Galvus Met^® (Tablets) Instructions for Use

ATC Code

A10BD08 (Metformin and vildagliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Vildagliptin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; combinations of oral hypoglycemic drugs

Pharmacological Action

Mechanism of action

The drug Galvus Met^® contains two hypoglycemic agents with different mechanisms of action: Vildagliptin, which belongs to the class of dipeptidyl peptidase-4 (DPP-4) inhibitors, and metformin (in the form of hydrochloride), a representative of the biguanide class. The combination of these components allows for more effective control of blood glucose concentration in patients with type 2 diabetes mellitus (T2DM) over 24 hours.

Vildagliptin, a representative of the class of pancreatic islet stimulators, selectively inhibits the enzyme DPP-4, improving glycemic control. Inhibition of DPP-4 activity leads to an increase in both basal and postprandial endogenous levels of incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Metformin reduces glucose production by the liver, reduces glucose absorption in the intestine, and reduces insulin resistance by enhancing glucose uptake and utilization by peripheral tissues.

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

Pharmacodynamic effects

Vildagliptin+metformin

The safety and efficacy of the individual components of the drug, as well as their simultaneous use, have been previously studied in clinical trials, which established an additional positive effect of adding vildagliptin to metformin therapy in patients with inadequately controlled T2DM.

In clinical trials, Vildagliptin did not affect body weight when added to metformin.

Vildagliptin

The use of vildagliptin in patients with T2DM leads to rapid and complete inhibition of DPP-4 activity, which is observed for 24 hours.

By increasing the concentration of GLP-1 and GIP, Vildagliptin increases the sensitivity of pancreatic β-cells to glucose, leading to improved glucose-dependent insulin secretion. The use of vildagliptin at doses of 50 mg and 100 mg per day in patients with T2DM caused a significant improvement in β-cell function parameters.

The degree of improvement in β-cell function depends on the degree of their initial damage; thus, in individuals without diabetes (with normal plasma glucose concentration), Vildagliptin does not stimulate insulin secretion and does not reduce glucose concentration. By increasing the concentration of endogenous GLP-1, Vildagliptin increases the sensitivity of α-cells to glucose, leading to improved glucose-dependent regulation of glucagon secretion. The reduction in elevated postprandial glucagon concentration, in turn, leads to a decrease in insulin resistance.

The increase in the insulin/glucagon ratio against the background of hyperglycemia, due to an increase in incretin hormone concentrations, causes a decrease in glucose production by the liver both during and after meals, leading to a decrease in plasma glucose concentration.

In addition, a decrease in plasma lipid concentration after meals was observed during the use of vildagliptin, which is not related to the improvement in pancreatic islet cell function mediated by the effect of vildagliptin on incretin hormone activity.

It is known that an increase in GLP-1 concentration can lead to delayed gastric emptying; however, such an effect is not observed during the use of vildagliptin.

Metformin

Metformin improves glucose tolerance in patients with T2DM, reducing plasma glucose concentration both before and after meals.

Unlike sulfonylurea derivatives, metformin does not cause hypoglycemia in patients with T2DM or in healthy individuals (except in special cases).

Therapy with the drug does not lead to the development of hyperinsulinemia. When using metformin, insulin secretion does not change, while fasting and daily plasma insulin concentrations may decrease.

When metformin was used at therapeutic doses in medium-duration clinical trials, as well as in long-term clinical trials, a favorable effect on lipoprotein metabolism was noted, regardless of its effect on glycemia: a decrease in the concentration of total cholesterol, LDL cholesterol, and triglycerides.

Pharmacokinetics

Vildagliptin+metformin

Studies have shown bioequivalence in terms of AUC and C_max in plasma for the drug Galvus Met^® in three different dosages (50 mg+500 mg, 50 mg+850 mg, and 50 mg+1000 mg) and vildagliptin and metformin taken in corresponding doses as separate tablets.

Food intake does not affect the extent and rate of absorption of vildagliptin as part of the drug Galvus Met^®. The C_max and AUC values of metformin as part of the drug Galvus Met^® when taken simultaneously with food decreased by 26% and 7%, respectively. In addition, food intake slowed the absorption of metformin, leading to an increase in the time to reach maximum concentration (T_max, from 2 to 4 hours). A similar change in C_max and AUC with food intake was also noted when metformin was used 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 the drug Galvus Met^® did not differ from that when both drugs were taken separately.

Vildagliptin

Absorption

When taken orally on an empty stomach, Vildagliptin is rapidly absorbed, and its C_max is reached 1.75 hours after administration.

When taken simultaneously with food, the rate of absorption of vildagliptin decreases slightly: a 19% decrease in C_max and an increase in the time to reach it to 2.5 hours are noted. However, food intake does not affect the extent of absorption and AUC. Vildagliptin is rapidly absorbed, and its absolute bioavailability after oral administration is 85%. C_max and AUC in the therapeutic dose range increase approximately proportionally to the dose.

