Vilgled

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VILGLAD (VILGLAD)

Composition:

active substance: vildagliptin;

1 tablet contains vildagliptin 50 mg;

excipients: microcrystalline cellulose, anhydrous lactose, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat tablets with bevelled edges, white to almost white in colour, with the imprint "V15" on one side and "H" on the other.

Pharmacotherapeutic group. Antidiabetic agents, excluding insulin. Dipeptidyl peptidase-4 inhibitors. Vildagliptin. ATC code A10BH02.

Pharmacological Properties

Pharmacodynamics

Vildagliptin belongs to the class of substances that enhance the function of pancreatic islet beta cells and is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4).

Administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. Inhibition of DPP-4 by vildagliptin increases endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) during both fasting and postprandial states.

By increasing endogenous levels of these incretin hormones, vildagliptin improves beta-cell sensitivity to glucose, leading to enhanced glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes with vildagliptin at doses of 50 to 100 mg daily significantly improved markers of beta-cell function, including HOMA-β (homeostatic model assessment of beta-cell function), the proinsulin-to-insulin ratio, and measures of beta-cell sensitivity during repeated oral glucose tolerance tests. In non-diabetic individuals (with normal blood glucose levels), vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances alpha-cell sensitivity to glucose, resulting in increased glucose-dependent glucagon secretion. The significant increase in the insulin-to-glucagon ratio during hyperglycemia, driven by elevated incretin hormone levels, leads to reduced glucose production during both fasting and postprandial states, thereby lowering glycemia.

The known effect of elevated GLP-1 levels on delayed gastric emptying is not observed during treatment with vildagliptin.

Pharmacokinetics

Absorption

After oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma concentration (Cmax) reached at approximately 1.7 hours. Co-administration with food slightly delays the time to reach Cmax to 2.5 hours but does not affect total exposure (AUC). Administration with food reduces the maximum concentration (Cmax) by 19%. Despite these changes, the magnitude is not considered clinically significant; therefore, vildagliptin can be administered independently of food intake. Absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%); vildagliptin is evenly distributed between plasma and red blood cells. The mean steady-state volume of distribution (Vss) after intravenous administration is 71 L, indicating extensive extravascular distribution.

Metabolism

Metabolism is the primary route of vildagliptin elimination in humans, accounting for 69% of the administered dose. The major metabolite, LAY151, is pharmacologically inactive and results from hydrolysis of the cyanide moiety, representing 57% of the dose. This is accompanied by glucuronide (BQS867) and amide hydrolysis (4% of dose). Data from in vitro studies using human kidney microsomes suggest that the kidneys may be one of the primary organs responsible for the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 partially contributes to the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized to any significant extent by cytochrome P450 enzymes. Therefore, concomitant administration of drugs that are inhibitors and/or inducers of CYP450 is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes. Thus, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Elimination

Following oral administration of [14C]-vildagliptin, approximately 85% of the dose is excreted in urine and 15% in feces. Renal excretion of unchanged vildagliptin accounts for 23% of the orally administered dose. After intravenous administration in healthy volunteers, total plasma and renal clearance of vildagliptin are 41 L/h and 13 L/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity

The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of vildagliptin increase almost proportionally with dose across the entire therapeutic dose range.

Special Patient Populations

Gender

No differences in the pharmacokinetics of vildagliptin were observed between healthy male and female volunteers of various ages and body mass index (BMI). Inhibition of DPP-4 by vildagliptin is independent of patient gender.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of vildagliptin was evaluated in patients with mild, moderate, and severe hepatic impairment based on Child-Pugh classification (scores ranging from 6 for mild to 12 for severe) compared to patients with normal hepatic function. Exposure to vildagliptin after a single dose was reduced by 20% and 8% in patients with mild and moderate hepatic impairment, respectively, whereas exposure increased by 22% in patients with severe hepatic impairment. The maximum change (increase or decrease) in vildagliptin exposure was approximately 30%, which is not considered clinically significant. No correlation was observed between the severity of hepatic impairment and changes in vildagliptin exposure.

