Galvus®

Brand Novartis

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Available since: 2019-09-19

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Clinical Pharmacology

The preparation Galvus Met includes 2 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 class of biguanides. The combination of these components allows you to more effectively control the concentration of blood glucose in patients with type 2 diabetes within 24 hours.

Vildagliptin

Vildagliptin is a member of the pancreatic islet stimulator class that selectively inhibits the enzyme DPP-4, which destroys type-1 glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP).

Rapid and complete inhibition of the activity of DPP-4 causes an increase in both basal and food-stimulated secretion of GLP-1 and HIP from the intestine into the systemic circulation throughout the day.

Increasing levels 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. The degree of improvement in β-cell function depends on the degree of their initial damage, so in individuals without diabetes mellitus (with a normal glucose concentration in the blood plasma), vildagliptin does not stimulate insulin secretion and does not reduce the glucose concentration.

By increasing levels of endogenous GLP-1, vildagliptin increases the sensitivity of α-cells to glucose, which leads to an improvement in the glucose-dependent regulation of glucagon secretion. A decrease in elevated glucagon concentration after a meal, in turn, causes a decrease in insulin resistance.

An increase in the insulin / glucagon ratio on the background of hyperglycemia, caused by 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, against the background of vildagliptin, there was a decrease in plasma lipid concentration after a meal, but this effect is not associated with its effect on GLP-1 or HIP and improved function of pancreatic islet cells.

It is known that an increase in the concentration of GLP-1 may lead to a slower gastric emptying, but this effect is not observed when using vildagliptin.

When using vildagliptin in 5759 patients with type 2 diabetes mellitus for 52 weeks as monotherapy or in combination with metformin, sulfonylurea derivatives, thiazolidinedione, or insulin, there was a significant long-term decrease in the concentration of glycated hemoglobin (HbA_1s) and blood glucose on an empty stomach.

Metformin

Metformin improves glucose tolerance in patients with type 2 diabetes, reducing plasma glucose concentrations both before and after meals. Metformin reduces the production of glucose by the liver, slows down the absorption of glucose in the intestine and reduces insulin resistance by increasing glucose uptake and utilization of peripheral tissues. Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia in patients with type 2 diabetes or in healthy individuals (except in special cases). Drug therapy does not lead to the development of hyperinsulinemia. When using metformin insulin secretion does not change, while insulin levels in the blood plasma on an empty stomach and during the day may decrease.

Metformin induces intracellular glycogen synthesis, acting on glycogen synthase, and enhances glucose transport by certain membrane glucose transfer proteins (GLUT-1 and GLUT-4).

With the use of metformin, there is a favorable effect on lipoprotein metabolism: a decrease in the concentration of total cholesterol, LDL cholesterol and triglycerides, which is not associated with the effect of the drug on the concentration of glucose in plasma.

Vildagliptin + Metformin

When using combination therapy with vildagliptin and metformin in 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 HbA_1s) and an increase in the proportion of patients in whom the decrease in HbA concentration_1s amounted to at least 0.6–0.7% (compared with the group of patients who continued to receive only metformin).

In patients receiving the combination of vildagliptin and metformin, a statistically significant change in body weight compared with the initial state was not observed. 24 weeks after the start of treatment in groups of patients who received vildagliptin in combination with metformin, there was a decrease in BAP and DAD in patients with arterial hypertension.

When using the combination of vildagliptin and metformin as the initial therapy of patients with type 2 diabetes mellitus, a dose-dependent decrease in HbA values was observed for 24 weeks._1s and body weight compared with monotherapy with these drugs. Cases of hypoglycemia were minimal in both treatment groups.

When using vildagliptin (50 mg 2 times a day) together / without metformin in combination with insulin (average dose - 41 U) in patients in a clinical study, HbA indicator_1s statistically significantly decreased - by 0.72% (initial indicator - on average 8.8%). The incidence of hypoglycemia in the treated group was comparable to the incidence of hypoglycemia in the placebo group.

