Agartha^® (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

A10BH02 (Vildagliptin)

Active Substance

Vildagliptin (Rec.INN registered by WHO)

Dosage Form

Agartha®

Tablets 50 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets from yellowish-white to light gray in color, round, flat, with a beveled edge, engraved with “AA3” on one side.

Excipients: microcrystalline cellulose (type M200LM), lactose, sodium carboxymethyl starch (type A), magnesium stearate.

14 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic drug – dipeptidyl peptidase-4 inhibitor

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; dipeptidyl peptidase-4 (DPP-4) inhibitors

Pharmacological Action

Mechanism of action

Vildagliptin, a member of the class of pancreatic islet stimulators, is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), which improves glycemic control. Inhibition of DPP-4 by vildagliptin leads to an increase in basal and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

Pharmacodynamic effects

When vildagliptin is used at a dose of 50-100 mg per day in patients with type 2 diabetes mellitus (T2DM), an improvement in the function of pancreatic beta-cells is observed. The degree of improvement in beta-cell function depends on the degree of their initial damage; thus, in individuals without T2DM (with normal blood 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 alpha-cells to glucose, leading to improved glucose-dependent regulation of glucagon secretion. The reduction of elevated glucagon concentration during meals, in turn, causes a decrease in insulin resistance.

The increase in the insulin/glucagon ratio against the background of hyperglycemia, due to an increase in the concentration of GLP-1 and GIP, causes a decrease in hepatic glucose production both during and after meals, leading to a decrease in blood plasma glucose concentration.

In addition, against the background of vildagliptin use, a decrease in postprandial blood lipid concentration is observed; however, this effect is not associated with its action on GLP-1 or GIP and the improvement of pancreatic islet cell function.

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

When vildagliptin was used in 5795 patients with T2DM for 52 weeks as monotherapy or in combination with metformin, sulfonylurea derivatives, thiazolidinedione, or insulin, a significant long-term reduction in glycated hemoglobin (HbA1c) and fasting blood glucose concentration was observed.

When using a combination of vildagliptin and metformin as initial therapy in patients with T2DM for 24 weeks, a dose-dependent reduction in HbA1c concentration was observed compared to monotherapy with these drugs. Cases of hypoglycemia were minimal in both therapy groups.

When vildagliptin was used at a dose of 50 mg once daily for 6 months in patients with T2DM with moderate (eGFR ≥ 30, 50 ml/min/1.73 m²) or severe (eGFR < 30 ml/min/1.73 m²) renal impairment, a clinically significant reduction in HbA1c concentration was observed compared to placebo.

When vildagliptin was used at a dose of 50 mg twice daily in combination with/without metformin and insulin (average dose 41 U/day), a reduction in HbA1c of 0.77% from the baseline mean value of 8.8% was demonstrated, with a statistically significant difference from placebo of 0.72%. The frequency of hypoglycemia in the vildagliptin group was comparable to that in the placebo group. When vildagliptin was used at a dose of 50 mg twice daily in combination with metformin (≥ 1500 mg/day) and glimepiride (≥ 4 mg/day), a statistically significant reduction in HbA1c level of 0.76% from the baseline mean value of 8.8% was shown.

Pharmacokinetics

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 observed. 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 binding of vildagliptin to plasma proteins is low (9.3%). Vildagliptin is distributed evenly between plasma and red blood cells. The distribution of vildagliptin is presumed to be extravascular. The V_d at steady state after IV administration is 71 L.

Metabolism

The main route of elimination of vildagliptin is biotransformation. In the human body, 69% of the vildagliptin dose undergoes biotransformation.

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.

Preclinical studies indicate a positive effect of DPP-4 on the hydrolysis of vildagliptin. Vildagliptin is metabolized without the involvement of cytochrome P450 isoenzymes. Vildagliptin is not a substrate for P450 (CYP) isoenzymes, does not inhibit or induce cytochrome P450 isoenzymes.

Elimination

After oral administration of the drug, about 85% of the dose is excreted by the kidneys and 15% through the intestines. Renal excretion of unchanged vildagliptin is 23%. With IV administration, the mean T_1/2 is 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.

Pharmacokinetics in special patient groups

Elderly individuals

In healthy elderly people (≥ 70 years), the overall exposure to vildagliptin (100 mg once daily) increased by 32%, while the peak plasma concentration increased by 18% compared to young healthy individuals (18-40 years). However, these changes are not considered clinically significant. Inhibition of DPP-4 by vildagliptin does not depend on the patient’s age within the studied age groups.

