Instructions for Ayglip tablets 50 mg blister No. 30
Composition
active ingredient: vildagliptin;
1 tablet contains vildagliptin 50 mg;
excipients: microcrystalline cellulose, anhydrous lactose, low-substituted hydroxypropylcellulose, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: tablets are round, with a flat surface, with beveled edges, from white to light yellowish in color.
Pharmacotherapeutic group
Hypoglycemic synthetic and other agents. Dipeptidyl peptidase-4 inhibitors. ATX code A10B H02.
Pharmacological properties
Pharmacodynamics
Vildagliptin belongs to the class of substances that enhance the function of beta cells of the pancreatic islet apparatus, is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4).
Vildagliptin administration results in rapid and complete inhibition of DPP-4 activity. Inhibition of DPP-4 by vildagliptin results in increased endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) during fasting and after meals.
By increasing endogenous levels of these incretin hormones, vildagliptin improves beta-cell sensitivity to glucose, leading to increased 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 beta-cell function, including HOMA-β (homeostatic model of β-cell function assessment), proinsulin to insulin ratio, and beta-cell sensitivity in a multiple meal tolerance test. In non-diabetic patients (with normal blood glucose levels), vildagliptin does not stimulate insulin secretion or lower glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin also increases the sensitivity of alpha cells to glucose, which leads to an increase in glucose-dependent glucagon secretion. The significant increase in the insulin-glucagon ratio during hyperglycemia caused by increased levels of the incretin hormone leads to a decrease in glucose production during fasting and after meals, which causes a decrease in glycemia.
The known effect of increased GLP-1 levels, which is to prolong gastric emptying, is not observed during treatment with vildagliptin.
Pharmacokinetics
Absorption
After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with peak plasma concentrations (Cmax) occurring 1.7 hours later. Concomitant administration with food slightly delays the time to reach Cmax in plasma to 2.5 hours, but does not affect the total exposure (AUC). Administration of vildagliptin with food results in a decrease in Cmax (19%). However, the magnitude of the change is not clinically significant, and Aiglip® can be taken without regard to 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 erythrocytes. The mean volume of distribution of vildagliptin at plateau after intravenous administration (Vss) is 71 liters, indicating extravascular distribution.
Metabolism
Metabolism is the major route of elimination of vildagliptin in humans, accounting for 69% of the administered dose. The major metabolite, LAY151, is pharmacologically inactive and is a hydrolysis product of the cyanide moiety, accounting for 57% of the dose, followed by glucuronide (BQS867) and amide hydrolysis (4% of the dose). Data from an in vitro study in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 is partially involved in the hydrolysis of vildagliptin, which was confirmed by an in vivo study in DPP-4-deficient rats.
Vildagliptin is not metabolised by cytochrome P450 enzymes to a detectable extent. Therefore, concomitant administration of medicinal products such as CYP450 inhibitors and/or inducers is not expected to affect the metabolic clearance of vildagliptin. In vitro studies have shown that vildagliptin does not inhibit or induce cytochrome P450 enzymes. Therefore, vildagliptin is unlikely to affect the metabolic clearance of concomitantly administered medicinal products metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Breeding
After oral administration of [14C]-vildagliptin, approximately 85% of the dose is excreted in the urine and 15% in the feces. Renal excretion of unchanged vildagliptin accounts for 23% of the oral dose. After intravenous administration to healthy volunteers, the total plasma and renal clearance of vildagliptin are 41 l/h and 13 l/h, respectively. The mean half-life after intravenous administration is approximately 2 hours. The half-life after oral administration is approximately 3 hours.
Linearity/nonlinearity
Vildagliptin Cmax and AUC increase almost proportionally with dose over the entire therapeutic dose range.
Certain patient groups
No differences in the pharmacokinetics of the drug were observed in healthy male and female volunteers of different ages and body mass index (BMI). DPP-4 inhibition by Ayglip® is independent of the patient's gender.