When using vildagliptin (50 mg 2 times a day) together with metformin (≥1500 mg) in combination with glimepiride (≥4 mg / day) in patients in a clinical trial, the HbA indicator_1s statistically significantly decreased - by 0.76% (from the average level - 8.8%).

Pharmacokinetics

Vildagliptin

Suction. When taken on an empty stomach, vildagliptin is rapidly absorbed, T_max - 1.75 h after administration. When taken simultaneously with food, the absorption rate of vildagliptin decreases slightly: there is a decrease in C_max by 19% and an increase in T_max up to 2.5 hours. However, food intake does not affect the degree of absorption and AUC.

Vildagliptin is rapidly absorbed, and its absolute bioavailability after oral administration is 85%. C_max 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 red blood cells. The distribution of vildagliptin is supposedly extravascular, V_ss after the on / in the introduction of 71 liters.

Metabolism. Biotransformation is the main route of vildagliptin excretion. In the human body, 69% of the drug dose is converted. The main metabolite is LAY151 (57% of the dose) is pharmacologically inactive and is the product of cyanocomponent hydrolysis. About 4% of the dose of the drug undergoes amide hydrolysis.

In experimental studies, there is a positive effect of DPP-4 on the hydrolysis of the drug. Vildagliptin is not metabolized with the participation of cytochrome P450 isoenzymes. According to research in vitro, vildagliptin is not a substrate of P450 isoenzymes, does not inhibit and does not induce cytochrome P450 isoenzymes.

Derivation. After ingestion, about 85% of the dose is excreted in the urine and 15% through the intestine, the renal excretion of unchanged vildagliptin is 23%. With a / in the introduction of the average T_1/2 reaches 2 h, the total plasma clearance and renal clearance of vildagliptin are 41 and 13 l / h, respectively. T_1/2 after ingestion is about 3 hours, regardless of dose.

Special patient groups

Gender, body mass index and ethnicity do not affect vildagliptin pharmacokinetics.

Liver dysfunction. In patients with mild and moderately impaired liver function (6–10 points according to the classification Child-pugh) after a single use of the drug, there is a decrease in bioavailability of vildagliptin by 20 and 8%, respectively.In patients with severe liver failure (12 points according to the classification Child-pugha) bioavailability of vildagliptin is increased by 22%. The maximum change in bioavailability of vildagliptin, an increase or decrease of up to 30% on average is not clinically significant. The correlation between the severity of liver dysfunction and the bioavailability of the drug was not detected.

Impaired renal function. In patients with mild, moderate and severe renal dysfunction, and patients with end-stage chronic renal failure on hemodialysis, there is an increase in C_max by 8–66% and AUC by 32–134%, not correlating with the severity of renal dysfunction, as well as an increase in AUC of the inactive metabolite LAY151 1.6–6.7 times, depending on the severity of the disorder. T_1/2 vildagliptin does not change. In patients with impaired mild renal function, dose adjustment of vildagliptin is not required.

Patients ≥65 years old. The maximum increase in bioavailability of the drug by 32% (increase in_max 18%) in people older than 70 years is not clinically significant and does not affect the inhibition of DPP-4.

Patients ≤18 years. The pharmacokinetic features of vildagliptin in children and adolescents under 18 years of age have not been established.

Metformin

Suction. The absolute bioavailability of metformin when administered orally in a dose of 500 mg on an empty stomach was 50–60%. T_max in plasma - 1.81–2.69 h after administration. With increasing doses of the drug from 500 to 1500 mg or in doses from 850 to 2250 mg orally, a slower increase in pharmacokinetic parameters was noted (than would be expected for a linear relationship). This effect is due not so much to a change in the elimination of the drug as to a slowdown in its absorption. Against the background of food intake, the extent and rate of absorption of metformin also decreased slightly. So, with a single dose of the drug in a dose of 850 mg with food there was a decrease in C_max and AUC by about 40 and 25% and an increase in T_max for 35 min The clinical significance of these facts has not been established.

