of CKD in patients undergoing hemodialysis or undergoing hemodialysis , the drug should be used in a dose of 50 mg 1 time / day. Patients aged ≥ 65 years Elderly patients do not need to adjust the dosing regimen of Galvus drug. Patients aged ≤ 18 years As there is no experience with the drug Galvus in children and adolescents under the age of 18, there is no It is recommended to use the drug in patients Comrade in this category.
Side effects
When using the Galvus drug at a dose of 50 mg 1 or 2 times / day, the frequency of discontinuation of therapy due to the development of adverse reactions (0.2% or 0.1%, respectively) was no higher than that in the placebo group (0.6%) or the comparator drug (0.5%). Against the background of monotherapy with Galvus at a dose of 50 mg 1 or 2 times / day, the incidence of hypoglycemia without increasing the severity of the condition was 0.5% (2 patients out of 409) and 0.3% (4 out of 1082), respectively, which is comparable with the comparator and placebo ( 0.2%). Infectious and parasitic diseases: very rarely - infections of the upper dy atelnyh ways nazofaringit.Narusheniya of the nervous system: often - dizziness; infrequently - headache. Disorders of the gastrointestinal tract: infrequently - constipation. Disorders of the blood vessels: infrequent - peripheral edema. Long-term clinical studies of up to 2 years did not reveal any additional deviations of the safety profile or unforeseen risks when using vildagliptin in monotherapy. When using the drug Galvus at a dose of 50 mg 1 or 2 times / day in combination with metformin When using the drug Galvus at a dose of 50 mg / day in combination with metformin, the frequency of discontinuation of therapy in idiopathies with the development of adverse reactions was 0.4% (in the vildagliptin groups (50 mg 2 times / day) + metformin and placebo + metformin there were no cases of discontinuation of therapy due to the development of adverse reactions). When using the drug Galvus in a dose of 50 mg 1 or 2 times / day in combination with metformin, hypoglycemia was observed in 0.9% and 0.5% of cases, respectively (in the placebo + metformin group, 0.4%). In the group of use of the drug Galvus, no severe hypoglycemia was observed. Combined therapy with vildagliptin + metformin did not affect the body weight of patients. Disorders of the nervous system: often - tremor, dizziness, headache. Disorders of the gastrointestinal tract: often - nausea Long-term clinical studies with a duration of up to 2 years did not reveal any additional deviations of the safety profile or unforeseen risks when using vildagliptin in combination with metformino. The study of the use of the combination of vildagliptin and metformin as a starting therapy for type 2 diabetes did not reveal any deviations in the safety profile or unforeseen risks.Galvus dose 50 mg / day in combination with sulfonylurea derivatives When using Galvus dose 50 mg / day in combination with glimepiride, the frequency of discontinuation of therapy due to the development of adverse reactions was 0.6% (compared with 0% in the glimepiride + placebo group) The frequency of hypoglycemia in patients who received the 50 mg / day dose of Galus along with glimepiride was 1.2% (compared to 0.6% in the placebo + glimepiride group). The use of Galvus at the recommended dose (50 mg / day) in combination with glimepiride did not show an increase in body weight. Infectious and parasitic diseases: very rarely - nasopharyngitis. Gastrointestinal disorders intestinal tract: infrequently - constipation. Violations of the nervous system: often - tremor, dizziness, headache, asthenia. When using the drug Galvus at a dose of 50 mg 1 or 2 times / day in combination with the derivatives of thiazolidine DionAbout the use of the drug Galvus at a dose of 50 mg / day in combination with pioglitazone, the frequency of discontinuation of therapy due to the development of adverse reactions was 0.7% (in the vildagliptin groups 100 mg / day + pioglitazone and placebo + pioglitazone cases of discontinuation of therapy due to the development of unwanted reactions noted). When using the drug Galvus at a dose of 50 mg / day in combination with pioglitazone at a dose of 45 mg, hypoglycemia was not observed; in the vildagliptin group (at a dose of 50 mg 2 times a day) + pioglitazone (at a dose of 45 mg) hypoglycemia was observed in 0.6% of cases, and in patients receiving placebo + pioglitazone at a dose of 45 mg, in 1.9% of cases. In the group of use of the drug Galvus was not observed development of severe hypoglycemia. The average increase in body weight compared with placebo in patients who received the drug Galvus at a dose of 50 mg 1 or 2 times / day together with pioglitazone, was +0.1 kg or +1.3 kg, respectively. When adding the drug Galvus at a dose of 50 mg 1 or 2 times per day to pioglitazone at a dose of 45 mg / day, the incidence of peripheral edema was 8.2% and 7%, respectively (compared with 2.5% against the background of pioglitazone monotherapy). However, with the initial combination therapy with vildagliptin at a dose of 50 mg 1 or 2 times / day, along with pioglitazone at a dose of 45 mg / day, the development of peripheral edema was observedin 3.5% or 6.1% of patients, respectively (compared to 9.3% with pioglitazone monotherapy at a dose of 30 mg / day). Disorders of the blood vessels: often - peripheral edema. Disorders of metabolism and nutrition: often - an increase in body weight. When using the drug Galvus in a dose of 50 mg 2 times / day in combination with insulin (with or without Metformin) When using the drug in combination with insulin (in combination with metformin or without Metformin), the frequency of discontinuation of therapy due to the development of side effects was equal to 0.3% in the vildag treatment group there was no cessation of treatment in the placebo group. When using the drug in combination with insulin (in combination with metformin or without metformin), there was no increase in the risk of hypoglycemia compared with the placebo + insulin combination (14% in the vildagliptin group and 16.4% in the placebo group). 