Agartha^® Met (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Romania, S.A. (Romania)

Or

Gedeon Richter-Rus, JSC (Russia)

Packaging and Quality Control Release

GEDEON RICHTER ROMANIA, S.A. (Romania)

Or

GEDEON RICHTER-RUS, JSC (Russia)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

A10BD08 (Metformin and vildagliptin)

Active Substances

Metformin (Rec.INN registered by WHO)

Vildagliptin (Rec.INN registered by WHO)

Dosage Forms

	Agartha® Met	Film-coated tablets, 50 mg+500 mg: 30 or 60 pcs.
		Film-coated tablets, 50 mg+850 mg: 30 or 60 pcs.
		Film-coated tablets, 50 mg+1000 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink, oval, biconvex, engraved with “AB2” on one side and with a score on the other.

Excipients: hydroxypropylcellulose, magnesium stearate; film coating (Opadry 03F240060 pink) contains: hypromellose 2910 (E464), talc (E553b), titanium dioxide (E171), macrogol 4000 (E1521), iron oxide red (E172), iron oxide yellow (E172), iron oxide black (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets yellow, oblong, biconvex, engraved with “AB3” on one side and with a score on the other.

Excipients: hydroxypropylcellulose, magnesium stearate; film coating (Opadry 03F220075 yellow) contains: hypromellose 2910 (E464), talc (E553b), titanium dioxide (E171), macrogol 4000 (E1521), iron oxide yellow (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets brown, oblong, biconvex, engraved with “AB4” on one side and with a score on the other.

Excipients: hydroxypropylcellulose, magnesium stearate; film coating (Opadry 03F265012 brown) contains: hypromellose 2910 (E464), talc (E553b), titanium dioxide (E171), macrogol 4000 (E1521), iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Combined oral hypoglycemic drug (dipeptidyl peptidase-4 inhibitor + biguanide)

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 Agartha^® 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 DPP-4 enzyme, 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 hepatic glucose production, decreases 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 certain 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 beta-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 beta-cell function parameters. The degree of improvement in beta-cell function depends on the degree of their initial damage; thus, in people without diabetes (with normal blood plasma glucose concentration), Vildagliptin does not stimulate insulin secretion or reduce glucose concentration.

By increasing the concentration of endogenous GLP-1, Vildagliptin increases the sensitivity of beta-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 during hyperglycemia, due to increased incretin hormone concentrations, causes a decrease in hepatic glucose production both during and after meals, leading to a decrease in plasma glucose concentration. Furthermore, a decrease in postprandial plasma lipid concentrations was observed with vildagliptin use; this effect is not related to improved pancreatic islet cell function and is 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, this effect is not observed with vildagliptin use.

Metformin

Metformin improves glucose tolerance in patients with T2DM by 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, independent of its effect on glycemia: a decrease in the concentration of total cholesterol, LDL cholesterol, and triglycerides.

Preclinical safety data

Animal studies lasting up to 13 weeks were conducted using the combination of components included in the drug Agartha^® Met. No new data regarding toxicity were identified with the use of the combined drug. The results of studies conducted separately for vildagliptin and metformin are presented below.

Vildagliptin

Delayed cardiac impulse conduction in dogs was observed with the use of vildagliptin at a dose of 15 mg/kg, which is 7 times the maximum recommended human dose (MRHD). Accumulation of foamy alveolar macrophages in the lungs was noted in rats and mice. The dose of vildagliptin at which this adverse effect was detected was 25 mg/kg (5 times higher than MRHD) in rats and 750 mg/kg (142 times higher than MRHD) in mice.

Gastrointestinal disturbances were identified in dogs, specifically soft stools, mucous stools, diarrhea, and, with higher doses, blood in the stool. The corresponding no-observed-adverse-effect level (NOAEL) for gastrointestinal effects was not established. Vildagliptin did not show mutagenic properties in genotoxicity tests in vitro and in vivo.