Liver disease
The effect of hepatic impairment on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate and severe hepatic impairment based on the Child-Pugh score (6 for mild to 12 for severe) compared to patients with normal hepatic function. Vildagliptin exposure after a single dose in patients with mild and moderate hepatic impairment was reduced (by 20% and 8%, respectively), while vildagliptin exposure in patients with severe impairment was increased by 22%. The maximum change (increase or decrease) in vildagliptin exposure was approximately 30%, which is not considered clinically relevant. There was no relationship between the severity of hepatic impairment and changes in vildagliptin exposure.
Kidney disease
An open-label, multiple-dose study was conducted to evaluate the pharmacokinetics of the lowest therapeutic doses 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 to <50 mL/min, and 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, the AUC of vildagliptin was increased compared to patients with normal renal function. The AUC of the 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) suggest that vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations were approximately 2-3-fold higher than in patients with severe renal impairment.
Vildagliptin was removed from the body by hemodialysis to a limited extent (3% during 3-4 hours of hemodialysis, which was started 4 hours after drug administration).
Elderly patients
In otherwise healthy subjects (aged 70 years and older), total exposure to vildagliptin (100 mg once daily) was increased by 32% and Cmax by 18% compared to younger healthy subjects (aged 18 to 40 years).
These changes, however, are not considered clinically significant. DPP-4 inhibition by vildagliptin is independent of age in the age groups studied.
Race
Limited data suggest that race has no significant effect on the pharmacokinetics of vildagliptin.
Indication
Treatment of adult patients with type II diabetes mellitus.
As monotherapy:
patients in whom diet and exercise alone do not provide sufficient control, and for patients in whom metformin is considered inappropriate due to contraindications or intolerance.
As part of dual oral therapy in combination with:
metformin for patients with inadequate glycemic control despite the use of the maximum tolerated dose of metformin monotherapy; sulfonylurea for patients with inadequate glycemic control despite the use of the maximum tolerated dose of sulfonylurea and for patients in whom the use of metformin is considered unacceptable due to contraindications or intolerance; thiazolidinedione for patients with inadequate glycemic control for whom the use of a thiazolidinedione is considered acceptable.
As part of triple oral therapy in combination with:
sulfonylurea and metformin when diet and exercise together with dual therapy with these drugs do not provide adequate glycemic control.
In combination with insulin (with or without metformin) when diet and exercise together with a stable dose of insulin do not provide adequate glycemic control.
Contraindication
Known hypersensitivity to vildagliptin or to any of the excipients.
Interaction with other medicinal products and other types of interactions
Vildagliptin has a low potential for drug interactions. Since vildagliptin is not a substrate of cytochrome P450 (CYP) enzymes and is not an inhibitor or inducer of CYP 450 enzymes, its interactions with other drugs that are substrates, inhibitors or inducers of these enzymes are unlikely.
Combination with pioglitazone, metformin, and glyburide
The results of studies conducted with these oral antidiabetic agents did not show a clinically significant pharmacokinetic interaction.
Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)
Clinical studies conducted in healthy volunteers did not show any clinically significant pharmacokinetic interaction. However, this has not been established in the target population.
Drug interaction studies in healthy volunteers have been conducted with amlodipine, ramipril, valsartan and simvastatin. No clinically significant pharmacokinetic interactions were observed in these studies when these drugs were co-administered with vildagliptin.
Combination with ACE inhibitors
When used simultaneously with ACE inhibitors, there is a higher risk of developing angioedema (see section "Adverse reactions").
As with other oral antidiabetic medicinal products, certain active substances, including thiazides, corticosteroids, thyroid hormone preparations and sympathomimetics, may reduce the hypoglycaemic effect of vildagliptin.
Application features
General
Aiglip® is not a substitute for insulin in insulin-dependent patients. It should not be used to treat patients with type 1 diabetes or diabetic ketoacidosis.
Kidney dysfunction
Experience in the treatment of patients with moderate or severe renal impairment, as well as patients with NNTC on hemodialysis, is limited. Therefore, the use of Ayglip® is not recommended in these patient groups.
Liver dysfunction
Ayglip® is not recommended for use in patients with impaired liver function, including patients with pre-treatment ALT or AST levels greater than 3 times the upper limit of normal.