Distribution. With a single ingestion in a dose of 850 mg apparent V_d metformin is (654 ± 358) l. The drug is practically not bound to plasma proteins, while sulfonylurea derivatives are associated with them by more than 90%. Metformin enters the red blood cells (probably an increase in this process over time). When using metformin according to the standard scheme (standard dose and frequency of administration) C_ss drug in blood plasma is reached within 24–48 hours and, as a rule, does not exceed 1 μg / ml. In controlled clinical trials with_max metformin in plasma did not exceed 5 μg / ml (even when taken in high doses).

Derivation. With a single / in the introduction of metformin to healthy volunteers, it is excreted by the kidneys in unchanged form. In this case, the drug is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted in the bile. Since the renal clearance of metformin is about 3.5 times that of creatinine, the main way to eliminate the drug is tubular secretion. When ingested, about 90% of the absorbed dose is eliminated through the kidneys during the first 24 hours, with T_1/2 from blood plasma is about 6.2 h. T_1/2 Metformin from whole blood is about 17.6 h, which indicates the accumulation of a significant part of the drug in red blood cells.

Special patient groups

Floor. No effect on the pharmacokinetics of metformin.

Liver dysfunction. In patients with hepatic insufficiency, the pharmacokinetic features of metformin were not studied.

Impaired renal function. In patients with reduced kidney function (as measured by creatinine clearance) T_1/2 Metformin from plasma and whole blood increases, and its renal clearance decreases in proportion to the decrease in creatinine clearance.

Patients ≥65 years old. According to limited data from pharmacokinetic studies, in healthy people ≥65 years, there was a decrease in the total plasma clearance of metformin and an increase in T_1/2 and C_max compared to young faces.These pharmacokinetic characteristics of metformin in people over 65 years of age are probably associated with changes in renal function. Therefore, in patients older than 80 years, the appointment of the drug Galvus Met is possible only with normal clearance of creatinine.

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

Patients of different ethnicity. There is no evidence of the influence of the ethnicity of patients on the pharmacokinetic characteristics of metformin. In controlled clinical trials of metformin in patients with diabetes mellitus type 2 of different ethnicity, the hypoglycemic effect of the drug was manifested to the same extent.

Vildagliptin + Metformin

Studies have shown bioequivalence in terms of AUC and C_max Galvus Met in 3 different dosages (50 mg + 500 mg, 50 mg + 850 mg and 50 mg + 1000 mg) and vildagliptin, and metformin, taken in appropriate doses as separate tablets.

Food does not affect the degree and rate of absorption of vildagliptin as part of Galvus Met. C values_max and AUC of metformin in the composition of the drug Galvus Met, while taking it with food, decreased by 26 and 7%, respectively. In addition, on the background of food intake, the absorption of metformin was slowed down, which led to an increase in T_max (2 to 4 hours). Similar change With_max and AUC on the background of food intake was also observed when using metformin separately, but in the latter case, the changes were less significant. The effect of food on the pharmacokinetics of vildagliptin and metformin as part of Galvus Met did not differ from that when taking both drugs separately.

Indications

Type 2 diabetes mellitus (in combination with diet therapy and exercise):
- with insufficient effectiveness of monotherapy with vildagliptin or metformin.
- in patients previously receiving the combination therapy with vildagliptin and metformin in the form of monodrugs.

Composition

1 coated tablet contains: vildagliptin 50 mg, metformin hydrochloride 1000 mg.
Excipients: hyprolosis, magnesium stearate, hypromellose, titanium dioxide (E171), macrogol 4000, talc, iron yellow oxide (E172).

Galvus® is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Galvus Met	Novartis	Switzerland	pills
Galvus	Novartis	Switzerland	pills