Hepatic impairment

In patients with mild and moderate hepatic impairment (6-9 points on the Child-Pugh scale) after a single dose of the drug, the bioavailability of vildagliptin decreases by 20% and 8%, respectively. In patients with severe hepatic impairment (10-12 points on the Child-Pugh scale), the bioavailability of vildagliptin increases by 22%. An increase or decrease in the maximum bioavailability of vildagliptin not exceeding 30% is not clinically significant.

No correlation was found between the severity of hepatic impairment and the bioavailability of the drug.

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.

When using the drug in patients with impaired renal function, dose adjustment may be required.

The elimination of vildagliptin during hemodialysis is limited (3% after a single dose 4 hours after the start of a procedure lasting more than 3-4 hours).

Children

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

Indications

Treatment of type 2 diabetes mellitus in adult patients (in combination with diet therapy and physical exercise)

• As monotherapy in case of ineffectiveness of diet therapy and physical exercise in patients with contraindications to the use of/intolerance to metformin or in case of ineffectiveness of metformin;
• In combination with metformin as initial drug therapy when diet therapy and physical exercise are insufficiently effective;
• As part of two-component combination therapy: with metformin or thiazolidinedione, or with insulin in case of ineffectiveness of diet therapy, physical exercise, and monotherapy with these drugs;
• As part of two-component combination therapy with sulfonylurea derivatives in patients with insufficient glycemic control on the maximum tolerated dose of a sulfonylurea derivative or in the presence of contraindications to the use of/intolerance to metformin;
• As part of triple combination therapy: in combination with sulfonylurea derivatives and metformin, in patients previously treated with sulfonylurea derivatives and metformin against the background of diet therapy and physical exercise, and who did not achieve adequate glycemic control;
• As part of triple combination therapy: in combination with insulin and metformin, in patients previously treated with insulin at a stable dose and metformin against the background of diet therapy and physical exercise, and who did not achieve adequate glycemic control.

ICD codes

Dosage Regimen

The drug Agartha^® is taken orally regardless of meals.

The dose of the drug Agartha^® should be selected individually depending on efficacy and tolerability.

The recommended dose of the drug Agartha^® is 50 mg once or twice daily. The maximum daily dose of the drug is 100 mg.

The recommended dose of the drug as monotherapy or as part of combination therapy with metformin, thiazolidinedione or insulin (in combination with metformin or without metformin), is 50 mg or 100 mg daily.

The recommended dose of the drug Agartha^®as part of dual combination therapy with sulfonylurea drugs is 50 mg once daily in the morning. In this patient population, the efficacy of the drug Agartha^® at a dose of 100 mg/day was similar to that at a dose of 50 mg/day.

The recommended dose of the drug Agartha^®as part of triple combination therapy (Vildagliptin + sulfonylurea derivatives + metformin) is 100 mg/day.

If glycemic control targets are not achieved with the maximum daily dose of 100 mg, the possibility of adding other hypoglycemic drugs, such as metformin, sulfonylurea derivatives, thiazolidinediones or insulin, to therapy with Agartha^® should be considered.

Special patient groups

In elderly patients, no adjustment of the dosing regimen of the drug Agartha^® is required.

In patients with mild renal impairment (eGFR < 60 ml/min/1.73 m²) and moderate renal impairment with eGFR 50-60 ml/min/1.73 m², no adjustment of the dosing regimen of the drug is required. In patients with moderate renal impairment with eGFR 30-50 ml/min/1.73 m² and severe renal impairment (eGFR 30 ml/min/1.73 m²), including end-stage chronic kidney disease (CKD) in patients on hemodialysis or undergoing hemodialysis, the drug should be used at a dose of 50 mg once daily.

Since there is no experience with the use of the drug Agartha^® in children and adolescents under 18 years of age, the use of the drug in patients of this category is not recommended.

Method of administration

A dose of 50 mg/day should be taken once daily in the morning, a dose of 100 mg/day should be divided into 2 doses – 50 mg in the morning and in the evening. If a dose is missed, the missed dose should be taken as soon as possible. A double dose should not be taken on the same day.

Adverse Reactions

When using the drug Agartha^® as monotherapy or in combination with other drugs, most adverse reactions (AR) were mild, temporary and did not require discontinuation of therapy. No correlation was found between the frequency of AR and age, gender, ethnicity, duration of use or dosing regimen.