A study of fertility and early embryonic development in rats did not reveal signs of impaired fertility, reproductive performance, or early embryonic development upon exposure to vildagliptin. Embryofetal toxicity was studied in rats and rabbits. In rats, an increased incidence of wavy ribs was observed in combination with a decrease in female body weight, with a NOAEL of 75 mg/kg (10 times the MRHD). In rabbits, a decrease in fetal weight and skeletal development deviations indicative of developmental delay were noted only in the presence of severe toxic effects on the female, with a NOAEL of 50 mg/kg (9 times the MRHD). A pre- and postnatal development study was conducted in rats. Deviations were noted only in the presence of toxic effects on the female at doses ≥150 mg/kg and included a temporary decrease in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study was conducted in rats that received the drug orally at doses up to 900 mg/kg (approximately 200 times the MRHD). No increase in the incidence of tumors associated with vildagliptin exposure was noted. Another two-year carcinogenicity study was conducted in mice that received the drug at a dose of 1000 mg/kg. An increased incidence of mammary gland adenocarcinomas and hemangiosarcoma was noted, with NOAELs of 500 mg/kg (59 times the MRHD) and 100 mg/kg (16 times the MRHD), respectively. It is considered that the increased incidence of these tumors in mice does not represent a significant risk to humans, given the absence of genotoxicity of vildagliptin and its main metabolite, the occurrence of tumors in only one species, and the high systemic exposure ratios at which these tumors were observed.

In a 13-week toxicity study of vildagliptin in cynomolgus monkeys at doses ≥5 mg/kg/day, skin lesions localized only on the limbs (front and rear paws, tail) and on the ears were recorded. At a dose of 5 mg/kg/day (approximately equivalent to human AUC at a 100 mg dose), only bullous lesions were noted. Despite continued therapy, they resolved and were not associated with histopathological abnormalities. Skin scaling, skin peeling, crusting, and tail sores with corresponding histopathological changes were noted at doses ≥20 mg/kg/day (approximately 3 times the human AUC at a 100 mg dose). Necrotic tail lesions were noted at doses ≥80 mg/kg/day. During the recovery period, skin lesions were irreversible in monkeys that received the drug for 4 weeks at a dose of 160 mg/kg/day.

Metformin

Within the framework of preclinical studies of metformin, which include conventional safety studies, repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity, no harm to human health was identified.

Pharmacokinetics

Vildagliptin + metformin

Absorption

Studies have shown bioequivalence in terms of AUC and C_max for the drug Agartha^® 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 Agartha^® Met. The C_max and AUC values of metformin as part of the drug Agartha^® Met when taken simultaneously with food decreased by 26% and 7%, respectively. Furthermore, food intake slowed the absorption of metformin, leading to an increase in the time to reach C_max (T_max, from 2.0 to 4.0 h). A similar change in C_max and AUC with food intake was also noted when metformin was used separately, although 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 Agartha^® 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 distributed evenly between plasma and erythrocytes. The distribution of vildagliptin is presumed to be extravascular, V_d at steady state after IV administration is 71 L.

Metabolism

Biotransformation is the main route of elimination for vildagliptin. In the human body, 69% of the drug dose is transformed. The main metabolite, LAY151 (57% of the dose), is pharmacologically inactive and is a product of hydrolysis of the cyano group. About 4% of the drug dose undergoes amide hydrolysis. In vivo studies in animals deficient in DPP-4 indicate a partial positive influence of this enzyme on the hydrolysis of vildagliptin. 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 IV administration in healthy volunteers, the mean T_1/2 reaches 2 hours, 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 dose.

Linearity (non-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.

Pharmacokinetic-pharmacodynamic relationship

Gender. In healthy volunteers of different genders, ages, and 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.

Renal impairment. 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 metabolite LAY151 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).

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

Elderly. 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 per day, is not clinically significant and does not affect DPP-4 inhibition.

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

Ethnicity. Ethnicity does not affect the pharmacokinetics of vildagliptin.

