AIGLIP

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

Composition:

Active substance: vildagliptin;

1 tablet contains vildagliptin 50 mg;

Excipients: microcrystalline cellulose, anhydrous lactose, low-substituted hydroxypropylcellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: round tablets with flat surface and bevelled edges, white to slightly yellowish in colour.

Pharmacotherapeutic group. Synthetic hypoglycemic agents and other agents. Dipeptidyl peptidase-4 inhibitors. ATC code A10BH02.

Pharmacological Properties

Pharmacodynamics

Vildagliptin belongs to a 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. By inhibiting DPP-4, 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.

As a result of increased 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 (homeostasis model assessment of β-cell function), the proinsulin-to-insulin ratio, and measures of beta-cell sensitivity during repeated meal 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 alpha-cell sensitivity to glucose, resulting in increased glucose-dependent glucagon secretion. The marked 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 lowering glycemia.

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

Clinical Efficacy and Safety

Over 15,000 patients with type 2 diabetes participated in double-blind, placebo- or active-controlled clinical trials with treatment duration exceeding 2 years. In these studies, vildagliptin was administered to over 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily, or 100 mg once daily. Over 5,000 male and over 4,000 female patients received vildagliptin at a dose of 50 mg once daily or 100 mg once daily. Over 1,900 patients aged ≥65 years received vildagliptin at a dose of 50 mg once daily or 100 mg once daily. In these trials, vildagliptin was used either as monotherapy in patients with type 2 diabetes who had not previously received antidiabetic medications, or in combination therapy in patients inadequately controlled with other antidiabetic agents.

Overall, vildagliptin improved glycemic control when used as monotherapy or in combination with metformin, sulfonylureas, or thiazolidinediones, as demonstrated by clinically meaningful reductions in HbA1c from baseline to study endpoint (see Table 1).

In clinical trials, the magnitude of HbA1c reduction with vildagliptin was greater in patients with higher baseline HbA1c levels.

In a 52-week, double-blind, controlled study, vildagliptin (50 mg twice daily) reduced baseline HbA1c by -1.0% compared to -1.6% with metformin (titrated to 2 g/day); statistically significant non-inferiority was not achieved. Patients receiving vildagliptin reported significantly lower rates of gastrointestinal adverse reactions compared to those receiving metformin.

In a 24-week, double-blind, controlled study, vildagliptin (50 mg twice daily) was compared with rosiglitazone (8 mg once daily). Mean HbA1c reduction was -1.20% with vildagliptin and -1.48% with rosiglitazone in patients with a mean baseline HbA1c of 8.7%. Patients receiving rosiglitazone experienced a mean increase in body weight (+1.6 kg), whereas no weight gain was observed in patients receiving vildagliptin (-0.3 kg). The incidence of peripheral edema was lower in the vildagliptin group than in the rosiglitazone group (2.1% vs. 4.1%, respectively).

In a 2-year clinical trial, vildagliptin (50 mg twice daily) was compared with gliclazide (up to 320 mg/day). After 2 years, mean HbA1c reduction was -0.5% with vildagliptin and -0.6% with gliclazide, compared to a mean baseline HbA1c of 8.6%. Statistically significant non-inferiority was not achieved. Vildagliptin was associated with fewer hypoglycemic events (0.7%) compared to gliclazide (1.7%).

In a 24-week study, vildagliptin (50 mg twice daily) was compared with pioglitazone (30 mg once daily) in patients with inadequate control on metformin (mean daily dose: 2020 mg). Mean HbA1c reduction from a baseline of 8.4% was -0.9% with the addition of vildagliptin to metformin and -1.0% with the addition of pioglitazone to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin, compared to +0.3 kg in those receiving vildagliptin added to metformin.

In a 2-year clinical trial, vildagliptin (50 mg twice daily) was compared with glimepiride (up to 6 mg/day, mean dose over 2 years: 4.6 mg) in patients receiving metformin (mean daily dose: 1894 mg). After 1 year, mean HbA1c reduction was -0.4% with vildagliptin added to metformin and -0.5% with glimepiride added to metformin from a mean baseline HbA1c of 7.3%. Change in body weight was -0.2 kg with vildagliptin versus +1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At the study endpoint (2 years), HbA1c levels were similar to baseline in both treatment groups, while differences in body weight and hypoglycemia incidence persisted.