The frequency of angioedema during therapy with the drug Agartha^® was ≥1/10000, but <1/1000 (rare category) and was similar to that in the control group. Cases of angioedema were most often observed when vildagliptin was used in combination with ACE inhibitors. In most cases, angioedema was mild and resolved on its own with continued vildagliptin therapy.

Rare cases of impaired liver function (including hepatitis) of an asymptomatic course were observed during therapy with the drug Agartha^®. In most cases, these disorders resolved on their own without complications, and liver function test abnormalities returned to normal after discontinuation of therapy. When using the drug Agartha^® 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% and 0.3%, respectively (compared to 0.2% in the control group). The increase in liver enzyme activity was mostly asymptomatic, non-progressive and not accompanied by cholestasis or jaundice.

AR are listed below (Tables 1-6) by system-organ class according to the MedDRA classification and by frequency of occurrence, arranged in descending order of severity: very common (≥1/10), common (≥1/100, but <1/10), uncommon (≥1/1000, but < /100), rare (≥1/10000, but <1/1000), very rare (< 1/10000), frequency unknown (cannot be calculated from available data).

When using the drug Agartha^® as monotherapy

When using vildagliptin at a dose of 100 mg/day, the frequency of therapy discontinuation due to the development of adverse reactions (0.3%) was no higher than that in the placebo group (0.6%) or the comparator drug group (0.5%).

During monotherapy with vildagliptin at a dose of 100 mg/day, the frequency of hypoglycemia without an increase in severity was 0.4%, which is comparable to the comparator drug and placebo (0.2%). Body weight did not change from baseline in clinical studies when Vildagliptin 100 mg/day was used as monotherapy (-0.3 kg and -1.3 kg in the vildagliptin and placebo groups, respectively).

Table 1. Frequency of adverse reactions when using vildagliptin in clinical studies as monotherapy at a dose of 100 mg/day

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

When using the drug Agartha^® at a dose of 100 mg/day in combination with metformin

When using vildagliptin at a dose of 100 mg/day in combination with metformin or placebo in combination with metformin, no cases of therapy discontinuation due to the development of adverse reactions were observed.

When using vildagliptin at a dose of 100 mg/day in combination with metformin, hypoglycemia was observed in 1% of cases (in the placebo + metformin group, hypoglycemia was observed uncommonly (0.4%)). No cases of severe hypoglycemia were observed in the vildagliptin group.

Body weight did not change from baseline in clinical studies when using the combination of vildagliptin at a dose of 100 mg/day and metformin (+0.2 kg and -1.0 kg in the vildagliptin and placebo groups, respectively).

Table 2. Frequency of adverse reactions when using vildagliptin in clinical studies at a dose of 100 mg/ day in combination with metformin

Long-term clinical studies lasting up to 2 years did not reveal any additional safety profile deviations or unforeseen risks with the use of vildagliptin in combination with metformin. A study of the use of the vildagliptin and metformin combination as initial therapy for type 2 diabetes did not reveal any safety profile deviations or unforeseen risks.

When using the drug Agartha^® at a dose of 50 mg/day in combination with sulfonylurea derivatives

When using vildagliptin at a dose of 50 mg/day in combination with glimepiride, the frequency of therapy discontinuation due to adverse reactions was 0.6% (compared to 0% in the glimepiride + placebo group).

The incidence of hypoglycemia in patients receiving Vildagliptin at a dose of 50 mg/day together with glimepiride was 1.2% compared to 0.6% in the placebo + glimepiride group. No cases of severe hypoglycemia were observed in the vildagliptin group.

Body weight did not change from baseline when Vildagliptin at a dose of 50 mg once daily was added to glimepiride therapy (-0.1 kg and -0.4 kg in the vildagliptin and placebo groups, respectively).

Table 3. Frequency of adverse reactions when using vildagliptin in clinical studies at a dose of 50 mg/day in combination with sulfonylurea derivatives

When using the drug Agartha^® at a dose of 100 mg/day in combination with a thiazolidinedione

When using vildagliptin at a dose of 100 mg/day + thiazolidinedione and placebo + thiazolidinedione, there were no cases of therapy discontinuation due to adverse reactions.

When using the combination of vildagliptin at a dose of 100 mg/day and pioglitazone, hypoglycemia developed in 0.6% of cases, while in patients receiving placebo and pioglitazone, it occurred in 1.9% of cases. No cases of severe hypoglycemia were observed in the vildagliptin group.

In the study of vildagliptin as add-on therapy to pioglitazone, the absolute increase in body weight in the placebo and vildagliptin 100 mg/day groups was 1.4 and 2.7 kg, respectively.

When vildagliptin at a dose of 100 mg/day was added to pioglitazone at a dose of 45 mg/day, the incidence of peripheral edema was 7% (compared to 2.5% with pioglitazone monotherapy).

Table 4. Frequency of adverse reactions when using vildagliptin in clinical studies at a dose of 100 mg/day in combination with a thiazolidinedione

When using the drug Agartha^® at a dose of 50 mg twice daily in combination with insulin (with or without metformin)

When using the drug in combination with insulin (in combination with metformin or without metformin), the frequency of therapy discontinuation due to adverse reactions was 0.3% in the vildagliptin therapy group; there were no cases of therapy discontinuation in the placebo group.

When using the drug in combination with insulin (in combination with metformin or without metformin), there was no increased risk of hypoglycemia compared to the placebo + insulin combination (14% in the vildagliptin group and 16.4% in the placebo group). Severe hypoglycemia developed in 2 patients in the vildagliptin group and in 6 patients in the placebo group.

At the end of the studies, the drug had no effect on mean body weight (body weight increased by +0.6 kg from baseline in the vildagliptin group, while it remained unchanged in the placebo group).

Table 5. Frequency of adverse reactions when using vildagliptin in clinical studies at a dose of 50 mg twice daily in combination with insulin (with or without metformin)

When using the drug Agartha^® at a dose of 50 mg twice daily in combination with sulfonylurea drugs and metformin

There were no cases of drug discontinuation related to adverse reactions in the group receiving combination therapy with vildagliptin, metformin, and glimepiride. In the group receiving combination therapy with placebo, metformin, and glimepiride, the frequency of therapy discontinuation related to adverse reactions 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).

Table 6. Frequency of adverse reactions when using vildagliptin at a dose of 50 mg twice daily in combination with sulfonylurea drugs and metformin

Post-marketing studies

During post-marketing studies, the following adverse reactions were identified (since reports are received voluntarily from a population of uncertain size, it is not possible to reliably determine the frequency of these adverse reactions, therefore they are classified as “frequency unknown”).

Gastrointestinal disorders frequency unknown – pancreatitis.

Hepatobiliary disorders frequency unknown – hepatitis (resolved after drug discontinuation), increased liver enzyme activity (resolved after drug discontinuation).

Musculoskeletal and connective tissue disorders frequency unknown – myalgia.

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk ratio. 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 to any excipients of the drug;
• Type 1 diabetes mellitus;
• Acute or chronic metabolic acidosis (including diabetic ketoacidosis with or without coma); diabetic ketoacidosis should be corrected with insulin therapy;
• Lactic acidosis (including history);
• Impaired liver function, including patients with elevated liver enzyme activity (ALT or AST) 3 times or more above the upper limit of normal (ULN);
• Chronic heart failure of functional class IV according to the NYHA classification (due to the lack of clinical study data on the use of vildagliptin in this group of patients);
• Hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (efficacy and safety of the drug have not been established).

Use in Pregnancy and Lactation

Pregnancy

There are insufficient data on the use of the drug Agartha^® in pregnant women, therefore the drug is contraindicated during pregnancy. Preclinical studies revealed reproductive toxicity at high doses; the potential risk to humans is unknown.

Breastfeeding period

The drug Agartha^® is contraindicated during breastfeeding, as it is unknown whether Vildagliptin passes into human breast milk.

Use in Hepatic Impairment

Contraindication: impaired liver function, including patients with elevated liver enzyme activity (ALT or AST) 3 times or more above the upper limit of normal (ULN).

The drug Agartha^® should not be used in patients with impaired liver function, including patients in whom ALT or AST activity before starting treatment with vildagliptin exceeds the ULN by 3 times or more.

Use in Renal Impairment

For patients with mild renal impairment (CrCl<50 ml/min), no dose adjustment of the drug Agartha^® is required. For patients with moderate or severe renal impairment, as well as with end-stage chronic renal failure, the recommended dose of the drug Agartha^® is 50 mg once daily.

Pediatric Use

The use of the drug Agartha^® in children under 18 years of age is not recommended. Efficacy and safety have not been studied. Data are not available.

Geriatric Use

In elderly patients, no adjustment of the dosing regimen of the drug Agartha^® is required.

Special Precautions

In preclinical studies, when used at doses 200 times higher than those recommended for humans, the drug did not cause fertility impairment.

If insulin therapy is necessary, the drug Agartha^® is used only in combination with insulin. The drug is contraindicated in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Heart failure

Since data on the use of vildagliptin in patients with CHF class III according to the NYHA classification are limited and do not allow a definitive conclusion, it is recommended to use the drug Agartha^® with caution in patients of this category.

The use of vildagliptin is not recommended in patients with CHF class IV according to the NYHA classification, due to the lack of clinical study data on the use of vildagliptin in this group of patients.

Renal impairment

Since experience with the use of the drug Agartha^® in patients with end-stage chronic kidney disease, on hemodialysis or undergoing hemodialysis, is limited, the drug should be used with caution in this category of patients.

Hepatic impairment

Since in rare cases, an increase in aminotransferase activity (usually without clinical manifestations) was observed with the use of vildagliptin, before using the drug Agartha^®, and also regularly during the first year of use (every 3 months), it is recommended to determine biochemical parameters of liver function. If an increase in aminotransferase activity is detected, a repeat test should be performed to confirm the result, and then biochemical parameters of liver function should be regularly determined until they normalize. If an increase in AST or ALT activity 3 or more times above the ULN is confirmed by a repeat test, it is recommended to discontinue the drug.

If jaundice or other signs of liver dysfunction develop during the use of the drug Agartha^®, therapy with the drug should be stopped immediately. After normalization of liver function parameters, treatment with the drug should not be resumed.

Hypoglycemia

Sulfonylurea drugs are known to potentially cause hypoglycemia. There is a risk of hypoglycemia with the simultaneous use of vildagliptin and sulfonylurea drugs. If necessary, the possibility of reducing the dose of sulfonylurea drugs should be considered to minimize the risk of hypoglycemia.

Acute pancreatitis

The use of the drug Agartha^® is associated with a risk of developing acute pancreatitis. The patient should be informed about the symptoms characteristic of acute pancreatitis. If acute pancreatitis is suspected, the drug should be discontinued. Therapy should not be resumed if acute pancreatitis was confirmed. The drug Agartha^® should be used with caution in patients with a history of acute pancreatitis.

Excipients

The drug Agartha^® contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

This drug contains less than 1 mmol (23 mg) of sodium per film-coated tablet, i.e., it is essentially sodium-free.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of vildagliptin on the ability to drive vehicles or operate machinery have not been conducted. If dizziness develops during the use of vildagliptin, patients should not drive vehicles or operate machinery.

Overdose

Information on vildagliptin overdose is limited.

Symptoms Vildagliptin is well tolerated when used at doses up to 200 mg/day. When using the drug at a dose of 400 mg/day, the following may be observed: muscle pain, rarely – mild and transient paresthesia, fever, edema, and transient increase in lipase activity (above 2 times the ULN). When the dose of vildagliptin is increased to 600 mg/day, limb edema may develop, accompanied by paresthesia and increased activity of CPK, AST, C-reactive protein level, and myoglobin. All overdose symptoms and changes in laboratory parameters are reversible after drug discontinuation.

Treatment In case of overdose, supportive treatment is recommended. Removal of vildagliptin from the body by hemodialysis is unlikely. However, the main hydrolytic metabolite of vildagliptin (LAY151) can be removed from the body by hemodialysis.

Drug Interactions

Vildagliptin has a low potential for drug interactions when used concomitantly with other drugs.

Since Vildagliptin is not a substrate of cytochrome P450 (CYP) isoenzymes, and also does not inhibit or induce these enzymes, interaction of vildagliptin with drugs that are substrates, inhibitors, or inducers of cytochrome P450 isoenzymes is unlikely.

When used concomitantly, Vildagliptin also does not affect the metabolism rate of drugs that are substrates of the isoenzymes: 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 (glibenclamide, pioglitazone, metformin) or with a narrow therapeutic range (amlodipine, digoxin, ramipril, simvastatin, valsartan, warfarin) has been established.

Thiazides, corticosteroids, thyroid hormone preparations, and sympathomimetics may reduce the hypoglycemic effect of vildagliptin, as well as other oral antidiabetic drugs.

The frequency of angioedema was higher with the concomitant use of vildagliptin with ACE inhibitors, while it was similar to that in the control group. In most cases, angioedema was of moderate severity and resolved on its own during continued therapy with vildagliptin.

Storage Conditions

The drug should be stored out of the reach of children at a temperature below 30°C (86°F) in the original packaging (blister in a cardboard carton) to protect it from moisture.

Shelf Life

Shelf life – 3 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.