Metformin

Absorption

The absolute bioavailability of metformin after oral administration of a 500 mg dose on an empty stomach was 50-60%. C_max is reached 2.5 hours after administration. When increasing the single dose of the drug from 500 mg to 1500 mg and from 850 mg to 2250 mg orally, a lack of dose dependence of pharmacokinetic parameters was noted. This effect is due not so much to a change in drug elimination as to a slowdown in its absorption. With food intake, the extent and rate of metformin absorption also decreased somewhat. Thus, with a single dose of the drug 850 mg with food, a decrease in C_max by approximately 40%, AUC by 25%, and an increase in T_max by 35 min 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 is practically not bound to plasma proteins, while sulfonylurea derivatives are more than 90% bound. 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. During controlled clinical trials, 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 the bile.

Excretion

Since the renal clearance of metformin is approximately 3.5 times greater than the glomerular filtration rate (GFR), the main route of drug elimination is tubular secretion.

When taken orally, approximately 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, indicating accumulation of a significant portion of the drug in erythrocytes.

Pharmacokinetic-Pharmacodynamic Relationship

Sex. In male and female patients with type 2 diabetes mellitus, no significant differences in the pharmacokinetic parameters of metformin were noted. Similarly, clinical studies have not shown a difference in the hypoglycemic effect of metformin between men and women with type 2 diabetes.

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

Hepatic Impairment. The pharmacokinetic characteristics of metformin have not been studied in patients with impaired liver function.

Elderly Patients. According to limited pharmacokinetic data from healthy volunteers aged ≥ 65 years, a decrease in total plasma clearance of metformin and an increase in T_1/2 and C_max were observed compared to younger volunteers. These pharmacokinetic features of metformin in individuals over 65 years of age are likely primarily associated with changes in renal function; therefore, in patients over 80 years of age, the use of Agarta^® Met is possible only with normal GFR.

Children. The pharmacokinetics of metformin in children aged at least 10 years have not been studied. The pharmacokinetic characteristics of metformin in children and adolescents under 18 years of age have not been established.

Ethnicity. There is no evidence of the influence of patient ethnicity on the pharmacokinetic characteristics of metformin. In controlled clinical studies of metformin in patients with type 2 diabetes of various ethnicities, the hypoglycemic effect of the drug was manifested to the same extent.

Indications

The drug Agarta^® Met is indicated for use in adult patients for the treatment of type 2 diabetes mellitus (in combination with diet therapy and physical exercise)

• In case of insufficient effectiveness of monotherapy with vildagliptin or metformin;
• In patients previously receiving combination therapy with vildagliptin and metformin as separate monodrugs;
• In combination with sulfonylurea derivatives (triple combination therapy) in patients previously treated with a sulfonylurea derivative and metformin without achieving adequate glycemic control;
• In triple combination therapy with insulin in patients previously receiving 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 and physical exercise and when improvement in glycemic control is necessary.

ICD codes

Dosage Regimen

Orally.

Agarta^® Met should be taken during or immediately after a meal to reduce the severity of gastrointestinal adverse events associated with the presence of metformin in the drug.

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

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

To reduce the severity of gastrointestinal adverse reactions (ARs) characteristic of metformin, Agarta^® Met should be taken with meals.

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 Agarta^® Met for ineffective vildagliptin monotherapy

Treatment with Agarta^® Met can be started with one tablet of 50 mg + 500 mg twice daily; after assessing the therapeutic effect, the dose can be gradually increased.

Initial dose of Agarta^® Met for ineffective metformin monotherapy

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

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

Depending on the doses of vildagliptin or metformin already taken, treatment with Agarta^® 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 based on effectiveness.

Starting dose of Agarta^® Met as initial therapy in patients with type 2 diabetes with insufficient effectiveness of diet therapy and physical exercise

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

Combination therapy with Agarta^® Met and a sulfonylurea derivative or insulin

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

Special Patient Groups

Patients with renal impairment

Before starting therapy with metformin-containing drugs (such as Agarta^® Met), GFR should be determined and then this parameter should 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 of 50 mg + 500 mg once daily; with GFR 45-59 ml/min/1.73 m², the initial dose of Agarta^® Met is 1 tablet 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 Agarta^® Met). In patients with GFR < 30 ml/min, the use of Agarta^® Met is contraindicated due to the presence of metformin in the drug.

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

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

Patients with hepatic impairment

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

Elderly patients

Metformin is excreted by the kidneys. Since patients over 65 years of age often have impaired renal function, the dose of Agarta^® 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 must be regularly monitored.