Distribution

The degree of binding of vildagliptin to plasma proteins is low (9.3%). The drug is evenly distributed between plasma and erythrocytes. The distribution of vildagliptin is presumably extravascular; the volume of distribution at steady state after intravenous administration (V_ss) is 71 L.

Metabolism

Biotransformation is the main route of elimination of vildagliptin. In humans, 69% of the drug dose undergoes transformation. 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 drug dose undergoes amide hydrolysis.

In in vivo studies in animals with DPP-4 deficiency, a partial positive influence of this enzyme on the hydrolysis of vildagliptin was noted. Vildagliptin is not metabolized by cytochrome P450 isoenzymes. According to in vitro studies, Vildagliptin does not inhibit or induce cytochrome CYP450 isoenzymes.

Elimination

After oral administration of radiolabeled vildagliptin, about 85% of the dose is excreted by the kidneys and 15% through the intestine; renal excretion of unchanged vildagliptin is 23%. With intravenous administration in healthy volunteers, the average T_1/2 reaches 2 hours; the total plasma clearance and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively. T_1/2 after oral administration is about 3 hours, regardless of the dose.

Linearity

Vildagliptin is rapidly absorbed; absolute bioavailability after oral administration is 85%. C_max and AUC of vildagliptin increase approximately proportionally to the dose when used in the therapeutic dose range.

Pharmacokinetics in special cases

Gender. In patients of different genders, ages, and body mass index (BMI), no changes in the pharmacokinetics of vildagliptin were noted. The degree of inhibition of DPP-4 activity by vildagliptin does not change depending on gender.

Obesity. No effect of BMI on the pharmacokinetic parameters of vildagliptin was noted. The degree of inhibition of DPP-4 activity by vildagliptin does not change depending on BMI.

Ethnicity. Ethnicity does not affect the pharmacokinetics of vildagliptin.

Patients with impaired liver function. In patients with mild and moderate liver impairment (6-10 points on the Child-Pugh scale) after a single oral dose of vildagliptin 100 mg, a decrease in the bioavailability of vildagliptin by 8% and 20%, respectively, was noted. In patients with severe liver impairment (12 points on the Child-Pugh scale), the bioavailability of vildagliptin increased by 22%. The maximum change in the bioavailability of vildagliptin (increase or decrease), on average up to 30%, is not clinically significant. No correlation was found between the severity of liver function impairment and the bioavailability of the drug.

Patients with impaired renal function. In patients with mild, moderate, or severe renal impairment, the AUC of vildagliptin increased compared to healthy volunteers by 1.4, 1.7, and 2 times, respectively. The AUC of the metabolite LAY151 increased by 1.6, 3.2, and 7.3 times, and the metabolite BQS867 by 1.4, 2.7, and 7.3 times in patients with mild, moderate, and severe renal impairment, respectively. Limited data in patients with end-stage chronic kidney disease (CKD) indicate that the parameters in this group are similar to those in patients with severe renal impairment. The concentration of the LAY151 metabolite in patients with end-stage CKD increased 2-3 times compared to the concentration in patients with severe renal impairment. The elimination of vildagliptin during hemodialysis is limited (3% during 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 by 32% (increase in C_max by 18%), noted in patients over 70 years of age without somatic pathology when taking vildagliptin at a dose of 100 mg/day, is not clinically significant and does not affect DPP-4 inhibition.

Use in patients under 18 years of age. The pharmacokinetics of metformin in children aged at least 10 years has not been studied. The pharmacokinetic features of vildagliptin in children and adolescents under 18 years of age have not been established.

Metformin

Absorption

The absolute bioavailability of metformin when taken orally at a dose of 500 mg on an empty stomach was 50-60%. C_max is reached 2.5 hours after administration. When the single dose of the drug was increased from 500 mg to 1500 mg, and from 850 mg to 2250 mg orally, a lack of dependence of pharmacokinetic parameters on the dose was noted.

This effect is due not so much to a change in drug elimination as to a slowdown in its absorption. Against the background of food intake, the extent and rate of metformin absorption also decreased somewhat. Thus, with a single dose of the drug at a dose of 850 mg with food, a decrease in C_max by approximately 40%, AUC by 25%, and an increase in T_max by 35 minutes were noted.

The clinical significance of these facts has not been established.

Distribution

After a single oral dose of 850 mg, the apparent V_d of metformin is 654±358 L. Metformin practically does not bind to plasma proteins, while sulfonylurea derivatives bind to them by more than 90%. Metformin penetrates into erythrocytes (this process is likely enhanced over time). When metformin is used according to the standard regimen (standard dose and frequency of administration), C_ss in plasma is reached within 24-48 hours and, as a rule, does not exceed 1 μg/ml. In controlled clinical trials, the C_max of metformin in plasma did not exceed 5 μg/ml (even when taken at maximum doses).

