Glipvilo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLYPVILO (GLYPVILO®)

Composition:

Active substance: vildagliptin;

1 tablet contains 50 mg of vildagliptin;

Excipients: mannite, hydroxypropylcellulose (type EF), low-substituted hydroxypropylcellulose, microcrystalline cellulose (type 112), sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, beveled-edge tablets of white or almost white color.

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

Pharmacological Properties

Pharmacodynamics

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

Mechanism of Action

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

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 meal tolerance tests. In non-diabetic patients (with normal blood glucose levels), vildagliptin does not cause stimulation of insulin secretion or reduction in glucose levels.

Due to increased endogenous levels of GLP-1, 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 in both fasting and postprandial states, thereby reducing glycemia.

The known effect of elevated GLP-1 levels to delay 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) observed at 1.7 hours. Concomitant food intake slightly delays the time to reach Cmax to 2.5 hours but does not affect total exposure (AUC). Administration of vildagliptin with food results in a 19% reduction in Cmax. Despite this, the magnitude of these changes is not clinically significant; therefore, Glipvilo 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 (Vss) following intravenous administration is 71 liters, indicating extensive extravascular distribution.

Biological Transformation

Metabolism is the primary route of elimination of vildagliptin 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 glucuronidation (BQS867) and amide hydrolysis (4% of the dose). Data from in vitro studies using human kidney microsomes indicate that the kidneys may be one of the main organs responsible for the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 partially contributes to the hydrolysis of vildagliptin, as confirmed in in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized by cytochrome P450 (CYP450) enzymes to any measurable extent. Therefore, co-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 concomitantly administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5.

Elimination

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 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

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

Special Patient Groups

Sex

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 sex.

Elderly Patients

In otherwise healthy patients aged 70 years and older, total AUC of vildagliptin (100 mg once daily) increased by 32% and Cmax 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 is independent of patient age within 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 classification 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 was reduced in patients with mild and moderate hepatic impairment (by 20% and 8%, respectively), whereas AUC increased by 22% in patients with severe hepatic impairment. The maximum change (increase or decrease) in vildagliptin AUC was approximately 30%, which is not considered clinically significant. No correlation was observed between the degree of hepatic impairment severity 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, 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) 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 was eliminated to a limited extent via hemodialysis (3% over a 3–4 hour hemodialysis session initiated 4 hours after drug administration).

Race

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

Clinical characteristics.

Indications.

Glypivyl® should be prescribed 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 treatment with metformin is considered inappropriate due to contraindications or intolerance;
• in combination with other antidiabetic medicinal products, including insulin, when treatment does not provide adequate glycemic control (for available data on various combinations, see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Vildagliptin has a low potential for interaction 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 significant interactions with other medicinal products that are substrates, inhibitors, or inducers of these enzymes are unlikely.

Combination with pioglitazone, metformin, and glipizide

Clinical studies conducted with these oral antidiabetic agents did not reveal clinically significant pharmacokinetic interactions.

Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)

Clinical studies conducted in healthy volunteers did not show clinically significant 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. In these studies, no clinically significant pharmacokinetic interactions were observed after concomitant administration of these drugs with vildagliptin.

Combination with ACE inhibitors

In patients receiving concomitant angiotensin-converting enzyme (ACE) inhibitors, there is an increased risk of developing angioedema.

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

Special precautions for use.

General

Glipvilo is not a substitute for insulin in insulin-dependent patients. The drug should not be used to treat patients with type 1 diabetes or diabetic ketoacidosis.

Renal impairment

Experience with the use of the drug in patients with moderate or severe renal impairment, as well as in patients with end-stage renal disease (ESRD) on hemodialysis, is limited; therefore, use of the drug is not recommended in these patient groups (see sections "Pharmacological properties" and "Dosage and administration").

Hepatic impairment

Glipvilo is not recommended for use in patients with hepatic impairment, including patients whose baseline ALT or AST levels were more than 3 times the upper limit of normal (ULN) prior to treatment (see sections "Pharmacological properties" and "Dosage and administration").

Monitoring of liver enzymes

Rare cases of liver dysfunction (including hepatitis) have been reported. In such cases, the course of the disorder was predominantly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment.

Prior to initiating Glipvilo therapy, LFTs should be performed to establish baseline values in the patient. LFT results should be monitored every 3 months during the first year of treatment, and periodically thereafter.

For patients in whom elevated transaminase levels are observed, repeat monitoring of liver function should be performed to confirm results, followed by continued monitoring with more frequent LFTs until abnormal levels return to normal. If ALT or AST levels increase to 3 times or more the ULN, discontinuation of Glipvilo therapy is recommended. If jaundice or other signs of liver dysfunction occur, Glipvilo should be discontinued. After discontinuation of the drug and normalization of LFT results, treatment with vildagliptin should not be restarted.