Children

The use of the Vildagliptin + metformin combination in children under 18 years of age is contraindicated. The safety and efficacy of the Vildagliptin + metformin combination in children have not been established to date.

Adverse Reactions

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

Rare cases of angioedema have been observed during therapy with the drug, with a similar frequency in the control group. Cases of angioedema were most frequently reported when the drug was used in combination with ACE inhibitors. In most cases, angioedema was mild and resolved on its own during continued vildagliptin therapy.

Liver function disorders (including hepatitis) of an asymptomatic nature have been rarely reported during vildagliptin therapy. In most cases, these disorders and deviations of liver function parameters from the norm resolved on their own without complications after discontinuation of the drug therapy. When using vildagliptin at a dose of 50 mg once or twice daily, the frequency of increased liver enzyme activity (ALT or AST >3×ULN) was 0.2% or 0.3%, respectively (compared to 0.2% in the control group). The increase in liver enzyme activity 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 adverse reactions (ARs) with metformin use are very common.

The frequency of gastrointestinal ARs during combination therapy with vildagliptin and metformin hydrochloride was 13.2% (when using 50 mg once daily or twice daily). With metformin monotherapy – 18.1%.

Below are the ARs possible both with the use of combination therapy with vildagliptin and metformin and with vildagliptin and metformin monodrugs. ARs are distributed by system-organ class in accordance with the MedDRA dictionary for regulatory activities, with an indication of the frequency of their occurrence according to WHO recommendations: very common (≥1/10); common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data), including isolated cases.

ARs possible with the combination of vildagliptin and metformin

Metabolism and nutrition disorders common – hypoglycemia.

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

Gastrointestinal disorders common – nausea.

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

Study of the use of the vildagliptin and metformin combination as initial therapy for type 2 diabetes did not reveal 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 there were no cases of therapy discontinuation 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).

ARs 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.

Investigations common – decreased blood glucose concentration.

General disorders and administration site conditions common – chills.

In combination with sulfonylurea drugs

There were no cases of drug withdrawal associated with the development of ARs in the group of combination therapy with vildagliptin, metformin, and glimepiride. In the group of combination therapy with placebo, metformin, and glimepiride, the frequency of ARs 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 identified (+ 0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

ARs 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 and nutrition disorders common – hypoglycemia.

Skin and subcutaneous tissue disorders common – hyperhidrosis.

General disorders and administration site conditions common – asthenia.

Vildagliptin as monotherapy

Infections and infestations uncommon – upper respiratory tract infection, nasopharyngitis.

Metabolism and nutrition 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 ARs noted with vildagliptin intake was observed.

During vildagliptin monotherapy 50 mg once daily, the frequency of therapy discontinuation due to ARs was 0.2%, 50 mg twice daily 0.1%, while in the placebo group it was 0.6%, and in the active comparator 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 to 0.2% in the placebo and active comparator groups. No serious or severe ARs were identified.

Vildagliptin monotherapy did not affect body weight.

Long-term clinical studies of up to 2 years did not reveal any additional deviations in the safety profile or unforeseen risks with the use of vildagliptin as monotherapy.

Post-marketing studies

Gastrointestinal disorders frequency not known – pancreatitis.

Hepatobiliary disorders frequency not known – hepatitis (resolved after drug discontinuation), increased liver enzyme activity (resolved after drug discontinuation).

Musculoskeletal and connective tissue disorders frequency not known – myalgia, arthralgia, in rare cases severe.

Skin and subcutaneous tissue disorders frequency not known – urticaria, exfoliative and bullous skin lesions, including bullous pemphigoid.

Metformin as monotherapy

Metabolism and nutrition 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, pruritus, urticaria).

Investigations very rare – decreased vitamin B₁₂ absorption, changes in liver function tests.

Decreased vitamin B₁₂ absorption and reduction in its serum concentration with metformin use has been very rare in patients taking the drug for a long time and, as a rule, was not of clinical significance.

The possibility of decreased vitamin B₁₂ absorption should be considered in patients with megaloblastic anemia.