Metabolism

After a single intravenous administration of metformin to healthy volunteers, it is excreted by the kidneys unchanged. The drug is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted in bile.

Elimination

Since the renal clearance of metformin is approximately 3.5 times higher than the creatinine clearance (CrCl), the main route of elimination of the drug is tubular secretion. When taken orally, about 90% of the absorbed dose is excreted by the kidneys within the first 24 hours; the T_1/2 from blood is about 6.2 hours. The T_1/2 of 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

Gender. In male and female patients with T2DM, no significant differences in the pharmacokinetic parameters of metformin were noted. Similarly, clinical trials have not shown any change in the hypoglycemic effect of metformin in men and women with T2DM.

Patients with impaired liver function. In patients with impaired liver function, the study of the pharmacokinetic features of metformin has not been conducted.

Patients with impaired renal function. In patients with impaired renal function (assessed by CrCl), the T_1/2 of metformin from plasma and whole blood increases, and its renal clearance decreases in proportion to the decrease in CrCl.

Use in patients aged ≥65 years. According to limited data from pharmacokinetic studies in healthy volunteers aged ≥65 years, a decrease in the total plasma clearance of metformin and an increase in T_1/2 and C_max were noted compared to younger volunteers. These features of the pharmacokinetics of metformin in persons over 65 years of age are probably primarily associated with changes in renal function, therefore, in patients over 80 years of age, the use of the drug Galvus Met^® is possible only with normal CrCl.

Use in patients under 18 years of age. The pharmacokinetics of metformin in children aged at least 10 years has not been studied. The pharmacokinetic features of metformin in children and adolescents under 18 years of age have not been established.

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

Indications

Type 2 diabetes mellitus in adult patients over 18 years of age (in combination with diet therapy and physical exercise)

• With insufficient effectiveness of vildagliptin or metformin monotherapy;
• In patients previously receiving combination therapy with vildagliptin and metformin as single drugs;
• 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 previously treated with insulin therapy at a stable dose and metformin without achieving adequate glycemic control;
• As initial therapy in patients with type 2 diabetes mellitus with insufficient effectiveness of diet therapy, physical exercise, and the need to improve glycemic control.

ICD codes

Dosage Regimen

Tablets

Administered orally. To reduce the severity of gastrointestinal adverse reactions characteristic of metformin, the drug Galvus Met^® should be taken with meals.

The dosage regimen of the drug Galvus Met^® should be selected individually depending on the effectiveness and tolerability of therapy. When using the drug Galvus Met^®, the recommended maximum daily dose of vildagliptin (100 mg) should not be exceeded.

The recommended initial dose of the drug Galvus Met^® should be selected taking into account the duration of diabetes and glycemic parameters, the patient’s condition, and the treatment regimens with vildagliptin and/or metformin previously used in the patient.

If a dose is missed, the missed dose should be taken as soon as possible. Taking a double dose of the drug within 1 day is not recommended.

Initial dose of Galvus Met^® for ineffective vildagliptin monotherapy

Therapy with Galvus Met^® can be started with one tablet of 50 mg+500 mg twice a day; after assessing the therapeutic effect, the dose can be gradually increased.

Initial dose of Galvus Met^® for ineffective metformin monotherapy

Depending on the dose of metformin already taken, treatment with Galvus Met^® can be started with one tablet of 50 mg+500 mg, 50 mg+850 mg, or 50 mg+1000 mg twice a day.

Initial dose of Galvus Met^® in patients previously receiving combination therapy with vildagliptin and metformin as separate tablets

Depending on the doses of vildagliptin or metformin already taken, therapy with Galvus Met^® should be started with a tablet as close as possible in dosage to the existing treatment, 50 mg+500 mg, 50 mg+850 mg, or 50 mg+1000 mg, and the dose should be adjusted depending on effectiveness.

Starting dose of Galvus Met^® as initial therapy in patients with T2DM with insufficient effectiveness of diet therapy and physical exercise

As initial therapy, Galvus Met^® should be used at an initial dose of 50 mg+500 mg once a day and, after assessing the therapeutic effect, the dose should be gradually increased to 50 mg+1000 mg twice a day.

Combination therapy with Galvus Met^® and sulfonylurea derivatives or insulin

The dose of Galvus Met^® is calculated based on a vildagliptin dose of 50 mg twice a day (100 mg/day) and metformin at a dose equal to that previously taken as a single drug.