Monitoring liver enzyme levels
Liver function disorders (including hepatitis) have been reported rarely. In such cases, the course of the complication in patients was mostly asymptomatic, without clinical consequences, and liver function tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed before starting treatment with Ayglip® to determine the patient's baseline values. LFTs should be monitored during treatment with the drug at intervals of once every three to four months for the first year of treatment, and periodically thereafter.
For patients who have experienced elevated transaminase levels, liver function should be re-monitored to confirm the results, and continued monitoring with frequent liver function tests should be continued until the abnormal levels return to normal. If ALT or AST levels are elevated to 3 or more times the upper limit of normal, it is recommended to discontinue treatment with Ayglip®. If jaundice or other signs of liver dysfunction occur, Ayglip® should be discontinued. Vildagliptin should not be restarted after discontinuation of treatment and TFP results have returned to normal.
Heart failure
A clinical study of vildagliptin in patients with NYHA functional class I-III heart failure showed that vildagliptin treatment was not associated with changes in left ventricular function or worsening of pre-existing congestive heart failure. Clinical experience in patients with NYHA functional class III heart failure is still limited and the results are inconclusive.
There is no experience of using vildagliptin in clinical trials in patients with NYHA functional class IV heart failure, therefore the drug is not recommended for use in these patients.
Skin disorders
In nonclinical toxicology studies, skin lesions, including blistering and ulceration of the extremities in monkeys, were reported. Although no increase in the incidence of skin lesions was observed in clinical studies, experience with skin complications in patients with diabetes is limited.
In addition, cases of bullous and exfoliative skin lesions have been reported in the post-marketing period.
Therefore, as per standard care for patients with diabetes, monitoring for skin abnormalities 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 characteristic symptoms of acute pancreatitis.
If pancreatitis is suspected, vildagliptin should not be continued. If acute pancreatitis is confirmed, vildagliptin should not be resumed.
Hypoglycemia
The use of sulfonylureas is known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulfonylurea may be at increased risk of hypoglycemia. Therefore, lower doses of the sulfonylurea may be used to reduce the risk of hypoglycemia.
Others
Ayglip® tablets contain lactose. Ayglip® is contraindicated in patients with rare hereditary problems of lactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of the drug on the ability to drive and use machines have not been conducted. Patients who experience dizziness should not drive or use machines.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate studies of the use of vildagliptin in pregnant women.
Animal studies have shown reproductive toxicity at high doses. The potential risk to humans is unknown. Due to the lack of data, Ayglip® should not be used during pregnancy.
Breastfeeding period
It is not known whether vildagliptin is excreted in human milk. Animal studies have shown excretion of vildagliptin in milk. Aiglip® should not be administered to women who are breastfeeding.
Fertility
No studies have been conducted on the effect of Ayglip® on human fertility.
Method of administration and doses
When used as monotherapy, in combination with metformin, in combination with a thiazolidinedione, in combination with metformin and a sulfonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, divided into two doses: 50 mg in the morning and 50 mg in the evening.
When used as part of a dual combination with a sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily, taken in the morning. In this patient population, vildagliptin 100 mg daily was not more effective than vildagliptin 50 mg once daily.
When used in combination with a sulfonylurea, low doses of the sulfonylurea may be used to reduce the risk of hypoglycemia.
Exceeding the dose of 100 mg is not recommended.
If a dose of Ayglip® 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 as part of triple oral therapy in combination with metformin and a thiazolidinedione have not been established.
Dosage for patients with hepatic or renal impairment
Ayglip® is not recommended for use in patients with impaired liver function, including patients with pre-treatment ALT or AST levels greater than 3 times the upper limit of normal.
For patients with mild renal impairment (creatinine clearance ≥ 50 ml/min) no dosage adjustment of Ayglip® is required. For patients with moderate or severe renal impairment or NNRTI, the recommended dose is 50 mg once daily.
Dosage for elderly patients
There is no need to change the dosage for patients over 65 years of age.
Dosage for children
The use of Ayglip® in children and adolescents under 18 years of age is not recommended due to a lack of data on safety and efficacy.
Method of application
For oral use.
Ayglip® can be taken regardless of food intake.
Children
The use of Ayglip® in children and adolescents under 18 years of age is not recommended due to a lack of data on safety and efficacy.