Isolated cases of abnormal liver function test results or cases of hepatitis observed during metformin use resolved after its discontinuation.

If a worsening of the clinical course of any of the adverse reactions listed in the instructions is noted or the patient notices any other adverse reactions not listed in the instructions, the physician should be informed.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. 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 or metformin and/or to any of the excipients in the drug;
• Severe renal failure or impaired renal function with GFR < 30 ml/min/1.73 m²;
• Acute conditions with a risk of renal function impairment: dehydration (repeated vomiting, diarrhea), 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);
• Impaired liver function, including patients with elevated liver enzyme activity (ALT or AST) 3 times or more above the upper limit of normal (3×ULN);
• Since lactic acidosis has been observed in some cases in patients with impaired liver function and may be one of the adverse reactions associated with metformin use, Agartha^® Met should not be used in patients with liver disease or impaired biochemical liver function parameters;
• Diabetic ketoacidosis; diabetic precoma, coma (diabetic ketoacidosis should be corrected with insulin therapy);
• Lactic acidosis, including history;
• Use of the drug within 48 hours before and at least 48 hours after radioisotope or X-ray examinations with intravascular administration of iodine-containing contrast medium;
• Extensive surgical operations and trauma, when insulin therapy is indicated;
• Type 1 diabetes mellitus;
• Chronic alcoholism, acute alcohol intoxication;
• Adherence to a low-calorie diet (less than 1000 kcal/day).

With caution

In patients receiving insulin therapy, the combination of Vildagliptin + metformin cannot replace insulin therapy. The combination of Vildagliptin + metformin should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Precautions are required when using the combination of Vildagliptin + metformin

• 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 eGFR 30-59 ml/min/1.73 m².

Use in Pregnancy and Lactation

Pregnancy

Adequate data on the use of vildagliptin in combination with metformin in pregnant women are not available. Preclinical studies of vildagliptin revealed reproductive toxicity at high doses. Animal studies did not reveal any signs of reproductive toxicity for metformin. Animal studies did not reveal signs of teratogenic effects for vildagliptin and metformin; however, when used at doses toxic to pregnant females, their fetotoxic effects were demonstrated.

The potential risk to humans is unknown. Agartha^® Met should not be taken during pregnancy.

Breastfeeding period

Preclinical studies have shown that Vildagliptin and metformin pass into breast milk. It is not known whether Vildagliptin passes into human breast milk, but it has been proven that metformin passes into human breast milk in small amounts.

Due to the potential risk of hypoglycemia in the newborn associated with the passage of metformin into breast milk and the lack of data for vildagliptin, the use of Agartha^® Met during breastfeeding is contraindicated.

Fertility

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

No negative effects on fertility in males and females were observed with the use of metformin at doses of 600 mg/kg/day, which is approximately 3 times the recommended human dose (based on body surface area).

Use in Hepatic Impairment

Contraindications: impaired liver function, including patients with elevated liver enzyme activity (ALT or AST) 3 times or more above the upper limit of normal; since lactic acidosis has been observed in some cases in patients with impaired liver function and may be one of the adverse reactions associated with metformin use, Agartha^® Met should not be used in patients with liver disease or impaired biochemical liver function parameters.

Use in Renal Impairment

Contraindications: renal failure or severe renal impairment with eGFR < 30 ml/min/1.73 m²; acute conditions with a risk of renal impairment: dehydration (repeated vomiting, diarrhea), fever, severe infectious diseases, hypoxic conditions (shock, sepsis, kidney infections, bronchopulmonary diseases).

Pediatric Use

The use of the Vildagliptin + metformin combination in children under 18 years of age is contraindicated. The safety and efficacy of the Vildagliptin + metformin combination in children have not been established to date.

Geriatric Use

Since impaired renal function is often observed in patients over 65 years of age, the dose of Agartha^® 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 monitored regularly.

Special Precautions

Vildagliptin

Impaired liver function

The use of the Vildagliptin + metformin combination is not recommended for patients with clinical or laboratory signs of impaired liver function, including patients with ALT or AST activity elevated more than 3 times the ULN prior to initiation of therapy.