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Dosage and Administration

The drug is administered orally. Dosing regimen Galvus Met should be selected individually depending on the effectiveness and tolerability. 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 treatment regimens of vildagliptin and / or metformin already used in the patient. To reduce the severity of side effects from the digestive system, characteristic of metformin, Galvus Met take during meals.
Initial dose of Galvus Met with vildagliptin monotherapy
Treatment with Galvus Met can be started with a single tablet at a dosage of 50 mg / 500 mg 2 times a day, and after evaluating the therapeutic effect, the dose can be gradually increased.
The initial dose of Galvus Met with the ineffectiveness of metformin monotherapy
Depending on the dose of metformin already taken, Galvus Met treatment can be started with one tablet at a dosage of 50 mg / 500 mg, 50 mg / 850 mg or 50 mg / 1000 mg 2 times a day.
Initial dose of Galvus Met in patients previously receiving the combination therapy with vildagliptin and metformin as separate pills
Depending on the doses already taken of vildagliptin or metformin, treatment with Galvus Met should be started with a pill as close as possible to the existing treatment 50 mg / 500 mg, 50 mg / 850 mg or 50 mg / 1000 mg, and titrated by effect.
Patients with impaired renal function
Galvus Met should not be used in patients with renal insufficiency or impaired renal function, with serum creatinine levels> 1.5 mg% (> 135 μmol / L) for men and ≥1.4 mg% (> 110 μmol / L) for women
Use in patients aged> 65 years
Metformin is excreted by the kidneys. Since in patients over 65 years of age, there is often a decrease in renal function, Galvus Met is prescribed for this category of patients in the minimum dose that ensures normalization of glucose levels only after determining CC for confirming normal renal function. When using the drug in patients older than 65 years, it is necessary to regularly monitor renal function.
Use in patients aged ≤ 18 years
Since the safety and efficacy of Galvus Met in children and adolescents under 18 years of age has not been studied, the drug is not recommended for use in this category of patients.

Adverse reactions

The following criteria were used to assess the incidence of adverse events (AE): very often (≥1 / 10); often (≥1 / 100, undesirable reactions, possibly associated with the use of combination therapy with vildagliptin and metformin (the incidence of which in the vildagliptin + metformin group differed from that of placebo and metformin by more than 2%):
From the nervous system:
often - headache, dizziness, tremor.
When using vildagliptin in combination with metformin in various doses, hypoglycemia was observed in 0.9% of cases (for comparison, in the placebo group in combination with metformin, it was 0.4%).
The incidence of AE on the part of the digestive system during vildagliptIMetformin combined therapy was 12.9%. When using metformin, similar AEs were observed in 18.1% of patients.
In groups of patients who received Metformin in combination with vildagliptin, gastrointestinal disturbances were observed 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 studies of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin as monotherapy.
When using vildagliptin as monotherapy:
From the nervous system:often - dizziness, headache;
From the digestive system:often - constipation;
Dermatological reactions:sometimes a skin rash;
From the musculoskeletal system:often - arthralgia.
Other:sometimes - peripheral edema
When using combination therapy with vildagliptin + metformin, there was no clinically significant increase in the incidence of the above-mentioned adverse events, which were observed when taking vildagliptin.
Against monotherapy with vildagliptin or metformin, the incidence of hypoglycemia was 0.4% (sometimes).
Vildagliptin monotherapy and vildagliptin + metformin combination therapy had no effect on patient weight.
Long-term clinical studies of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks when using vildagliptin as monotherapy. Postmarketing research:
During post-marketing studies, the following adverse reactions were identified: frequency unknown - urticaria.
Changes from laboratory indicators When using vildagliptin at a dose of 50 mg 1 time per day or 100 mg per day (in 1 or 2 doses) for 1 year, the frequency of increased activity of alanine namitransferase (AlAt) and aspartate aminotransferase (AsAt) is more than 3 times as compared with the upper limit of normal (VGN) was 0.3% and 0.9%, respectively (0.3% in the placebo group).
Increased activity of AlAt and AsAt, as a rule, was asymptomatic, did not increase and was not accompanied by cholestasis or jaundice.
When using metformin as monotherapy:
Metabolic disorders:very rarely - reduced vitamin B absorption₁₂lactic acidosis. On the part of the digestive system: very often - nausea, vomiting, diarrhea, abdominal pain, loss of appetite; often - metallic taste in the mouth.
Liver and biliary tract:very rarely - violations of the biochemical parameters of liver function.
From the skin and subcutaneous tissue: very rarely - skin reactions (in particular, erythema, pruritus, urticaria).
Since the decrease in the absorption of vitamin B₁₂ and a decrease in its serum concentration on the background of metformin was observed very rarely in patients who received the drug for a long time, this undesirable phenomenon has no clinical significance. Consider the possibility of reducing the absorption of vitamin B₁₂ follows only in patients with megaloblastic anemia.
Individual cases of impaired biochemical parameters of liver function or hepatitis, which were observed during the use of metformin, were resolved after discontinuation of metformin.