Renal Impairment

An open-label, multiple-dose study was conducted to evaluate the pharmacokinetics of the lowest therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment, as defined by creatinine clearance (mild impairment: 50 to < 80 mL/min; moderate impairment: 30 to < 50 mL/min; severe impairment: < 30 mL/min), compared to a control group with normal renal function.

In patients with mild, moderate, and severe renal impairment, AUC of vildagliptin was increased compared to patients with normal renal function. AUC values for metabolites LAY151 and BQS867 increased on average by approximately 1.5-, 3-, and 7-fold in patients with mild, moderate, and severe renal impairment, respectively. Limited data in patients with end-stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment. Concentrations of LAY151 were approximately 2–3 times higher than in patients with severe renal impairment.

Vildagliptin is removed to a limited extent by hemodialysis (3% over a 3–4 hour hemodialysis session initiated 4 hours after drug administration).

Elderly Patients

In otherwise healthy elderly patients (aged 70 years and older), total exposure to vildagliptin (100 mg once daily) increased by 32%, and peak plasma concentration increased by 18%, compared to younger healthy volunteers (aged 18–40 years).

However, these changes are not considered clinically significant. DPP-4 inhibition by vildagliptin is independent of patient age within the studied age groups.

Race

Limited data suggest that race does not have a clinically significant effect on the pharmacokinetics of vildagliptin.

Clinical Characteristics

Indications

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus:

‒ as monotherapy in patients for whom the use of metformin is considered inappropriate due to contraindications or intolerance;

‒ in combination with other antidiabetic medicinal products, including insulin, when they do not provide adequate glycemic control (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics" for available data on various combinations).

Contraindications

Known hypersensitivity to vildagliptin or to any of the excipients.

Interaction with other medicinal products and other forms of interaction

Vildagliptin has a low potential for interaction with other drugs. Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and is neither an inhibitor nor an inducer of CYP450 enzymes, clinically relevant interactions with other medicinal products that are substrates, inhibitors, or inducers of these enzymes are unlikely.

Combination with pioglitazone, metformin, and glimepiride

Results from studies conducted with these oral antidiabetic agents did not show clinically relevant pharmacokinetic interactions.

Digoxin (P-gp substrate), warfarin (CYP2C9 substrate)

Clinical studies conducted in healthy volunteers did not show clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan, or simvastatin

Drug interaction studies in healthy volunteers have been conducted with amlodipine, ramipril, valsartan, and simvastatin. These studies did not reveal any clinically relevant pharmacokinetic interactions following co-administration with vildagliptin.

Combination with ACE inhibitors

An increased risk of angioedema may occur in patients taking ACE inhibitors concomitantly (see section "Adverse reactions").

As with other oral antidiabetic agents, certain active substances, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics, may reduce the hypoglycemic effect of vildagliptin.

Special precautions for use

General

Vildagliptin is not a substitute for insulin in insulin-dependent patients. The drug should not be used to treat patients with type I diabetes or diabetic ketoacidosis.

Renal impairment

Experience with the use of vildagliptin in patients with moderate or severe renal impairment, as well as in patients with end-stage renal disease (ESRD) on hemodialysis, is limited. Therefore, the use of the drug is not recommended in these patient groups.

Hepatic impairment

Vildagliptin is not recommended for use in patients with hepatic impairment, including patients in whom the levels of ALT or AST before treatment were more than 3 times the upper limit of normal.

Monitoring of liver enzyme levels

Rare cases of liver function abnormalities (including hepatitis) have been reported. In such cases, the course of the event was mostly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment. Before initiating treatment with Galvus, LFTs should be performed to establish baseline values in the patient. LFT results should be monitored during the first year of treatment at intervals of every 3–4 months, and periodically thereafter.