Rare cases of impaired liver function (including hepatitis) have been reported with the use of vildagliptin. These cases were generally asymptomatic, without clinical consequences, and liver function parameters 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 elevated aminotransferase activity is detected, a repeat examination should be performed to confirm the result, and then biochemical liver function parameters should be regularly determined until they normalize. If an increase in AST or ALT activity to 3 or more times the ULN is confirmed upon repeat examination, the drug should be discontinued. If jaundice or other signs of impaired liver function develop during treatment with 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 (e.g., associated with severe diarrhea or vomiting, fever, or reduced fluid intake), a patient taking metformin-containing drugs (e.g., the Vildagliptin + metformin combination) should immediately stop taking the aforementioned drugs and seek medical help. In patients taking drugs containing metformin (e.g., the Vildagliptin + metformin combination), therapy with drugs that can sharply worsen renal function (e.g., antihypertensive drugs, diuretics, NSAIDs) should be initiated with caution. Other risk factors include: alcohol abuse, impaired liver function, inadequately controlled diabetes mellitus, 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 cramps, asthenia and hypothermia followed by coma. If symptoms suggestive of lactic acidosis develop, the patient should stop taking Agartha^® Met and seek immediate medical attention. Laboratory and instrumental examination data: decreased blood pH (<7.35), increased plasma lactate concentration >5 mmol/L, as well as an increased anion gap and an increased lactate/pyruvate ratio.

Renal function monitoring

EGFR 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 the Vildagliptin + metformin combination) is contraindicated in patients with eGFR < 30 ml/min/1.73 m²; in the presence of conditions that can impair renal function, the use of the aforementioned 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, the dose of metformin-containing drugs (such as the Vildagliptin + metformin combination) in such patients 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 drugs affecting renal function or the distribution of metformin. Caution should be exercised when used concomitantly with drugs that can affect renal function, have a significant effect on hemodynamics, or inhibit renal transport and increase the systemic exposure of metformin.

Use of iodine-containing X-ray contrast agents for intravascular administration. Intravenous administration of iodine-containing 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 use of metformin-containing drugs (such as the Vildagliptin + metformin combination) should be temporarily discontinued before the procedure or for the duration of the procedure; use should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilized renal function.

Alcohol consumption. Ethanol has been found to enhance the effect of metformin on lactate metabolism. The patient should be warned against alcohol abuse while taking metformin-containing drugs (such as the Vildagliptin + metformin combination). Alcohol intoxication is associated with an increased risk of lactic acidosis, especially during prolonged fasting, insufficient nutrition, and impaired liver function.

Vitamin B₁₂ content

Metformin has been found to cause an asymptomatic decrease in plasma 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 vitamin B₁₂ replacement therapy, the serum vitamin B₁₂ concentration quickly normalizes. In patients receiving metformin-containing drugs (such as the Vildagliptin + metformin combination), a complete blood count should be monitored at least once a year. If deviations in hematological parameters from the norm are detected, the etiology of such disorders should be clarified and appropriate treatment should be carried out. Some patients (e.g., patients with insufficient intake or impaired absorption of vitamin B₁₂ or calcium) are predisposed to a decrease in plasma vitamin B₁₂ concentration. In such patients, determining the plasma vitamin B₁₂ concentration 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 the Vildagliptin + metformin combination) should be stopped immediately.

Surgical interventions

During surgical interventions with general, spinal or epidural anesthesia (except for minor operations not associated with restriction of food and fluid intake), the use of metformin-containing drugs (such as the Vildagliptin + metformin combination) should be discontinued.

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

Patients with impaired liver function

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

Worsening of the condition in patients with type 2 diabetes mellitus who previously responded to therapy

If deviations in laboratory parameters from the norm are detected or if clinical symptoms of a general deterioration in condition appear (especially with vague and blurred symptoms) in patients with a previous adequate response to therapy, laboratory diagnostics should be immediately performed to detect ketoacidosis and/or lactic acidosis. If acidosis is detected, the drug should be discontinued immediately and necessary measures to correct the patient’s condition should be taken.