Contraindications

renal failure or impaired renal function: with serum creatinine level ≥1.5 mg% (> 135 μmol / liter) for men and ≥1.4 mg% (> 110 μmol / liter) for women;
acute conditions that are at risk of developing renal dysfunction: dehydration (with diarrhea, vomiting), fever, severe infectious diseases, hypoxia (shock, sepsis, renal infections, bronchopulmonary diseases);
acute and chronic heart failure, acute myocardial infarction, acute cardiovascular failure (shock);
respiratory failure;
abnormal liver function;
acute or chronic metabolic acidosis (including diabetic ketoacidosis with or without coma). Diabetic ketoacidosis should be adjusted by insulin therapy;
lactic acidosis (including a history);
the drug is not prescribed 2 days before surgery, radioisotope, x-ray studies with the introduction of contrast agents and within 2 days after their implementation;
pregnancy;
lactation period;
type 1 diabetes;
chronic alcoholism, acute alcohol poisoning;
compliance with low-calorie diets (less than 1000 calories per day);
children's age up to 18 years (efficiency and safety of use is not established);
Hypersensitivity to vildagliptin or metformin or any other components of the drug.

Drug interactions

Vildagliptin + Metformin
With simultaneous use of vildagliptin (100 mg 1 time per day) and metformin (1000 mg 1 time per day), there were no clinically significant pharmacokinetic interactions between them. Neither during clinical trials, nor during the wide clinical use of Galvus Met in patients who received other concomitant drugs and substances, unforeseen interactions have been identified.

Vildagliptin
Vildagliptin has a low potential for drug interaction. Since vildagliptin is not a substrate of cytochrome P (CYP) 450 enzymes, nor does it inhibit or induce these enzymes, its interaction with drugs that are substrates, inhibitors or inducers of P (CYP) 450 is unlikely. With simultaneous use of vildagliptin does not affect the metabolic rate of drugs that are enzyme substrates: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 / 5. Clinical 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.

Metformin
Furosemide increases C_max and AUC of metformin, but does not affect its renal clearance. Metformin reduces C_max and AUC of furosemide and also does not affect its renal clearance.
Nifedipine increases absorption, C_max and AUC of metformin; in addition, it increases its excretion in the urine. Metformin has virtually no effect on the pharmacokinetic parameters of nifedipine.
Glibenclamide does not affect the pharmacokinetic / pharmacodynamic parameters of metformin. Metformin generally reduces C_maxand AUC of glibenclamide, however, the magnitude of the effect varies greatly. For this reason, the clinical significance of such an interaction remains unclear.
Organic Cations, for example, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin, etc., which are excreted by the kidney by canalicular secretion, can theoretically interact with metformin, since they compete for common renal tubular transport systems. Thus, cimetidine increases both plasma / blood metformin concentration 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 with drugs that affect kidney function or the distribution of metformin in the body.
Other drugs- Some drugs can cause hyperglycemia and reduce the effectiveness of hypoglycemic agents. Such drugs include thiazides and other diuretics, glucocorticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium antagonists and isoniazid. When prescribing such concomitant medications 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. It is not recommended to take danazol at the same time in order to avoid the hyperglycemic action of the latter. If necessary, treatment with danazol and after discontinuation of the latter requires a dose adjustment of metformin under the control of glucose levels. Chlorpromazine: when taken in large doses (100 mg per day) increases blood glucose levels, reducing the release of insulin. When treating neuroleptics and after discontinuation of the latter, a dose adjustment of the drug is required under the control of glucose level.
Iodine radiopaque agents: Radtological study using iodine radiopaque agents may cause the development of lactic acidosis in patients with diabetes mellitus against the background of functional renal failure.
Beta-2 injectable sympathomimetics: increase glycemia due to beta-2 receptor stimulation. In this case, glycemia control is necessary. If necessary, the appointment of insulin is recommended. With simultaneous use of metformin with sulfonylurea derivatives, insulin, acarbose, salicylates, hypoglycemic action may increase.
Since the use of metformin in patients with acute alcohol intoxication increases the risk of developing lactic acidosis (especially when fasting, wasting, or liver failure), during treatment with Galusus Met should refrain from the use of alcohol and medicines containing ethyl alcohol.