In a 52-week study, vildagliptin (50 mg twice daily) was compared with gliclazide (mean daily dose 229.5 mg) in patients inadequately controlled on metformin (baseline metformin dose 1928 mg/day). After 1 year, mean HbA1c reduction was -0.81% with vildagliptin added to metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (mean baseline HbA1c 8.5%); statistically significant non-inferiority was achieved (95% CI: -0.11 to 0.20). Change in body weight with vildagliptin was +0.1 kg compared to +1.4 kg with gliclazide.

In a 24-week study, the efficacy of a fixed-dose combination of vildagliptin and metformin (titrated to 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) was evaluated as initial therapy in patients not previously on antidiabetic medication. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1c by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin 1000 mg twice daily by -1.36%, and vildagliptin 50 mg twice daily by -1.09%, from a mean baseline HbA1c of 8.6%. The reduction in HbA1c was greater in patients with baseline levels ≥10.0%.

A 24-week, multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the effect of vildagliptin 50 mg once daily versus placebo in 515 patients with type 2 diabetes and moderate (N=294) or severe (N=221) renal impairment. At baseline, 68.8% and 80.5% of patients with moderate and severe renal impairment, respectively, were receiving insulin (mean daily dose 56 and 51.6 units, respectively). In patients with moderate renal impairment, vildagliptin significantly reduced HbA1c compared to placebo (difference: -0.53%) from a mean baseline of 7.9%. In patients with severe renal impairment, vildagliptin significantly reduced HbA1c compared to placebo (difference: -0.56%) from a mean baseline of 7.7%.

A 24-week, randomized, double-blind, placebo-controlled study involving 318 patients evaluated the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg/day) and glimepiride (≥4 mg/day). Vildagliptin in combination with metformin and glimepiride significantly reduced HbA1c compared to placebo. The placebo-corrected mean reduction from a mean baseline HbA1c of 8.8% was -0.76%.

A 24-week, randomized, double-blind, placebo-controlled study was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with stable doses of basal or premixed insulin (mean daily dose 41 units), with or without concomitant metformin (N=276 with metformin, N=173 without). Vildagliptin in combination with insulin significantly reduced HbA1c compared to placebo. In the overall population, the placebo-corrected mean reduction from a mean baseline HbA1c of 8.8% was -0.72%. In subgroups receiving insulin with or without concomitant metformin, the placebo-corrected mean HbA1c reductions were -0.63% and -0.84%, respectively. The incidence of hypoglycemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin showed no increase in body weight (+0.2 kg), while those receiving placebo experienced a slight weight loss (-0.7 kg).

In another 24-week study in patients with advanced type 2 diabetes inadequately controlled on insulin (short- and long-acting, mean insulin dose 80 IU/day), the mean reduction in HbA1c with the addition of vildagliptin (50 mg twice daily) to insulin was statistically significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).

A 52-week, multicenter, randomized, double-blind study was conducted in patients with type 2 diabetes and chronic heart failure (NYHA functional class I-III) to evaluate the effect of vildagliptin 50 mg twice daily (N=128) versus placebo (N=126) on left ventricular ejection fraction. Vildagliptin was not associated with changes in left ventricular function or worsening of pre-existing chronic heart failure. Overall, cardiovascular events were balanced. However, in patients with NYHA class III heart failure, more cardiac events were observed in the vildagliptin group compared to placebo. However, there was an imbalance in baseline cardiovascular risk favoring placebo, and the number of events was low, precluding definitive conclusions. Vildagliptin significantly reduced HbA1c compared to placebo (difference: 0.6%) from a mean baseline of 7.8% at week 16. In the subgroup with NYHA class III, the HbA1c reduction compared to placebo was smaller (difference: 0.3%), but this finding is limited by the small number of patients (n=44). The incidence of hypoglycemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.

