Gliclazide-zdorovya

INSTRUCTIONS FOR MEDICAL USE of the medicinal product GLICLAZIDE-ZDOROV'YA (GLICLAZIDE-Zdorovye)

Composition:

Active substance: gliclazide;

1 tablet contains gliclazide 80 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, povidone, colloidal anhydrous silicon dioxide, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: nearly white, flat cylindrical tablets with a bevel.

Pharmacotherapeutic group. Antidiabetic agents. Sulfonamides, derivatives of sulfonylurea. ATC code A10BB09.

Pharmacological Properties.

Pharmacodynamics. A hypoglycemic agent, a second-generation sulfonylurea derivative, possessing pronounced hypoglycemic, hemovascular, and antioxidant properties.

Hypoglycemic properties. The mechanism of hypoglycemic action is determined by both increased insulin secretion and enhanced insulin effectiveness. Gliclazide stimulates insulin secretion by pancreatic β-cells, accompanied by mobilization and enhancement of endogenous insulin release; potentiates the insulin-secretory action of glucose. Increases tissue sensitivity to insulin by increasing the number of insulin-sensitive receptors on target cells. Improves glucose utilization by stimulating muscle glycogen synthase. Exerts a direct effect on intracellular calcium ion transport, thereby improving the biphasic response of pancreatic β-cells to food intake: in patients with type 2 diabetes, gliclazide restores the early peak of insulin secretion (immediate first phase of insulin release) and enhances the second phase of insulin secretion (delayed phase). Elevated postprandial insulin levels and C-peptide secretion are maintained even after 2 years of treatment.

The hypoglycemic effect develops gradually; administration of the drug reduces the time interval between food intake and the onset of insulin secretion. Normalizes the glycemic profile within several days of treatment.

Hematological properties. Gliclazide partially inhibits platelet adhesion and aggregation, reduces levels of platelet activation markers, normalizes vascular permeability, prevents the development of microthrombosis, helps prevent microcirculatory disturbances, including diabetic retinopathy, and increases fibrinolytic activity (by enhancing plasminogen activator release).

Antioxidant properties. Gliclazide exerts antioxidant effects. In patients with type 2 diabetes, gliclazide reduces plasma levels of lipid peroxides, increases superoxide dismutase activity in erythrocytes, increases plasma thiol content, and enhances total antioxidant capacity.

The hemovascular and antioxidant properties of gliclazide contribute to a reduced risk of vascular complications in patients with diabetes. Furthermore, in diabetic nephropathy, gliclazide helps reduce proteinuria and normalize arterial pressure. In patients with obesity, when following an appropriate diet, it promotes reduction in body weight.

Pharmacokinetics. After oral administration, it is rapidly and completely absorbed from the gastrointestinal tract. Bioavailability is approximately 90%. C_max in blood is reached within 11–14 hours. Plasma protein binding is 94.2%. It is metabolized in the liver via oxidation, hydroxylation, and glucuronidation, forming 8 inactive metabolites. T_½ is 20 hours, allowing twice-daily dosing. It is excreted in the form of metabolites, primarily by the kidneys.

Clinical characteristics.

Indications. Type II diabetes mellitus (non-insulin-dependent) in adults, when blood glucose concentration cannot be controlled by diet, physical exercise, or weight reduction alone.

Contraindications.

• Hypersensitivity to gliclazide or other sulfonylurea drugs;
• hypersensitivity to sulfonamides or to any component of the drug;
• insulin-dependent diabetes;
• severe hepatic or renal insufficiency; in such cases insulin therapy is recommended;
• diabetic ketoacidosis;
• diabetic precoma or coma;
• severe trauma, burns, or infectious diseases in the acute phase;
• concomitant treatment with miconazole;
• concomitant treatment with quinolones;
• pregnancy and breastfeeding period.

Interaction with other medicinal products and other forms of interaction. Additional administration of other medicinal products may enhance or reduce the effect of gliclazide on blood glucose levels. Therefore, their use is possible only with physician's approval.

Medicinal products whose concomitant administration may increase the risk of hypoglycemia

Contraindicated concomitant use. Miconazole (for systemic use, oral gel) enhances the hypoglycemic effect, possibly leading to symptoms of hypoglycemia and even coma.

Quinolones enhance the hypoglycemic effect, possibly causing severe, profound, persistent hypoglycemia that is difficult to control, or leading to coma, particularly in elderly patients with renal insufficiency.

Not recommended concomitant use. Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea derivatives (by displacing their binding to plasma proteins and/or reducing their excretion). It is recommended to use other nonsteroidal anti-inflammatory drugs or to warn the patient and emphasize the importance of self-monitoring of blood glucose. If necessary, the dose of the antidiabetic drug may be adjusted during and after phenylbutazone treatment.