Patients with impaired renal function

Before starting therapy with metformin-containing drugs (such as Galvus Met^®), GFR should be determined; this indicator should then be monitored at least once a year. In patients at risk of worsening pre-existing renal impairment, as well as in elderly patients, renal function should be monitored more frequently, for example, every 3-6 months.

In patients with moderate renal impairment (with GFR 30-44 ml/min/1.73 m²), the drug should be taken as 1 tablet in a dose of 50 mg + 500 mg once daily; with GFR 45-59 ml/min/1.73 m² the initial dose of Galvus Met^® is 1 tablet in a dose of 50 mg + 500 mg or 50 mg + 850 mg, the daily dose of the drug should not exceed 50 mg + 1000 mg – once daily. In patients with GFR < 60 ml/min, factors contributing to an increased risk of lactic acidosis should be assessed before starting therapy with metformin-containing drugs (such as Galvus Met^®). In patients with GFR < 30 ml/min, the use of Galvus Met^® is contraindicated, which is due to the presence of metformin in the drug.

Depending on the current state of renal function, the following recommendations for the dose of the active substances of the drug should be followed.

If the required dose for one of the 2 active substances is not available when using Galvus Met^®, two separate monodrugs of vildagliptin and metformin should be used instead of the combination drug.

Patients with hepatic impairment

The use of Galvus Met^® is not recommended for patients with clinical or laboratory signs of hepatic impairment, including patients with elevated ALT or AST >3 x ULN prior to treatment initiation.

Use in patients aged ≥65 years

Metformin is excreted by the kidneys. Since patients over 65 years of age often have impaired renal function, the dose of Galvus Met^® in these patients should be adjusted based on renal function parameters. When using the drug in patients over 65 years of age, renal function should be regularly monitored.

Children

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

Adverse Reactions

Vildagliptin+metformin

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

Rare cases of angioedema during therapy with the drug have been observed with a similar frequency in the control group. Most often, cases of angioedema were noted when the drug was used in combination with ACE inhibitors. In most cases, angioedema was mild and resolved spontaneously during continued therapy with vildagliptin.

During therapy with vildagliptin, rare cases of asymptomatic hepatic impairment (including hepatitis) were observed. In most cases, these disorders and deviations of liver function tests from the norm resolved on their own without complications after discontinuation of therapy with the drug. When using vildagliptin at a dose of 50 mg once or twice daily, the frequency of increases in liver enzymes ALT or AST to more than 3 times the ULN was 0.2% or 0.3%, respectively (compared to 0.2% in the control group). The increase in liver enzymes was in most cases asymptomatic, non-progressive and not accompanied by cholestasis or jaundice.

Vildagliptin did not affect body weight when added to metformin.

Gastrointestinal disorders when using metformin are reported very frequently. The frequency of ADRs from the gastrointestinal tract during combination therapy with vildagliptin and metformin hydrochloride was 13.2% (when used at a dose of 50 mg once daily or twice daily). When using metformin monotherapy – 18.1%.

The following are adverse reactions (ADRs) that are possible both with the use of combination therapy with vildagliptin and metformin, and with monodrugs of vildagliptin and metformin.

ADRs are distributed by system-organ classes in accordance with the MedDRA regulatory activity dictionary, indicating the frequency of their occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

Metabolism disorders common – hypoglycemia.

Nervous system disorders common – tremor, headache, dizziness; uncommon – increased fatigue.

Gastrointestinal disorders common – nausea.

Long-term clinical studies lasting up to 2 years did not reveal any changes in the safety profile or unforeseen risks when using vildagliptin in combination with metformin.

Study of the use of the Vildagliptin + metformin combination as initial therapy in type 2 diabetes did not reveal any deviations in the safety profile or unforeseen risks.

In combination with insulin

In controlled clinical studies using vildagliptin 50 mg twice daily in combination with insulin with or without metformin, the frequency of therapy discontinuation due to adverse reactions was 0.3% in the vildagliptin group, while no therapy discontinuations were reported in the placebo group.

The frequency of hypoglycemia was comparable in both groups (14.0% in the vildagliptin group and 16.4% in the placebo group). In the vildagliptin group, cases of severe hypoglycemia were noted in two patients, in the placebo group – in 6 patients.

At the end of the study, Vildagliptin had no effect on mean body weight (body weight increased by +0.6 kg from baseline in the vildagliptin group, no changes were noted in the placebo group).

ADRs in patients receiving Vildagliptin 50 mg twice daily in combination with insulin (with or without metformin) are presented below.

Nervous system disorders common – headache.

Gastrointestinal disorders common – nausea, gastroesophageal reflux; uncommon – diarrhea, flatulence.

Laboratory and instrumental data common – decreased blood glucose concentration.

General disorders common – chills.