A five-year, multicenter, randomized, double-blind study (VERIFY) was conducted in patients with type 2 diabetes to evaluate the effect of early combination therapy with vildagliptin and metformin (N=998) versus standard initial monotherapy with metformin followed by combination with vildagliptin (sequential therapy group) (N=1003) in newly diagnosed patients with type 2 diabetes. The combination regimen of vildagliptin 50 mg twice daily plus metformin resulted in a statistically and clinically significant relative reduction in the risk of "time to confirmed initial treatment failure" (HbA1c ≥7%) compared to metformin monotherapy in treatment-naïve patients with type 2 diabetes over 5 years of follow-up (HR [95% CI]: 0.51 [0.45, 0.58]; p<0.001). The rate of initial treatment failure (HbA1c ≥7%) was 429 (43.6%) in the combination therapy group and 614 (62.1%) in the sequential therapy group.

Cardiovascular Disease

A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV clinical trials of monotherapy and combination therapy lasting more than 2 years (mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) showed that treatment with vildagliptin was not associated with an increased cardiovascular risk compared to comparator agents. The composite endpoint of major adverse cardiovascular events (MACE), including acute myocardial infarction, stroke, or cardiovascular death, was similar for vildagliptin compared to combined active control and placebo [Mantel-Haenszel risk ratio (M-H RR): 0.82 (95% CI: 0.61–1.11)]. MACE occurred in 83 of 9,599 (0.86%) patients receiving vildagliptin and in 85 of 7,102 (1.20%) patients receiving comparator agents. Evaluation of each individual MACE component showed no increased risk (similar M-H RR). Confirmed cases of heart failure (HF), defined as HF requiring hospitalization or new-onset HF, were reported in 41 (0.43%) patients receiving vildagliptin and 32 (0.45%) patients receiving comparator agents, with an M-H RR of 1.08 (95% CI: 0.68–1.70).

Key efficacy results of vildagliptin in placebo-controlled monotherapy and add-on combination therapy studies (primary efficacy in the intention-to-treat (ITT) population)

Table 1

Pharmacokinetics.

Absorption

After oral administration in a fasting state, vildagliptin is rapidly absorbed, with maximum plasma concentration (Cmax) observed at 1.7 hours. Concomitant intake with food slightly delays the time to reach Cmax in plasma 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 changes is not clinically significant; therefore, Aiglip**®** can be taken independently of food intake. Absolute bioavailability is 85%.

Distribution

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

Metabolism

Metabolism is the main elimination pathway of vildagliptin 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, along with glucuronide (BQS867) and amide hydrolysis (4% of the dose). Data obtained from in vitro studies using human kidney microsomes indicate that the kidneys may be one of the primary organs contributing to the hydrolysis of vildagliptin into its major 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 enzymes to a measurable extent. Therefore, concomitant use of drugs such as inhibitors and/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 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.

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 are 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

Cmax and AUC for vildagliptin 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 Aiglip**®** is independent of patient gender.

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 classification scores (ranging from 6 for mild to 12 for severe) compared to patients with normal liver function. Exposure to vildagliptin after a single dose in patients with mild and moderate hepatic impairment was reduced (by 20% and 8%, respectively), whereas exposure in patients with severe hepatic impairment increased by 22%. 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 determined by creatinine clearance (mild renal impairment: 50 to <80 mL/min; moderate renal impairment: 30 to <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 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 was 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 Cmax by 18%, compared to younger healthy volunteers (aged 18 to 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 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.

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 the cytochrome P450 (CYP) 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 from studies conducted with these oral antidiabetic agents showed no clinically relevant pharmacokinetic interactions.

Digoxin (Pgp 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 in healthy volunteers have been conducted with amlodipine, ramipril, valsartan, and simvastatin. These studies revealed no clinically relevant pharmacokinetic interactions after co-administration with vildagliptin.

Combination with ACE inhibitors

When used concomitantly with ACE inhibitors, there is an increased risk of angioedema (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

Aiglip® 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 the drug in patients with ESRD on haemodialysis is limited. Therefore, Aiglip® should be used with caution in these patient groups.

Hepatic impairment

Aiglip® is not recommended for use in patients with hepatic impairment, including patients whose baseline levels of ALT or AST were more than 3 times above the upper limit of normal prior to treatment.

Monitoring of liver enzyme levels

Rare cases of liver dysfunction (including hepatitis) have been reported. In such cases, the course in patients was mostly asymptomatic, without clinical consequences, and liver function test (LFT) results returned to normal after discontinuation of treatment. Before initiating treatment with Aiglip®, LFTs should be performed to establish baseline values in the patient. Monitoring of LFT results should be performed during treatment with the drug every three 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 the results, as well as further monitoring with frequent liver function testing until abnormal levels return to normal. If ALT or AST levels increase to 3 times or more above the upper limit of normal, discontinuation of Aiglip® is recommended.