Pregnancy and Lactation

In experimental studies when prescribing vildagliptin in doses 200 times higher than recommended, the drug did not cause impairment of fertility and early embryo development and did not have a teratogenic effect on the fetus. When prescribing vildagliptin in combination with metformin at a ratio of 1:10, no teratogenic effect on the fetus was also detected.

Since pregnant women do not have sufficient data on the use of the drug Galvus Met, the use of the drug during pregnancy is contraindicated.

When violations of glucose metabolism in pregnant women, there is an increase in the risk of developing congenital anomalies, as well as the frequency of neonatal morbidity and mortality. For normalization of blood glucose levels during pregnancy, insulin monotherapy is recommended.

Since it is not known whether vildagliptin or metformin is excreted in human breast milk, use of Galvus Met during breastfeeding is contraindicated.

Special instructions

In patients receiving insulin, Galus Meth cannot replace insulin.
Vildagliptin
Liver function disorders
Since, when using vildagliptin, an increase in the activity of aminotransferases (usually without clinical manifestations) was noted somewhat more often than in the control group, before prescribing Galvus Met, and also regularly during drug treatment, it is recommended to determine the biochemical indicators of liver function. If a patient has an increased activity of aminotransferases, this result should be confirmed by repeated research, and then the biochemical indicators of liver function should be determined regularly until they normalize. If the excess of the activity of AsAt or AlAt is 3 or more times higher than VGN is confirmed by repeated research, the drug is recommended to be canceled.