In combination with sulfonylurea drugs

No cases of drug discontinuation associated with the development of ADRs were noted in the combination therapy group with vildagliptin, metformin and glimepiride. In the combination therapy group with placebo, metformin and glimepiride, the frequency of ADRs was 0.6%.

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

At the end 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).

ADRs in patients receiving Vildagliptin 50 mg twice daily in combination with metformin and sulfonylurea drugs are presented below.

Nervous system disorders common – dizziness, tremor.

Metabolism disorders common – hypoglycemia.

Skin and subcutaneous tissue disorders common – hyperhidrosis.

General disorders common – asthenia.

Vildagliptin as monotherapy

Infections and infestations very rare – upper respiratory tract infections, nasopharyngitis.

Metabolism disorders uncommon – hypoglycemia.

Nervous system disorders common – dizziness; uncommon – headache.

Gastrointestinal disorders uncommon – constipation.

Musculoskeletal and connective tissue disorders uncommon – arthralgia.

Vascular disorders uncommon – peripheral edema.

When using combination therapy with vildagliptin and metformin, no clinically significant increase in the frequency of the above ADRs noted with vildagliptin was observed.

During vildagliptin monotherapy 50 mg once daily, the frequency of therapy discontinuation due to ADRs was 0.2%, 50 mg twice daily 0.1%, and in the placebo group – 0.6%, in the comparator drug group – 0.5%.

In the vildagliptin monotherapy study, the frequency of hypoglycemia was 0.5% among patients receiving Vildagliptin 50 mg once daily and 0.3% – 50 mg twice daily, compared with 0.2% in the placebo and comparator drug groups. No serious or severe ADRs were identified.

Vildagliptin monotherapy did not affect body weight.

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

Post-marketing studies

Gastrointestinal disorders frequency unknown – pancreatitis.

Hepatobiliary disorders frequency unknown – hepatitis (resolved spontaneously after drug discontinuation), increased liver enzymes (resolved spontaneously after drug discontinuation), cholecystitis.

Musculoskeletal and connective tissue disorders frequency unknown – myalgia, arthralgia, in rare cases severe.

Skin and subcutaneous tissue disorders frequency unknown – urticaria, exfoliative and bullous skin lesions, including bullous pemphigoid, cutaneous vasculitis.

Metformin in monotherapy

Metabolism disorders very common – decreased appetite; very rare – lactic acidosis.

Gastrointestinal disorders very common – flatulence, nausea, vomiting, diarrhea, abdominal pain; common – dysgeusia.

Hepatobiliary disorders very rare – hepatitis.

Skin and subcutaneous tissue disorders very rare – skin reactions (in particular, erythema, itching, urticaria).

Laboratory and instrumental data very rare – decreased absorption of vitamin B₁₂, changes in liver function tests.

Decreased absorption of vitamin B₁₂ and a decrease in its serum concentration during metformin use was very rare in patients taking the drug for a long time and, as a rule, was not of clinical significance. The possibility of decreased absorption of vitamin B₁₂ should be considered in patients with megaloblastic anemia.

Isolated cases of deviations of liver function tests from the norm or cases of hepatitis, which were observed during metformin use, resolved after its discontinuation.

Reporting of adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to vildagliptin and/or to any of the excipients included in the drug;
• Severe renal failure or renal impairment with glomerular filtration rate (GFR) <30 ml/min/1.73 m²;
• Acute conditions with a risk of renal impairment: dehydration (repeated vomiting, with diarrhea, vomiting), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);
• Clinically significant manifestations of acute or chronic diseases that can lead to tissue hypoxia (including acute heart failure, chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
• Hepatic impairment, including patients with elevated liver enzymes (ALT or AST more than 3 times the ULN (3×ULN). Since in some cases lactic acidosis was observed in patients with hepatic impairment, which may be one of the adverse reactions (ADRs) of metformin, Galvus Met^® should not be used in patients with liver disease or impaired biochemical parameters of liver function;
• Diabetic ketoacidosis; diabetic precoma, coma. Diabetic ketoacidosis should be corrected with insulin therapy;
• Lactic acidosis (including history);
• Taking the drug for 48 hours before and at least 48 hours after radioisotope or X-ray studies with intravascular administration of iodine-containing contrast agent;
• Extensive surgical operations and injuries when insulin therapy is indicated;
• Pregnancy;
• Breastfeeding period;
• Type 1 diabetes mellitus;
• Chronic alcoholism, acute alcohol intoxication;
• Adherence to a low-calorie diet (less than 1000 kcal/day);
• Age under 18 years (due to lack of data on the efficacy and safety of the drug in children and adolescents under 18 years).

With caution

• In patients with a history of pancreatitis;
• In patients over 60 years of age performing heavy physical work, due to an increased risk of lactic acidosis;
• In patients with renal impairment with GFR 30-59 ml/min/1.73 m².