If jaundice or other signs of liver dysfunction occur, Aiglip® should be discontinued.

After discontinuation of treatment and normalization of LFT results, treatment with vildagliptin should not be restarted.

Heart failure

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 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 vildagliptin in patients with NYHA functional class IV heart failure; therefore, the drug is not recommended for use in these patients.

Skin disorders

In preclinical toxicological studies, skin lesions including blistering and ulceration of extremities were reported in monkeys. Although no increased incidence of skin lesions was observed during clinical trials, experience with 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, as part of 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, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycaemia

Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination with a sulphonylurea may be prone to hypoglycaemia. Therefore, to reduce the risk of hypoglycaemia, lower doses of sulphonylurea may be considered.

Other

Aiglip® tablets contain lactose. If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

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, Aiglip® should not be used during pregnancy.

Breastfeeding

It is unknown whether vildagliptin is excreted in human breast milk. Animal studies have shown excretion of vildagliptin into animal milk. Aiglip® should not be administered to women who are breastfeeding.

Fertility

Studies on the effect of Aiglip® on human fertility have not 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 not drive or operate 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 sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily in the morning. In this patient population, vildagliptin at a dose of 100 mg once daily was not more effective than vildagliptin at a dose of 50 mg once daily.

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

Doses exceeding 100 mg are not recommended.

If a dose of Aiglip® 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.

Dosing in Patients with Hepatic or Renal Impairment

Aiglip® is not recommended for patients with hepatic impairment, including patients in whom baseline ALT or AST levels were three times higher than the upper limit of normal.

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min), no dose adjustment of Aiglip® is required. 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.

Dosing in Pediatric Patients

Aiglip® is not recommended for children and adolescents under 18 years of age due to lack of data on safety and efficacy.

Method of Administration

For oral use.

Aiglip® can be administered independently of food intake.

Children

Aiglip® is not recommended for 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 possible symptoms of overdose were 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, development of edema, and transient 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. 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.

Short description of 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 occurrence of adverse reactions and patient age or race, duration of drug intake, or daily dose.

Hypoglycaemia has been reported in patients receiving vildagliptin in combination with sulphonylurea derivatives and insulin. A risk of acute pancreatitis has been reported with vildagliptin use (see section "Special warnings and precautions for use").

Adverse reactions observed during double-blind studies in patients treated with vildagliptin as monotherapy or as part of 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, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions reported in patients receiving vildagliptin

as monotherapy or as add-on therapy in controlled clinical trials

and in the post-marketing period.

Table 2

Description of individual adverse reactions

Hepatic impairment

Isolated cases of hepatic dysfunction (including hepatitis) have been reported. These cases were generally asymptomatic, without clinical consequences, and liver function test results returned to normal after discontinuation of treatment. In controlled monotherapy and add-on therapy trials of up to 24 weeks duration, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal (defined as present in at least two consecutive measurements or at the last visit during treatment) was 0.2%, 0.3%, and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily, and 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 events was observed in the group where vildagliptin was used in combination with an ACE inhibitor. Most events were mild in severity and resolved without discontinuation of vildagliptin.

Hypoglycemia

Hypoglycemia was infrequent with vildagliptin (0.4%) as monotherapy in comparative controlled monotherapy trials versus 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. Following addition of pioglitazone, hypoglycemia occurred in 0.6% of patients receiving vildagliptin and in 1.9% of those receiving placebo. With the addition of a sulfonylurea, hypoglycemia occurred in 1.2% of patients receiving vildagliptin and in 0.6% of those receiving placebo. After adding a sulfonylurea and metformin, hypoglycemia occurred in 5.1% of patients receiving vildagliptin and in 1.9% of those receiving placebo. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycemia was 14% for vildagliptin and 16% for placebo.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions are required for this medicinal product.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak", production of bulk products from manufacturers: Bluepharma Indústria Farmacêutica S.A., Portugal (manufacturing, primary and secondary packaging, batch control, batch release); AET Laboratories Private Limited, India (manufacturing, primary and secondary packaging, batch control, batch release).

Manufacturer's address and location of its operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine