Bidspitin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIDSIPTIN (BIDSIPTIN)

Composition:

Active substance: vildagliptin;

1 tablet contains 50 mg of vildagliptin;

Excipients: lactose, sodium stearyl fumarate, microcrystalline cellulose, sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physicochemical properties: round tablets, white or almost white.

Pharmacotherapeutic group. Synthetic antidiabetic drugs and other agents. 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 leads to increased endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) during fasting 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 doses of 50 to 100 mg daily significantly improved markers of β-cell function, including HOMA-β (homeostatic model assessment of β-cell function), proinsulin-to-insulin ratio, and measures of β-cell sensitivity during repeated oral glucose tolerance tests. In individuals without diabetes (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 after meals, thereby lowering 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. However, these changes are not considered clinically significant; therefore, the medicinal product BIDSSIPIN can be taken independently of food intake. Absolute bioavailability is 85%.

Distribution

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

Biotransformation

Metabolism is the main route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The primary metabolite (LAY151) is pharmacologically inactive and results from hydrolysis of the cyanogroup, 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 main organs responsible for the hydrolysis of vildagliptin to its primary inactive metabolite, LAY151. DPP-4 partially participates in the hydrolysis of vildagliptin, as confirmed by in vivo studies in DPP-4-deficient rats.

Vildagliptin is not metabolized by cytochrome P450 (CYP450) enzymes to any clinically detectable extent. Therefore, concomitant administration of drugs such as inhibitors or inducers of CYP450 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 were 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 of vildagliptin in plasma and the area under the plasma concentration-time curve (AUC) increase almost proportionally with dose across the entire therapeutic dose range.

Special patient populations

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 was independent of patient age in 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 Child–Pugh score (ranging from 6 for mild to 12 for severe impairment), compared to patients with normal liver function. AUC of vildagliptin after single-dose administration 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 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 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 by 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 effect on the pharmacokinetics of vildagliptin.

Clinical characteristics.

Indications

The medicinal product BIDSIPTIN 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 unacceptable 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 interaction with other drugs. Since vildagliptin is not a substrate of the CYP450 enzyme and is neither an inhibitor nor an inducer of CYP450 enzymes, clinically relevant interactions with other drugs that are substrates, inhibitors, or inducers of these enzymes are unlikely.

Combination with pioglitazone, metformin, and glipizide

Results of 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. During these studies, no clinically significant pharmacokinetic interactions were observed after concomitant administration of these agents with vildagliptin.

Combination with ACE inhibitors

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

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

Special precautions for use.

The medicinal product BIDSEPTIN 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 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 medicinal product is not recommended in these patient groups (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and administration").

Hepatic impairment

BIDSEPTIN is not recommended for use in patients with hepatic impairment, including patients in whom alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels before treatment exceeded the upper limit of normal (ULN) by more than 3 times (see sections "Pharmacokinetics" and "Dosage and administration").

Monitoring of liver enzyme levels

Rare cases of hepatic dysfunction (including hepatitis) have been reported. These abnormalities in patients were mostly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal levels after discontinuation of treatment.

Prior to initiating treatment with BIDSEPTIN, LFTs should be performed to establish baseline values in the patient. Monitoring of LFT results during treatment with the drug is required during the first year of treatment at 3-month intervals, and periodically thereafter.

In patients who show elevated transaminase levels, repeat monitoring of liver function should be performed to confirm the results, followed by continued frequent monitoring of LFTs until abnormal levels return to normal. If ALT or AST levels increase to 3 times or more above ULN, discontinuation of treatment with BIDSEPTIN is recommended. If jaundice or other signs of hepatic dysfunction occur, patients should discontinue use of the medicinal product BIDSEPTIN. After discontinuation of treatment and normalization of LFT results, reinitiation of treatment with vildagliptin is not recommended.

Heart failure (HF)

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

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

Cases of skin lesions, including blistering and ulcers on the 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.

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 pancreatitis is suspected, vildagliptin should not be continued. If acute pancreatitis is confirmed, vildagliptin should not be restarted.

Hypoglycemia

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

Sodium

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

Lactose intolerance

The medicinal product BIDSEPTIN contains lactose. This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

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 at high doses of the drug. The potential risk to humans is unknown. Due to the lack of data, the medicinal product BIDSEPTIN should not be used during pregnancy.

Lactation period

It is not known whether vildagliptin is excreted in human breast milk. Animal studies have shown excretion of vildagliptin into animal milk. The medicinal product BIDSEPTIN 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 affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted. Patients experiencing dizziness should avoid driving or operating other 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 developing hypoglycemia, low doses of sulfonylurea may be considered.

Doses exceeding 100 mg of the medicinal product are not recommended.

If a dose of BIDSIPTIN 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

Elderly Patients

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

Patients with Hepatic or Renal Impairment

The medicinal product BIDSIPTIN is not recommended for patients with hepatic impairment, including patients who have baseline ALT or AST levels more than three times the upper limit of normal (ULN).

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

Method of Administration

For oral use.

BIDSIPTIN may be administered independently of food intake.

Children

BIDSIPTIN 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

Information on possible overdose symptoms was obtained from a dose-tolerance 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 temporary elevation of lipase levels. At a dose of 600 mg, one volunteer developed swelling of the legs and arms, 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 removed by hemodialysis; however, most of the hydrolysis metabolites (LAY 151) can be eliminated by hemodialysis.

Adverse reactions

Summary of safety profile

Data on the safety of the drug were obtained from randomized, double-blind, placebo-controlled studies of at least 12 weeks’ duration involving a total of 5451 patients who received 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 and transient, and did not require discontinuation of treatment. There was no identified relationship between the occurrence of adverse reactions and patient age or race, duration of drug exposure, or daily dose. Cases of hypoglycemia were reported in patients receiving vildagliptin concomitantly with sulfonylureas and insulin. There have been reports of a risk of developing acute pancreatitis with the use of vildagliptin.

List of adverse reactions

Adverse reactions observed during double-blind studies in patients receiving vildagliptin as monotherapy and in combination therapy are listed below by system organ class and absolute frequency for each indication. 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), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Description of individual 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 elevations in ALT or AST levels to ≥ 3 times the upper limit of normal (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

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 angiotensin-converting enzyme (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. No serious or severe events were reported. 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 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 frequency of hypoglycemia was 14% in the vildagliptin group and 16% in the placebo group.

Reporting suspected adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. 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. 3 years.

Storage conditions. Store protected from light and moisture at temperatures not exceeding 30 °C, in the original cardboard packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. SAG MANUFACTURING, S.L.U.

Manufacturer's address and location of its business operations.

Saramera Nacional I, Km 36 San Agustin del Guadalix, 28750 Madrid, Spain.

Marketing Authorization Holder.

Mega Lifesciences (Australia) Pty Ltd.

Address of the Marketing Authorization Holder.

60, National Avenue, Pakenham, Victoria 3810, Australia.