In patients receiving insulin treatment, Galvus Met^® cannot replace insulin therapy. Galvus Met^® should not be used to treat type 1 diabetes or diabetic ketoacidosis.

Use in Pregnancy and Lactation

Pregnancy

There are insufficient data on the use of Galvus Met^® in pregnant women, therefore the drug is contraindicated during pregnancy. In animal studies of vildagliptin, reproductive toxicity was identified when high doses were administered. Animal studies of metformin showed no reproductive toxicity. The potential risk to humans is unknown.

Breastfeeding

Preclinical studies have shown that Vildagliptin and metformin pass into the milk of lactating animals. There are no data on the passage of vildagliptin into human breast milk; metformin passes in small amounts. Due to the inability to exclude the risk of ADRs in the child, the use of Galvus Met^® during breastfeeding is contraindicated.

Fertility

No studies have been conducted on the effect of the Vildagliptin + metformin combination drug on human fertility. In animal studies, the use of vildagliptin at doses 200 times the recommended dose did not cause fertility impairment.

No negative effect on fertility in males and females was observed when using metformin at doses of 600 mg/kg/day, which is approximately 3 times the recommended human dose (when recalculated based on body surface area).

Use in Hepatic Impairment

Galvus Met^® should not be used in patients with liver disease or impaired biochemical parameters of liver function.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure or renal impairment with glomerular filtration rate (GFR) <30 ml/min.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety of use have not been established).

Geriatric Use

Drugs containing metformin are recommended to be used with caution in patients over 60 years of age when performing heavy physical work, due to an increased risk of lactic acidosis.

Special Precautions

Vildagliptin

Hepatic impairment

The use of the Vildagliptin+metformin combination drug is not recommended for patients with clinical or laboratory signs of hepatic impairment, including patients with elevated ALT or AST more than 3 times ULN prior to treatment initiation.

Rare cases of hepatic impairment (including hepatitis) have been reported with the use of vildagliptin. These cases were generally asymptomatic, without clinical consequences, and liver function tests returned to normal after discontinuation of therapy. Liver function should be examined before starting therapy with the Vildagliptin+metformin combination, then monitored every 3 months during the first year of drug use, and then periodically. If an increase in aminotransferase activity is detected, a repeat examination should be performed to confirm the result, and then biochemical parameters of liver function should be regularly determined until they normalize. If an excess of AST or ALT activity of 3 or more times the ULN is confirmed upon repeated examination, the use of the drug should be discontinued. If jaundice or other signs of liver dysfunction develop during the use of the Vildagliptin + metformin combination, therapy should be stopped immediately. After normalization of liver function parameters, treatment with the drug should not be resumed.

Metformin

Lactic acidosis

Lactic acidosis is a very rare but serious metabolic complication, most often occurring with a sharp deterioration in renal function, as well as with cardiorespiratory syndromes, sepsis. With a sharp deterioration in renal function, metformin accumulates in the body, which contributes to an increased risk of lactic acidosis.

In case of dehydration (for example, associated with severe diarrhea or vomiting, fever, or reduced fluid intake), a patient taking metformin-containing drugs (for example, Galvus Met^®) should immediately stop taking the above drugs and seek medical help.

In patients taking drugs containing metformin (for example, Galvus Met^®), therapy with drugs that can sharply worsen renal function (for example, antihypertensive drugs, diuretics, NSAIDs) should be started with caution. Other risk factors include: alcohol abuse, hepatic impairment, inadequately controlled diabetes, ketoacidosis, prolonged fasting, conditions associated with hypoxia, as well as simultaneous use of drugs that can cause lactic acidosis.

Diagnosis of lactic acidosis

The patient and/or the patient’s caregivers should be informed about the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle spasm, asthenia and hypothermia followed by coma. If symptoms develop that suggest the development of lactic acidosis, the patient should stop taking metformin-containing drugs (for example, Galvus Met^®) and immediately seek medical help. Laboratory and instrumental examination data: decreased blood pH (<7.35), increased serum lactate concentration >5 mmol/l, as well as an increased anion gap and an increased lactate/pyruvate ratio.

Renal function monitoring

GFR should be determined before starting therapy and this parameter should be monitored periodically during therapy with the drug. The use of metformin-containing drugs (such as Galvus Met^®) is contraindicated in patients with GFR <30 ml/min; in the presence of conditions that may impair renal function, the use of the above drugs should be temporarily suspended.

Since metformin is largely excreted by the kidneys, the risk of its accumulation and the development of lactic acidosis increases with the increasing severity of renal impairment. Since old age may be accompanied by deterioration of renal function, in patients of this category the dose of metformin-containing drugs (such as Galvus Met^®) should be carefully adjusted to select the minimum dose that provides an adequate glycemic effect, with regular monitoring of renal function.