Metformin
Lactic acidosis
Lactic acidosis is a very rare but severe metabolic complication that occurs when metformin accumulates in the body. Lactic acidosis against the use of metformin was observed mainly in patients with diabetes mellitus with high renal insufficiency. The risk of developing lactic acidosis is increased in patients with diabetes mellitus that is difficult to treat, with ketoacidosis, prolonged fasting, prolonged alcohol abuse, liver failure, and diseases causing hypoxia.
With the development of lactic acidosis, shortness of breath, abdominal pain and hypothermia, followed by coma. The following laboratory parameters are of diagnostic value: a decrease in blood pH, serum lactate concentration above 5 nmol / l, as well as an increased anion interval and an increased lactate / pyruvate ratio. If metabolic acidosis is suspected, the drug should be discontinued, and the patient should be hospitalized immediately.
Kidney function control
Since metformin is largely excreted by the kidneys, the risk of its accumulation and the development of lactic acidosis is the higher, the more renal function is impaired. When using Galvus Met, you should regularly evaluate your kidney function, especially in the following conditions that contribute to its violation: the initial phase of treatment with antihypertensive drugs, hypoglycemic agents or NSAIDs. As a rule, kidney function should be assessed before starting Galvus Meg treatment, and then at least 1 time per year for patients with normal renal function and at least 2–4 times per year for patients with serum creatinine above VGN. In patients with a high risk of impaired renal function, it should be monitored more than 2-4 times a year. If signs of deterioration in kidney function appear, Galvus Met should be abolished.
Use of iodine-containing radiopaque agents for intravascular administration
When conducting radiological studies requiring intravascular administration of iodine-containing radiopaque agents, Galvus Met should be temporarily canceled (during the study, or directly in front of it, and also within 48 hours after the study), since intravascular administration of iodine-containing radiocontrast agents may lead to a sharp deterioration in function kidney and increase the risk of lactic acidosis. You can resume taking Galvus Met only after re-evaluating kidney function.
Hypoxia
In acute cardiovascular insufficiency (shock), acute heart failure, acute myocardial infarction and other conditions characterized by hypoxia, lactic acidosis and prerenal acute renal failure may develop. When the above conditions occur, the drug should be immediately canceled.
Surgical interventions
At the time of surgical interventions (with the exception of small operations not related to the restriction of food and fluid intake), Galvus Met should be canceled. You can resume taking the drug after the patient begins to eat on his own and it is shown that his kidney function is not impaired.
Alcohol consumption
Alcohol has been found to enhance the effect of metformin on lactate metabolism. Patients should be warned about the inadmissibility of alcohol abuse during the use of Galvus Met.
Vitamin B content₁₂
It has been established that metformin causes an asymptomatic decrease in the serum concentration of vitamin B in approximately 7% of cases.₁₂. Such a decrease in very rare cases leads to the development of anemia. Apparently, after the abolition of metformin and / or replacement therapy with vitamin B₁₂ serum concentration of vitamin b₁₂ quickly normalized. Patients receiving Galvus Met are advised to perform a complete blood count at least once a year and, if any irregularities are detected, determine their cause and take appropriate measures. Apparently, in some patients (for example, in patients with insufficient consumption or impaired absorption of vitamin B₁₂ or calcium) there is a predisposition to reduce the serum concentration of vitamin B₁₂. In such cases, it may be recommended to determine the serum concentration of vitamin B₁₂ at least 1 time in 2-3 years.
Deterioration of patients with type 2 diabetes who previously responded to therapy
If a patient with type 2 diabetes mellitus who previously responded to therapy has signs of deterioration (changes in laboratory parameters or clinical manifestations), and the symptoms are not clearly expressed, then tests should be carried out to detect ketoacidosis and / or lactic acidosis. If acidosis is confirmed in one form or another, you should immediately cancel Galus Met and take appropriate measures.
Hypoglycemia
Typically, patients who receive only Galvus Met have no hypoglycemia, but it can occur on the background of a low-calorie diet (when intense physical exertion is not compensated by caloric intake) or on the background of alcohol consumption. Hypoglycemia is most likely in elderly, debilitated or debilitated patients, as well as on the background of hypopituitarism, adrenal insufficiency or alcohol intoxication. In elderly patients and in those receiving beta-blockers, the diagnosis of hypoglycemia may be difficult.
Reducing the effectiveness of hypoglycemic agents
Under stress (fever, trauma, infection, surgery, etc.) that has arisen in a patient receiving hypoglycemic agents according to a stable scheme, a sharp decrease in the effectiveness of the latter for some time is possible. In this case, it may be necessary to cancel Galvus Met and prescribe insulin. You can resume treatment with Galvus Met after the end of the acute period.

Overdosage

Vildagliptin
Vildagliptin is well tolerated when administered at a dose of up to 200 mg / day. With the use of the drug at a dose of 400 mg / day, muscle pain can occur, rarely, light and transient paresthesias, fever, edema, and a transient increase in lipase concentration (2 times higher than VGN). Increasing the dose of vildagliptin to 600 mg / day may lead to edema of the extremities accompanied by paresthesias and an increase in the concentration of creatinine phosphokinase, AsAt, C-reactive protein and myoglobin. All symptoms of overdose and changes in laboratory parameters disappear 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.

Metformin
There have been several cases of overdose of metformin, including as a result of ingestion of the drug in an amount of more than 50 grams. With overdose of metformin, hypoglycemia was observed in about 10% of cases (however, its connection with the administration of the drug has not been established); in 32% of cases - lactic acidosis was noted. Early symptoms of lactic acidosis are nausea, vomiting, diarrhea, decrease in body temperature, abdominal pain, muscle pain, and there may be an increase in breathing, dizziness, impaired consciousness, and coma. Metformin is eliminated from the blood by hemodialysis (with clearance up to 170 ml / min) without the development of hemodynamic disturbances. Thus, hemodialysis can be used to remove metformin from the blood during an overdose of the drug.
In the case of overdose, it is necessary to carry out appropriate symptomatic treatment, based on the patient's condition and clinical manifestations.

Studies and clinical trials of Galvus (Click to expand)