Overdose
Information on overdose with vildagliptin is limited.
Symptoms
Information on possible symptoms of overdose was obtained in the course of a dose escalation study in healthy volunteers receiving vildagliptin for 10 days. At a dosage of 400 mg, three cases of muscle pain were observed, as well as several cases of mild and transient paresthesia, fever, edema, and transient elevations in lipase levels. At a dosage of 600 mg, one volunteer developed edema of the legs and arms, a significant increase in creatinine phosphokinase (CPK) levels, accompanied by increases in AST, C-reactive protein, and myoglobin. Three volunteers in this group had edema of both legs, accompanied in two cases by paresthesia. All symptoms and laboratory abnormalities resolved after discontinuation of the study drug.
Treatment
In case of overdose, supportive therapy is recommended. Vildagliptin is not removed by hemodialysis, however, most of the hydrolysis metabolites (LAY 151) can be removed by hemodialysis.
Adverse reactions
Safety data for vildagliptin were obtained in controlled studies in patients receiving vildagliptin at a daily dose of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) as monotherapy and in combination with another drug. Most adverse reactions that occurred with vildagliptin were mild in nature and transient and did not require discontinuation of treatment. No relationship was found between the development of adverse reactions and the patient's age or race, duration of drug administration, or daily dose.
Isolated cases of angioedema reported with vildagliptin were observed at a similar frequency to the control group. A higher percentage of such cases were observed in the group where vildagliptin was used in combination with an ACE inhibitor. Most of the events were mild in severity and resolved on discontinuation of vildagliptin.
Adverse reactions observed during double-blind studies in patients taking vildagliptin as monotherapy and in combination therapy are listed below for each indication by system organ class and absolute frequency. The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (> 10,000, ≤ 1/1,000), very rare (≤ 1/10,000), frequency unknown (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Vildagliptin Monotherapy: Adverse reactions reported in patients receiving vildagliptin 100 mg/day as monotherapy in double-blind studies.
Infections and infestations: very rare - upper respiratory tract infection, nasopharyngitis.
Metabolic: infrequently - hypoglycemia.
From the nervous system: often - dizziness; infrequently - headache.
Cardiovascular system: infrequently - peripheral edema.
Gastrointestinal: infrequently - constipation.
Musculoskeletal and connective tissue disorders: infrequently - arthralgia.
Skin: possible hypersensitivity reactions.
Description of selected adverse reactions
In controlled studies of vildagliptin monotherapy, the overall incidence of early discontinuation of treatment due to adverse reactions was not higher in patients treated with vildagliptin 100 mg daily than in patients treated with placebo or comparators.
In comparative controlled monotherapy studies, uncommon cases of hypoglycaemia were observed in 0.4% of patients treated with vildagliptin 100 mg daily compared to 0.2% of patients treated with active comparator or placebo, with no serious or severe events.
In clinical studies, when vildagliptin at a dose of 100 mg per day was prescribed as monotherapy, the body weight of patients did not change compared to baseline.
Clinical studies of up to 2 years duration did not reveal any additional signs of danger or unforeseen risks with vildagliptin monotherapy.
Combination with metformin: Adverse reactions reported in patients receiving vildagliptin 100 mg daily in combination with metformin during studies.
Metabolic: often - hypoglycemia.
From the nervous system: often - tremor, dizziness, headache; infrequently - fatigue.
Gastrointestinal: often - nausea.
Description of selected adverse reactions
In controlled clinical trials of the combination of vildagliptin 100 mg/day with metformin, no discontinuations due to adverse reactions were reported in either the vildagliptin 100 mg/day + metformin or placebo + metformin groups.
In clinical trials, hypoglycemia was common in patients receiving vildagliptin 100 mg/day in combination with metformin (1%) and uncommon in patients receiving placebo + metformin (0.4%). No cases of severe hypoglycemia were reported in the vildagliptin groups.
In clinical studies, when vildagliptin 100 mg per day was added to metformin, the body weight of patients did not change compared to baseline.
In clinical studies of up to 2 years or more, no additional safety or unexpected risks were identified when vildagliptin was added to metformin.