Hypoglycemia

As a rule, hypoglycemia is not observed in patients receiving therapy only with the Vildagliptin + metformin combination, but it can occur against the background of a low-calorie diet (when intense physical activity is not compensated by the calorie content of food), or against the background of alcohol consumption. The development of hypoglycemia is most likely in the elderly, debilitated or emaciated patients, as well as against the background of hypopituitarism, adrenal insufficiency or alcohol intoxication. In elderly patients and in persons receiving beta-blockers, the diagnosis of hypoglycemia may be difficult.

Reduced effectiveness of hypoglycemic agents

During stress (including fever, trauma, infection, surgery) developing in patients receiving hypoglycemic drugs according to the standard regimen, a sharp decrease in their effectiveness for some time is possible. In this case, it may be necessary to temporarily discontinue therapy with the Vildagliptin + metformin combination and switch the patient to insulin therapy.

Resumption of treatment with the Vildagliptin + metformin combination is possible after the acute period has ended.

Effect on the ability to drive vehicles and operate machinery

Studies on the effect of the drug on the ability to drive vehicles and operate machinery have not been conducted. Patients who may experience dizziness as an adverse reaction should avoid driving vehicles and operating machinery.

Overdose

Vildagliptin

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 2 times the ULN). 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 CPK, C-reactive protein and myoglobin, and AST activity is possible. All symptoms of overdose and changes in laboratory parameters disappear after discontinuation of the drug.

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

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

With simultaneous use of vildagliptin (100 mg once daily) and metformin (1000 mg once daily), no clinically significant pharmacokinetic interaction between them was noted. The drug interaction for each active substance is well studied. Neither during clinical studies nor during widespread clinical use of the Vildagliptin + metformin combination in patients simultaneously receiving other drugs and substances was any unforeseen interaction identified.

The available information on interactions for each active substance is presented below.

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 is unlikely. With simultaneous use, Vildagliptin does not affect the metabolism rate of drugs that are substrates of the enzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

No clinically significant interaction of vildagliptin with oral drugs most commonly used in the treatment of type 2 diabetes mellitus (glibenclamide, pioglitazone, metformin) or 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 almost no effect on the pharmacokinetic parameters of nifedipine.

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

Iodine-containing X-ray contrast agents

The use of metformin-containing drugs (such as the Vildagliptin + metformin combination) should be temporarily discontinued before the procedure or for the duration of the procedure; use should be resumed no earlier than 48 hours after the procedure, after receiving laboratory confirmation of stabilized renal 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 protein [MATE], 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

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

Other drugs

Some drugs can adversely affect kidney function, thereby increasing the risk of lactic acidosis, for example, NSAIDs, including selective COX-2 inhibitors, ACE inhibitors, diuretics, especially “loop” diuretics. In patients receiving therapy with metformin-containing drugs (for example, the drug Agarta^® Met) at the beginning of treatment, as well as with the simultaneous use of the listed drugs, kidney function should be carefully monitored.

In healthy volunteers, no changes in their pharmacokinetic parameters were observed with the simultaneous 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, glucocorticosteroids, phenothiazines, glucagon, thyroid hormone preparations, including levothyroxine sodium, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, slow calcium channel blockers, and isoniazid. When using such drugs simultaneously or, conversely, when they are discontinued, it is recommended to carefully assess the effectiveness of glycemic control and adjust the dose of metformin.

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

Injectable β₂-sympathomimetics: increase glycemia due to stimulation of β₂-adrenergic receptors. In this case, glycemic control is necessary. If necessary, insulin use is recommended.

With simultaneous use of metformin 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), when taking the Vildagliptin + metformin combination, one should refrain from consuming alcohol and medicines containing ethyl alcohol.

Metformin may reduce the effect of indirect anticoagulants.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging (blister in a cardboard box) to protect from light, at a temperature below 25°C (77°F).

Shelf Life

The shelf life of the film-coated tablets, 50 mg + 500 mg, manufactured by JSC GEDEON RICHTER-RUS is 2 years.

The shelf life of the film-coated tablets, 50 mg + 850 mg, 50 mg + 1000 mg, manufactured by JSC GEDEON RICHTER-RUS and Gedeon Richter Romania A.O. is 1.5 years.

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.