Heart failure (HF)

A clinical study of vildagliptin use in patients with NYHA functional class I–III heart failure showed that treatment with vildagliptin was not associated with changes in left ventricular function or worsening of existing congestive heart failure. Clinical experience with the drug in patients with NYHA functional 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 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 of the extremities, have been reported in monkeys. Although an increased incidence of skin lesions was not observed during clinical trials, experience regarding skin complications in patients with diabetes mellitus is limited.

Additionally, 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.

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 therapy is not recommended.

Hypoglycemia

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

Sodium

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

Use during pregnancy or breastfeeding.

Pregnancy

There are 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, Glipvilo should not be used during pregnancy.

Breastfeeding period

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

Fertility

No studies on the effect of the drug on human fertility have been conducted.

Ability to affect reaction speed 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 experiencing dizziness should avoid driving or operating machinery.

Method of Administration and Dosage

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 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, to reduce the risk of hypoglycemia, low doses of sulfonylurea may be considered.

Doses exceeding 100 mg of the drug are not recommended.

If a dose of Glipvilo 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 thiazolidinedione have not been established.

Special Patient Groups

Dosing in elderly patients (≥ 65 years)

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

Dosing in patients with hepatic or renal impairment

Glipvilo 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 (ULN).

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

Method of Administration

For oral use.

Glipvilo can be administered independently of food intake.

Children

Glipvilo is not recommended for use 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

Data on potential overdose symptoms were obtained from a tolerability study involving dose escalation 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 temporary elevation of lipase levels. At a dose of 600 mg, one volunteer developed swelling of the feet and hands, 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 in two cases was associated with paresthesia. All symptoms and laboratory abnormalities resolved after discontinuation of the investigational drug.

Treatment

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

Adverse reactions.

Data on the safety of the drug were obtained from double-blind, placebo-controlled studies lasting at least 12 weeks, involving a total of 5451 patients who received vildagliptin at a daily dose of 100 mg (50 mg twice daily). Of these patients, 4662 received vildagliptin as monotherapy and 829 received placebo.

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

Adverse reactions observed during double-blind studies in patients receiving vildagliptin either as monotherapy or in combination therapy are listed below for each indication by system organ class and absolute frequency. Frequency is 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 based on available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed in patients receiving vildagliptin 100 mg daily as monotherapy during double-blind studies

Table 1

Description of individual adverse reactions.

Hepatic function disorders

Rare cases of hepatic function disorders (including hepatitis) have been reported. These cases were asymptomatic, without clinical consequences, and liver function recovered after discontinuation of treatment. According to data from controlled monotherapy and combination therapy studies up to 24 weeks, the incidence of ALT or AST levels increasing to ≥ 3 × ULN (defined as present in at least two consecutive measurements or at the last treatment visit) was 0.2% for vildagliptin 50 mg once daily, 0.3% for vildagliptin 50 mg twice daily, and 0.2% for all comparator agents. These transaminase elevations were asymptomatic, non-progressive in nature, and not associated with cholestasis or jaundice.

Angioedema

Rare cases of angioedema have been reported with vildagliptin use, occurring at the same frequency as in the control group. A higher number of cases was reported when vildagliptin was administered in combination with an angiotensin-converting enzyme (ACE) inhibitor. Most cases were mild and resolved with continued use of vildagliptin.

Hypoglycemia

In comparative controlled monotherapy studies, hypoglycemia, which was uncommon, occurred in 0.4% of patients receiving vildagliptin as monotherapy, compared to 0.2% of patients in the active comparator or placebo group. No severe or serious cases of hypoglycemia were reported.

Hypoglycemia occurred in 1% of patients receiving vildagliptin as add-on to metformin, versus 0.4% of patients receiving placebo. Hypoglycemia occurred in 0.6% of patients receiving pioglitazone as add-on to vildagliptin, versus 1.9% of patients receiving placebo. Hypoglycemia occurred in 1.2% of patients receiving sulfonylurea with vildagliptin, versus 0.6% of patients receiving placebo.

When sulfonylurea and metformin were used together, hypoglycemia occurred in 5.1% of patients receiving vildagliptin, versus 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 suspected adverse reactions.

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years

Storage conditions. No special temperature storage conditions are required for this medicinal product. Store in the original packaging to protect from moisture.

Keep out of reach of children.

Packaging. 15 tablets per blister, 2 or 4 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's location and address of place of business.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.