Vildagliptin

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

Composition:

Active substance: vildagliptin (vildagliptin);

One tablet contains 50 mg of vildagliptin;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets from white to light yellow in color, round-shaped with a biconvex surface.

Pharmacotherapeutic group. Blood glucose lowering agents, excluding insulin. Dipeptidyl peptidase-4 (DPP-4) inhibitors. ATC code A10BH02.

Pharmacological Properties

Pharmacodynamics

Vildagliptin is a member of the class of substances that enhance the function of pancreatic islet β-cells and is a potent and selective inhibitor of DPP-4.

Mechanism of Action

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

Pharmacodynamic Effects

As a result of increased endogenous levels of these incretin hormones, vildagliptin improves β-cell sensitivity to glucose, leading to enhanced glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes with the drug at doses of 50 to 100 mg per day significantly improved markers of β-cell function, including HOMA-β (homeostatic model assessment of β-cell function), the proinsulin-to-insulin ratio, and measures of β-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.

Due to increased endogenous GLP-1 levels, vildagliptin also enhances α-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 fasting and postprandial periods, thereby decreasing glycemia.

The known effect of elevated GLP-1 levels—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 (C_max) reached within 1.7 hours. Co-administration with food slightly delays the time to reach C_max to 2.5 hours but does not affect total exposure (AUC). Administration of vildagliptin with food reduces C_max by 19%. However, these changes are not considered clinically significant; therefore, the drug can be administered independently of food intake. Absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%), and vildagliptin is evenly distributed between plasma and red blood cells. The mean volume of distribution at steady state (V_ss) after intravenous administration is 71 liters, 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 cyano group, representing 57% of the dose, followed by glucuronide (BQS867) and amide hydrolysis (4% of the 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 measurable extent by cytochrome P450 (CYP450) enzymes. Therefore, concomitant administration of drugs such as CYP450 inhibitors and/or inducers is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have demonstrated that vildagliptin neither inhibits nor induces CYP450 enzymes. Thus, vildagliptin is unlikely to affect the metabolic clearance of co-administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Excretion

After 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 to healthy volunteers, total plasma and renal clearance of vildagliptin were 41 L/h and 13 L/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

Linearity/Non-linearity

C_max and AUC of vildagliptin in plasma increase almost proportionally with dose across the entire therapeutic dose range.

Special Patient Populations

Gender

No differences in the pharmacokinetics of the drug 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.

Geriatric Patients

In otherwise healthy patients aged 70 years and older, total AUC of vildagliptin (100 mg once daily) increased by 32% and C_max in plasma by 18% compared to younger healthy volunteers (aged 18 to 40 years). However, these changes are not considered clinically significant. Inhibition of DPP-4 by vildagliptin was independent of patient age across the studied age groups.

Hepatic Impairment

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

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 renal impairment – 50 to < 80 mL/min, moderate renal impairment – 30–50 mL/min, severe renal impairment – < 30 mL/min), compared to a control group of study participants with normal renal function.

In patients with mild, moderate, and severe renal impairment, vildagliptin AUC increased on average by 1.4-, 1.7-, and 2-fold, respectively, 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) show that vildagliptin AUC 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).

Race

Limited data indicate 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 metformin use 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.

Contraindications.

Hypersensitivity to vildagliptin or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Vildagliptin has a low potential for interactions with other drugs. Since vildagliptin is not a substrate of the CYP450 enzyme system 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 showed no clinically relevant pharmacokinetic interactions.

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

Clinical studies conducted in healthy volunteers showed no clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.

Combination with amlodipine, ramipril, valsartan, or simvastatin

Drug interaction studies were conducted in healthy volunteers with amlodipine, ramipril, valsartan, and simvastatin. These studies revealed no clinically relevant pharmacokinetic interactions after concomitant administration with vildagliptin.

Combination with ACE inhibitors

In patients concurrently taking angiotensin-converting enzyme (ACE) inhibitors, there is an increased risk of angioedema (see section "Adverse reactions").

As with other oral antidiabetic medicinal products, certain concomitant drugs, including thiazides, corticosteroids, thyroid hormones, and sympathomimetics, may reduce the hypoglycemic effect of vildagliptin.

Special precautions.

General

The medicinal product is not a substitute for insulin in insulin-dependent patients. The drug should not be used for the treatment of patients with type 1 diabetes or diabetic ketoacidosis.

Renal impairment

Experience with the use of the drug in patients with end-stage renal disease (ESRD) on hemodialysis is limited; therefore, the medicinal product should be used with caution in such patients (see sections "Pharmacokinetics" and "Dosage and administration").

Hepatic impairment

The medicinal product Vildaglyptin is not recommended for use in patients with hepatic impairment, including patients whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels prior to treatment were more than 3 times the upper limit of normal (ULN) (see sections "Pharmacokinetics" and "Dosage and administration").

Monitoring of liver enzymes

Rare cases of liver dysfunction (including hepatitis) have been reported. These abnormalities were mostly asymptomatic in patients, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment. Prior to initiating treatment with the drug, LFTs should be performed to establish the patient's baseline values. LFT results should be monitored during treatment with the drug every 3 months during the first year of treatment, and periodically thereafter. In patients who experience elevated transaminase levels, repeat monitoring of liver function should be performed to confirm the results, followed by continued frequent monitoring of LFTs until the abnormal levels return to normal. If ALT or AST levels increase to 3 times or more the ULN, discontinuation of the drug is recommended.