Combination with a sulfonylurea: Adverse reactions reported in patients receiving vildagliptin 50 mg in combination with a sulfonylurea in double-blind studies.
Infections and infestations: very rarely - nasopharyngitis.
Metabolic: often - hypoglycemia.
From the nervous system: often - tremor, dizziness, headache, asthenia.
Gastrointestinal: infrequently - constipation.
Description of selected adverse reactions
In controlled clinical trials of the combination of vildagliptin 50 mg and a sulfonylurea, the overall incidence of early discontinuation of treatment due to adverse reactions was 0.6% in the combination of vildagliptin 50 mg with a sulfonylurea versus 0% in the placebo + sulfonylurea treatment group.
In clinical trials, the incidence of hypoglycemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% in the placebo + glimepiride group. No severe hypoglycemia was reported in the vildagliptin treatment groups.
In clinical studies, when vildagliptin 50 mg/day was added to glimepiride, the body weight of patients did not change compared to baseline.
Metabolic: often - weight gain; infrequently - hypoglycemia.
From the nervous system: infrequently - headache, asthenia.
Cardiovascular system: often - peripheral edema.
Description of selected adverse reactions
In controlled clinical trials of the combination of vildagliptin 100 mg/day and a thiazolidinedione, no early discontinuation of treatment due to adverse reactions was reported in either the vildagliptin 100 mg/day and thiazolidinedione treatment group or the placebo + thiazolidinedione treatment group.
In clinical trials, hypoglycemia was uncommon in patients treated with vildagliptin + pioglitazone (0.6%) but common in patients treated with placebo + pioglitazone (1.9%). No severe cases of hypoglycemia were reported in the vildagliptin treatment groups.
In the pioglitazone add-on therapy study, the absolute weight gain with placebo and vildagliptin 100 mg daily was 1.4 and 2.7 kg, respectively.
The percentage of peripheral edema when vildagliptin 100 mg daily was added to the maximum dose of pioglitazone used as background medication (45 mg once daily) was 7.0% compared to 2.5% when pioglitazone was used alone as background medication.
Combination with metformin and a sulfonylurea. Adverse reactions reported in patients receiving vildagliptin 50 mg twice daily in combination with metformin and a sulfonylurea.
Metabolic: often - hypoglycemia.
From the nervous system: often - dizziness, tremor.
Skin and subcutaneous tissue disorders: often – hyperhidrosis.
General disorders: often - asthenia.
Description of selected adverse reactions
No cases of premature discontinuation of treatment due to adverse reactions were reported in the vildagliptin + metformin + glimepiride treatment group compared to 0.6% in the placebo + metformin + glimepiride treatment group.
The incidence of hypoglycemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride group compared to 1.9% for the placebo + metformin + glimepiride group). One severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, the effect on average body weight was neutral.
Combination with insulin: Adverse reactions reported in patients receiving vildagliptin 100 mg/day in combination with insulin (with or without metformin) in double-blind studies.
Metabolic: often - decreased blood glucose level.
From the nervous system: often - headache, chills.
On the part of the gastrointestinal tract: often - nausea, gastroesophageal reflux disease; infrequently - diarrhea, flatulence.
Description of selected adverse reactions
In controlled clinical trials with vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence of early discontinuation of treatment due to adverse reactions was 0.3% in the vildagliptin group, while no early discontinuation due to adverse reactions was observed in the placebo group.
The incidence of hypoglycemia was similar in both treatment groups. Severe hypoglycemia was observed in 2 patients in the vildagliptin group and 6 patients in the placebo group.
At the end of the study, the effect on average body weight was neutral.
Postmarketing experience with vildagliptin.
Gastrointestinal tract: frequency unknown - pancreatitis.
On the part of the hepatobiliary system: frequency unknown - hepatitis (reversible after discontinuation of the drug), deviations in liver function tests from the norm (reversible after discontinuation of the drug).
Skin and subcutaneous tissue disorders: frequency unknown - urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid.
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
The medicinal product does not require any special storage conditions.
Keep out of reach of children.
Packaging
10 tablets in a blister. 3 or 6 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak" (production from bulk products of the manufacturer AET Laboratories Private Ltd., India).
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