For patients in whom elevated transaminase levels are observed, repeat monitoring of liver function should be performed to confirm the results, as well as continued frequent monitoring of liver function tests until the abnormal levels return to normal. If ALT or AST levels increase to 3 times or more above the upper limit of normal, discontinuation of Galvus is recommended. Patients who develop jaundice or other signs of liver dysfunction should discontinue use of Galvus. After discontinuation of the drug and normalization of LFT results, treatment with vildagliptin should not be restarted.

Heart failure

A clinical study of vildagliptin use in patients with heart failure of NYHA functional classes I–III showed that treatment with vildagliptin was not associated with changes in left ventricular function or worsening of existing congestive heart failure. Clinical experience with use in patients with NYHA class III heart failure remains limited and results are not convincing.

There is no clinical experience with the use of vildagliptin in patients with NYHA class IV heart failure; therefore, the drug is not recommended for use in these patients.

Skin disorders

In preclinical toxicological studies, skin lesions including formation of blisters and ulcers on extremities were reported in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin complications in patients with diabetes is limited.

Furthermore, during the post-marketing period, cases of bullous and exfoliative skin reactions have been reported.

Therefore, in accordance with standard care for patients with diabetes, monitoring for skin disorders such as blister or ulcer formation is recommended.

Acute pancreatitis

The use of vildagliptin is associated with a risk of developing acute pancreatitis. Patients should be informed about the typical symptoms of acute pancreatitis.

If acute pancreatitis is suspected, vildagliptin should not be continued. If acute pancreatitis is confirmed, reinitiation of vildagliptin treatment is not recommended. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycemia

It is known that sulfonylureas can cause hypoglycemia. Patients receiving vildagliptin in combination with a sulfonylurea may be prone to hypoglycemia. Therefore, lower doses of sulfonylureas may be considered to reduce the risk of hypoglycemia.

Other

The drug Galvus tablets contain lactose. This medicinal product should not be used in patients with rare hereditary conditions such as lactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The drug contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There are currently no adequate studies on the use of vildagliptin in pregnant women.

Animal studies have shown reproductive toxicity when high doses of the drug were administered. The potential risk to humans is unknown. Due to the lack of data, the drug should not be used during pregnancy.

Breastfeeding

It is unknown whether vildagliptin passes into human breast milk. Animal studies have shown that vildagliptin is excreted into animal milk. The drug should not be administered to women who are breastfeeding.

Fertility

Studies on the effect of vildagliptin on human fertility have not been conducted.

Ability to influence the speed of reactions when driving or operating machinery

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted. Patients who experience dizziness should not drive or operate machinery.

Dosage and Administration

When used as monotherapy, in combination with metformin, in combination with a thiazolidinedione, in combination with metformin and a sulfonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, administered in two divided doses: 50 mg in the morning and 50 mg in the evening.

When used in combination with a sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily in the morning. In this patient population, vildagliptin 100 mg once daily was not more effective than vildagliptin 50 mg once daily.

When used in combination with a sulfonylurea, lower doses of the sulfonylurea may be considered to reduce the risk of hypoglycemia.

Doses exceeding 100 mg of the drug are not recommended.

If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

The safety and efficacy of vildagliptin in triple oral therapy in combination with metformin and a thiazolidinedione have not been established.

Dosing in patients with hepatic or renal impairment

Vigled is not recommended for patients with hepatic impairment, including patients whose baseline ALT or AST levels are more than 3 times the upper limit of normal.

No dose adjustment is required for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min). For patients with moderate or severe renal impairment or end-stage renal disease (ESRD), the recommended dose is 50 mg once daily.

Dosing in elderly patients

No dose adjustment is required for patients aged 65 years and older.

Administration

For oral use.

Vigled can be administered regardless of food intake.

Pediatric population

The use of the drug is not recommended in children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Overdose

Information regarding vildagliptin overdose is limited.