2 patients in the vildagliptin group and 6 patients in the placebo group developed severe hypoglycemia. At the time of completion of the study, the drug had no effect on the average body weight (body weight increased by +0.6 kg compared with in vildagliptin group and in the placebo group remained unchanged). Violations of the nervous system: often - headache, unknown - asthenia. Violations of the gastrointestinal tract: often - nausea, gastroesophageal reflux; infrequently - diarrhea, flatulence. General disorders and disorders at the injection site: often - chills. Metabolism and nutrition disorders: often - hypoglycemia. When using Galvus at a dose of 50 mg 2 times / day in combination with sulfonylurea drugs and metformin. Cancellation incidents the drug associated with AEs in the combination therapy group with vildagliptin, metformin and glimepiride was not observed. In the placebo, metformin and glimepiride combination therapy group, the incidence of adverse events was 0.6%. Hypoglycemia was often observed in both groups (5.1% in the combination group with vildagliptin, metformin and glimepiride and 1.9% in the combination group of placebo, metformin and glimepiride). 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 found (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group). Violations of the nervous system: often - dizziness, tremor,asthenia. Disorders of metabolism and nutrition: often - hypoglycemia. Disorders of the skin and subcutaneous tissues: often - hyperhidrosis. Post-registration studies During the post-registration studies, the following adverse reactions were identified (because messages were received on a voluntary basis from a population of uncertain size, reliably it is not possible to determine the frequency of development of these adverse events, and therefore they are classified as unknown frequency): hepatitis (reversible upon discontinuation of therapy ), urticaria, pancreatitis, bullous and exfoliative skin lesions, arthralgia, in rare cases severe, myalgia, increased activity of liver enzymes. The patient must be warned that if any of the side effects indicated in the instructions are aggravated, or if any other side effects are noticed, not indicated in the instructions should be reported to the doctor.
Overdose
Vildagliptin is well tolerated when used at a dose of up to 200 mg / day. When using the drug at a dose of 400 mg / day, muscle pain may occur, rarely - light and transient paresthesias, fever, edema, and a transient increase in lipase activity (higher than VGN 2 times) . By increasing the dose of vildagliptin to 600 mg / day, it is possible to develop edema of the extremities, accompanied by paresthesias and increased activity of CPK, C-reactive protein and myoglobin, AST activity. All symptoms of overdose and changes in laboratory parameters are reversible after discontinuation of the drug. Removal of the drug from the body through dialysis is unlikely. However, the main hydrolytic metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.
Interaction with other drugs
Vildagliptin has a low potential for drug interaction. Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes, nor does it inhibit or induce these enzymes, it is unlikely that vildagliptin interacts with drugs that are substrates, inhibitors or inducers of P450 (CYP). With simultaneous use of vildagliptin also does not affect the metabolic rate of drugs that are enzyme substrates: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5.Clinically significant interaction of vildagliptin with drugs most often used in the treatment of type 2 diabetes (glibenclamide, pioglitazone, metformin) or with a narrow therapeutic range (amlodipine, digoxin, ramipril, simvastatin, valsartan, warfarin) has not been established. glands, sympathomimetics can reduce the hypoglycemic effect of vildagliptin, as well as other oral antidiabetic drugs. The incidence of angioedema was higher e with simultaneous use of vildagliptin with ACE inhibitors, while it was similar to that in the control group. In most cases, angioedema was of moderate severity and was resolved on its own during the continuation of therapy with vildagliptin.
special instructions
In preclinical studies, when used in doses 200 times higher than those recommended for humans, the drug did not cause fertility disorders. When insulin therapy is needed, Galvus is used only in combination with insulin. The drug is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Heart failureSince the data on the use of vildagliptin in patients with CHF III FC according to NYHA classification (see Table 1 below) are limited and do not allow a final conclusion, it is recommended with caution use of the drug Galvus in patients of this category. It is not recommended to use vildagliptin in patients with CHF IV FC according to the NYHA classification, due to the lack of data from clinical studies on the use of vildagliptin in patients of this group.