Interactions

Concomitant use of medicinal products affecting kidney function or the distribution of metformin. Caution should be exercised when used concomitantly with drugs that can affect kidney function, have significant hemodynamic effects, or affect the distribution of metformin in the body, such as organic cations eliminated by the kidneys via tubular secretion.

Use of iodinated contrast agents for intravascular administration. Intravenous administration of iodinated X-ray contrast agents can provoke the development of contrast-induced nephropathy, leading to the accumulation of metformin in the body and an increased risk of lactic acidosis. The administration of Galvus Met^® should be temporarily discontinued before the procedure or for the duration of the procedure; administration should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilized kidney function.

Alcohol consumption

Ethanol has been shown to enhance the effect of metformin on lactate metabolism. Patients should be warned against alcohol abuse while taking metformin-containing drugs (such as Galvus Met^®).

Alcohol intoxication is associated with an increased risk of lactic acidosis, especially during prolonged fasting, insufficient nutrition, and impaired liver function.

Vitamin B₁₂ levels

Metformin has been shown to cause an asymptomatic decrease in serum vitamin B₁₂ concentration in approximately 7% of cases. Such a decrease very rarely leads to the development of anemia. After discontinuation of metformin and/or replacement therapy with vitamin B₁₂, the serum vitamin B₁₂ concentration quickly normalizes. In patients receiving metformin-containing drugs (such as Galvus Met^®), a complete blood count should be monitored at least once a year. If abnormalities in hematological parameters are detected, the etiology of such disorders should be clarified and appropriate treatment initiated. Some patients (e.g., patients with insufficient intake or malabsorption of vitamin B₁₂ or calcium) are predisposed to decreased serum vitamin B₁₂ levels. In such patients, determining serum vitamin B₁₂ levels at least once every 2-3 years may be of diagnostic value.

Hypoxia

Cardiovascular collapse (shock), acute heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia are associated with lactic acidosis and may also contribute to prerenal azotemia. If the above conditions occur, the use of metformin-containing drugs (such as Galvus Met^®) should be discontinued immediately.

Surgical interventions

During surgical interventions with general, spinal, or epidural anesthesia (except for minor surgeries not associated with restriction of food and fluid intake), the use of metformin-containing drugs (such as Galvus Met^®) should be discontinued.

Resumption of the drug is possible no earlier than 48 hours after the intervention or after the resumption of oral food intake, after receiving laboratory confirmation of stabilized kidney function.

Patients with impaired liver function

Since lactic acidosis, which is one of the adverse reactions associated with the use of metformin, has been observed in some cases in patients with impaired liver function, the Vildagliptin + metformin combination should not be used in patients with liver diseases or abnormalities in liver function biochemical parameters.

Worsening of condition in patients with type 2 diabetes mellitus previously responsive to therapy

If abnormalities in laboratory parameters are detected or if clinical symptoms of a worsening general condition appear (especially with vague and blurred symptoms) in patients with a previous adequate response to therapy, immediate laboratory diagnostics should be performed to detect ketoacidosis and/or lactic acidosis. If acidosis is detected, the drug should be discontinued immediately and necessary corrective measures should be taken.

Hypoglycemia

As a rule, hypoglycemia is not observed in patients receiving therapy with Galvus Met^® alone, but it may occur against the background of a low-calorie diet (when intense physical exertion is not compensated by food caloric intake) or against the background of alcohol consumption. The development of hypoglycemia is most likely in elderly, debilitated, or emaciated patients, as well as against the background of hypopituitarism, adrenal insufficiency, or alcohol intoxication. Diagnosis of hypoglycemia may be difficult in elderly patients and in persons receiving beta-blockers.

Reduced effectiveness of hypoglycemic agents

During stress (fever, trauma, infection, surgery, etc.) developing in patients receiving hypoglycemic agents according to the standard regimen, a sharp decrease in their effectiveness may occur for some time. In this case, it may be necessary to temporarily discontinue Galvus Met^® and administer insulin therapy. Resumption of treatment with Galvus Met^® is possible after the acute period has ended.

Effect on the ability to drive vehicles and machinery

The effect of Galvus Met^® on the ability to drive vehicles and machinery has not been studied. If dizziness occurs while taking the drug, one should refrain from driving vehicles and operating machinery.

Overdose

Vildagliptin

Symptoms in clinical studies, when the drug was taken at a dose of 400 mg/day, muscle pain was observed, and rarely – mild transient paresthesia, fever, edema, and transient increase in lipase activity (above the upper limit of normal by 2 times). When using vildagliptin at doses up to 600 mg/day, the development of limb edema accompanied by paresthesia and an increase in the concentration of creatine phosphokinase, C-reactive protein and myoglobin, and AST activity is possible. All overdose symptoms and changes in laboratory parameters disappear after discontinuation of the drug.