Symptoms

Information on potential overdose symptoms was obtained from a dose escalation tolerability study in healthy volunteers who received vildagliptin for 10 days. At a dose of 400 mg, three cases of muscle pain were observed, along with several cases of mild and transient paresthesia, fever, edema, and temporary increases in lipase levels. At a dose of 600 mg, one volunteer developed swelling of the hands and feet, a marked increase in creatine phosphokinase (CPK) levels accompanied by elevated AST, C-reactive protein, and myoglobin levels. Three volunteers in this group developed bilateral leg edema, which was accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Treatment

In case of overdose, supportive therapy is recommended. Vildagliptin is not removed by hemodialysis; however, most of the hydrolysis metabolites (LAY 151) can be removed by hemodialysis.

Adverse Reactions

Short description of the safety profile

Safety data were obtained from a total of 5451 patients who received vildagliptin at a daily dose of 100 mg (50 mg twice daily) in randomized, double-blind, placebo-controlled studies of at least 12 weeks’ duration. Of these patients, 4622 received vildagliptin as monotherapy and 829 received placebo.

The majority of adverse reactions in these studies were mild in nature, transient, and did not require discontinuation of treatment. No association was observed between the development of adverse reactions and patient age or race, duration of drug exposure, or daily dose.

Hypoglycemia has been reported in patients receiving vildagliptin in combination with sulfonylurea derivatives and insulin. Acute pancreatitis has been reported with the use of vildagliptin (see section "Special Warnings and Precautions for Use").

Adverse reactions observed during double-blind studies in patients receiving vildagliptin as monotherapy or as part of combination therapy are listed below by system organ class and absolute frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (≤ 1/10000), frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing seriousness.

Adverse reactions reported in patients receiving vildagliptin
as monotherapy or as add-on therapy
in controlled clinical studies and in the post-marketing period

Description of selected adverse reactions

Hepatic impairment

Isolated cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, patients were generally asymptomatic without clinical consequences, and liver function returned to normal after discontinuation of treatment. According to data from controlled monotherapy and add-on therapy studies of up to 24 weeks duration, the incidence of elevations in ALT or AST levels ≥ 3 times the upper limit of normal (defined as present in at least two consecutive measurements or at the last visit during treatment) for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily, and all comparator agents was 0.2%, 0.3%, and 0.2%, respectively. Transaminase elevations were predominantly asymptomatic, did not progress, and were not associated with cholestasis or jaundice.

Angioedema

Isolated cases of angioedema reported in association with vildagliptin occurred at a frequency similar to that in the control group. A higher incidence of such cases was observed in the group where vildagliptin was used in combination with an ACE inhibitor. Most events were mild in severity and resolved while continuing vildagliptin treatment.

Hypoglycemia

Hypoglycemia was infrequent with vildagliptin monotherapy (0.4%) in comparative controlled monotherapy studies with active comparator or placebo (0.2%). No severe or serious cases of hypoglycemia were reported. When used as add-on to metformin, hypoglycemia occurred in 1% of patients receiving vildagliptin and in 0.4% of patients receiving placebo. After adding pioglitazone, hypoglycemia occurred in 0.6% of patients receiving vildagliptin and in 1.9% of patients receiving placebo. When added to sulfonylurea, hypoglycemia occurred in 1.2% of patients receiving vildagliptin and in 0.6% of patients receiving placebo. After adding sulfonylurea and metformin, hypoglycemia occurred in 5.1% of patients receiving vildagliptin and in 1.9% of patients receiving placebo. In patients receiving vildagliptin in combination with insulin, the frequency of hypoglycemia was 14% for vildagliptin and 16% for placebo.

Reporting of adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 ºC, protected from moisture and out of reach of children.

Packaging

10 tablets per blister, 10 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer

Hetero Labs Limited, India / Hetero Labs Limited, India.

Manufacturer's address and location of its business operations

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India /
Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.