If jaundice or other signs of liver dysfunction occur, patients should discontinue the medicinal product. After discontinuation of treatment with the drug and normalization of LFT results, reinitiation of vildaglyptin therapy is not recommended.

Heart failure (HF)

A clinical study of vildaglyptin use in patients with NYHA (New York Heart Association) functional class I–III heart failure showed that treatment with vildaglyptin was not associated with changes in left ventricular function or worsening of existing congestive HF compared to placebo. Clinical experience with the use of the drug in patients with NYHA functional class III heart failure remains limited and results are inconclusive.

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

Skin disorders

Cases of skin lesions, including blistering and ulceration on extremities, have been reported in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience regarding skin complications in patients with diabetes mellitus is limited. Furthermore, during the post-marketing period, cases of bullous and exfoliative skin lesions have been reported. Therefore, in accordance with standard care for patients with diabetes mellitus, monitoring for skin disorders such as blistering or ulceration is recommended.

Acute pancreatitis

The use of vildaglyptin 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, vildaglyptin should not be continued. Upon confirmation of acute pancreatitis, vildaglyptin should not be restarted.

Hypoglycemia

Sulfonylureas are known to cause hypoglycemia. Patients receiving vildaglyptin in combination with a sulfonylurea may be at increased risk of hypoglycemia. Therefore, lower doses of sulfonylurea may be considered to reduce the risk of hypoglycemia.

Excipients

The drug contains lactose; therefore, if the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate studies on the use of vildaglyptin 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 medicinal product should not be used during pregnancy.

Lactation period

It is unknown whether vildaglyptin passes into human breast milk. Animal studies have shown excretion of vildaglyptin into animal milk. The medicinal product should not be administered to women who are breastfeeding.

Fertility

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

Ability to influence reaction rate when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Patients experiencing dizziness should avoid driving or operating machinery.

Method of Administration and Dosage.

Dosage

Adults

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

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

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

Doses exceeding 100 mg of the drug are not recommended.

If a dose of the medication is missed, it should be taken as soon as remembered. 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 thiazolidinedione have not been established.

Additional Information in Specific Patient Populations

Elderly patients (≥ 65 years of age)

Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Patients with renal impairment

No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min). For patients with moderate to severe renal impairment or with end-stage renal disease (ESRD), the recommended dose is 50 mg once daily (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Patients with hepatic impairment

The drug is not recommended for use in patients with hepatic impairment, including patients whose baseline ALT or AST levels are more than 3 times the upper limit of normal (ULN) (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Method of Administration

For oral use.

The drug can be administered independently of food intake (see section "Pharmacokinetics").

Children.

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-titration 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, development of edema, and transient elevation of lipase levels. At a dose of 600 mg, one volunteer developed swelling of the hands and feet, a marked increase in creatine phosphokinase 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 eliminated by hemodialysis.

Adverse reactions.

Summary of safety profile

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

The majority of adverse reactions observed during these studies were mild in nature, transient, and did not require discontinuation of treatment. No association was observed between the occurrence of adverse reactions and patient age or race, duration of drug intake, or daily dose. Cases of hypoglycemia were reported in patients receiving vildagliptin concomitantly with sulfonylureas and insulin. Risk of acute pancreatitis has been reported with vildagliptin use (see section "Special warnings and precautions for use").

Tabulated list of adverse reactions

Adverse reactions observed during double-blind studies in patients treated with vildagliptin as monotherapy or in 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 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions reported during controlled clinical trials and in the post-marketing period in patients treated with vildagliptin as monotherapy or in combination therapy:

Description of selected adverse reactions

Hepatic function disorders

Isolated cases of hepatic dysfunction (including hepatitis) have been reported. These cases 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 ALT or AST elevations ≥ 3 times ULN (identified during two consecutive measurements or at the final visit) was 0.2%, 0.3%, and 0.2% with vildagliptin 50 mg once daily, twice daily, and with all comparator agents, respectively. Transaminase elevations were predominantly asymptomatic, did not progress, and were not associated with cholestasis or jaundice.

Angioedema

Cases of angioedema reported in association with vildagliptin use were infrequent and occurred at a similar rate as in the control group. A higher incidence of such events 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

In comparative controlled monotherapy studies, hypoglycemia, which was infrequent, occurred in 0.4% of patients receiving vildagliptin compared with 0.2% of patients in the active comparator or placebo group. There were no reports of serious or severe events. When vildagliptin was used in combination with metformin, hypoglycemia occurred in 1% of patients receiving vildagliptin and in 0.4% of patients receiving placebo. When pioglitazone was added, hypoglycemia occurred in 0.6% of patients receiving vildagliptin and in 1.9% of patients receiving placebo. When a sulfonylurea was added, hypoglycemia occurred in 1.2% of patients receiving vildagliptin and in 0.6% of patients receiving placebo. When both a sulfonylurea and metformin were added, 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 incidence of hypoglycemia was 14% in the vildagliptin group and 16% in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical 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 of 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 3 or 6 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and location of business activity. 100 Shevchenka Street, Boryspil, Kyiv Oblast, Ukraine, 08301.