Treatment: removal of the drug from the body by dialysis is unlikely. However, the main hydrolytic metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.

Metformin

Treatment the most effective method for removing lactate and metformin is hemodialysis. In case of overdose, appropriate symptomatic treatment should be carried out, based on the patient’s condition and clinical manifestations.

Drug Interactions

Vildagliptin and metformin

When vildagliptin (100 mg once daily) and metformin (1000 mg once daily) were used concomitantly, no clinically significant pharmacokinetic interaction between them was noted. Neither during clinical studies nor during widespread clinical use of Galvus Met^® has any unforeseen interaction been identified in patients simultaneously receiving other drugs and substances.

Vildagliptin

Vildagliptin has a low potential for drug interactions.

Since Vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and does not inhibit or induce these isoenzymes, its interaction with drugs that are substrates, inhibitors, or inducers of P450 (CYP) is unlikely. When used concomitantly, Vildagliptin does not affect the metabolism rate of drugs that are substrates of the following enzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5.

No clinically significant interaction of vildagliptin with drugs most commonly used in the treatment of type 2 diabetes mellitus (glibenclamide, pioglitazone, metformin) or those with a narrow therapeutic range (amlodipine, digoxin, ramipril, simvastatin, valsartan, warfarin) has been established.

Metformin

Furosemide increases the C_max and AUC of metformin but does not affect its renal clearance. Metformin reduces the C_max and AUC of furosemide and also does not affect its renal clearance.

Nifedipine increases the absorption, C_max, and AUC of metformin; in addition, it increases its renal excretion. Metformin has virtually no effect on the pharmacokinetic parameters of nifedipine.

Glibenclamide does not affect the pharmacokinetic/pharmacodynamic parameters of metformin. Metformin, in general, reduces the C_max and AUC of glibenclamide, but the magnitude of the effect varies greatly. For this reason, the clinical significance of such an interaction remains unclear.

Iodinated contrast agents. The administration of Galvus Met^® should be temporarily discontinued before the procedure or for the duration of the procedure; administration should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilized kidney function.

Drugs that reduce the clearance of metformin. Concomitant use of drugs affecting the common tubular transport systems involved in the renal excretion of metformin (e.g., inhibitors of organic cation transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] protein, such as ranolazine, vandetanib, dolutegravir, and cimetidine) may lead to increased systemic exposure to metformin.

Substrates of organic cation transporters 1 and 2 (OCT1 and OCT2)

Metformin is a substrate of organic cations OCT1 and OCT2. When used concomitantly with metformin

• OCT1 inhibitors (such as verapamil) may reduce the hypoglycemic effect of metformin;
• OCT1 inducers (such as rifampicin) may increase the absorption of metformin in the gastrointestinal tract and enhance its hypoglycemic effect;
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin and lead to an increase in its plasma concentration;
• OCT1 and OCT2 inhibitors (such as crizotinib, olaparib) may reduce the hypoglycemic effect of metformin.

Other drugs

Some drugs may adversely affect kidney function, thereby increasing the risk of lactic acidosis, for example, NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, ACE inhibitors, diuretics, especially “loop” diuretics. In patients receiving therapy with metformin-containing drugs (e.g., Galvus Met^®), kidney function should be carefully monitored when initiating and during concomitant use of the above agents.

In healthy volunteers, no changes in pharmacokinetic parameters were observed with the concomitant use of metformin and propranolol, or with the use of metformin and ibuprofen.

Some drugs can cause hyperglycemia and contribute to a decrease in the effectiveness of hypoglycemic agents. Such drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormone preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are used concomitantly or, conversely, upon their discontinuation, it is recommended to carefully assess the effectiveness of glycemic control and adjust the dose of metformin.

Concomitant use of danazol is not recommended to avoid its hyperglycemic effect. If treatment with danazol is necessary and after its discontinuation, adjustment of the metformin dose under blood glucose control is required.

Chlorpromazine when used in high doses (100 mg/day) increases glycemia by reducing insulin release. When treating with antipsychotics and after their discontinuation, dose adjustment of the Vildagliptin + metformin combination under blood glucose control is required.

Injectable beta₂-sympathomimetics increase glycemia due to stimulation of β₂-adrenoceptors. In this case, glycemic control is necessary. If necessary, insulin administration is recommended.

When metformin is used concomitantly with sulfonylurea derivatives, insulin, acarbose, salicylates, an enhancement of the hypoglycemic effect is possible.

Since the use of metformin in patients with acute alcohol intoxication increases the risk of lactic acidosis (especially during fasting, exhaustion, or impaired liver function), alcohol consumption and medications containing ethanol should be avoided while taking the Vildagliptin + metformin combination.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years. The drug should not be used after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.