Alcohol increases the risk of hypoglycemic reactions (by inhibiting compensatory mechanisms), which may lead to hypoglycemic coma. Consumption of alcohol and alcohol-containing products should be avoided.

Combinations requiring caution. Acetylsalicylic acid and phenelzine do not enhance the hypoglycemic effect of gliclazide but may prolong its action.

Cimetidine, ranitidine, fluconazole, other antidiabetic agents, NSAIDs (especially salicylates), sulfonamides, ACE inhibitors (enalapril, captopril), H2-receptor antagonists, indirect anticoagulants, monoamine oxidase inhibitors, diazepam, tetracyclines, chloramphenicol, fibrates, ethanol, coumarin derivatives, disopyramide enhance the hypoglycemic effect of gliclazide. Barbiturates, glucocorticoids, diuretics, estrogens, thyroid hormones, and abuse of laxatives reduce the effectiveness of gliclazide. Sulfonamide drugs may enhance the action of gliclazide.

Particular caution is required when dosing monoamine oxidase inhibitors, which enhance insulin secretion.

Concomitant administration of β-adrenergic blockers may mask the symptoms of hypoglycemia. Gliclazide may be combined with insulin in non-insulin-dependent diabetes or with metformin or other biguanide derivatives (phenformin), although hypoglycemia may occur in some cases due to enhanced hypoglycemic effect. It is not combined with other sulfonylurea derivatives.

Additionally, reduction in glucose levels may result from interaction with other antidiabetic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists), β-blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, sulfonamides, clarithromycin, and nonsteroidal anti-inflammatory drugs.

Medicinal products whose concomitant administration may increase the risk of hyperglycemia

Not recommended concomitant use. Danazol exerts a diabetogenic effect. If it is impossible to avoid using this drug, the patient should be warned and the importance of self-monitoring of blood and urine glucose emphasized. If necessary, the dose of the antidiabetic drug may be adjusted during and after danazol treatment.

Combinations requiring caution. Chlorpromazine (neuroleptic), when used in high doses (over 100 mg per day), increases blood glucose levels (due to reduced insulin release). The patient should be warned and the importance of self-monitoring of blood glucose emphasized. If necessary, the dose of the antidiabetic drug may be adjusted during and after neuroleptic treatment.

Glucocorticoids (for systemic and local use: intra-articular, topical, and rectal formulations) and tetracosactide increase blood glucose levels, possibly leading to ketoacidosis (by reducing carbohydrate tolerance). The patient should be warned and the importance of self-monitoring of blood glucose emphasized, especially at the beginning of treatment. If necessary, the dose of the antidiabetic drug may be adjusted during and after glucocorticoid treatment.

Ritodrine, salbutamol, terbutaline (intravenous) may increase blood glucose levels due to β2-agonist effects.

St. John's wort (Hypericum perforatum) decreases gliclazide concentration. Therefore, regular monitoring of blood glucose levels is important.

Combinations that should be taken into account

Anticoagulants (e.g., warfarin). When used concomitantly with anticoagulants, sulfonylurea derivatives may potentiate their anticoagulant effect. If necessary, the dose of anticoagulants may be adjusted.

Special precautions for use

The drug should be taken against the background of diet therapy. Alcohol must not be consumed during treatment with gliclazide due to the risk of developing pronounced hypoglycemia. The risk of hypoglycemia is also increased with irregular food intake.

In case of clinical inefficacy of the medicinal product or decompensation of diabetes mellitus, insulin therapy must be initiated. During pregnancy and whenever surgical intervention is required, treatment should be switched to insulin. Therapy should be initiated cautiously, with gradual dose escalation according to age, diet, severity of disease, physical activity, and under mandatory monitoring of blood and urine glucose levels. Hypoglycemia is rare but possible with irregular meals and concomitant alcohol consumption. Mild hypoglycemic reactions not requiring medical intervention may occur more frequently.

Hypoglycemia. This drug should be prescribed only if the patient adheres to a regular meal schedule (including breakfast). Regular intake of carbohydrates is very important. Delayed meals, insufficient food intake, or low carbohydrate content increase the risk of hypoglycemia.

Hypoglycemia is more likely to occur with low-calorie or irregular diet, prolonged or intense physical exertion, alcohol consumption, or concomitant use of other hypoglycemic agents. Worsening glycemic control in patients receiving antidiabetic drugs may be triggered by St. John's wort (Hypericum perforatum) or any concomitant therapy that may affect gliclazide metabolism.

When using sulfonylurea drugs, mild or severe hypoglycemia may develop. In cases of severe and prolonged hypoglycemia, hospitalization and administration of glucose for several days may be necessary.

Factors increasing the risk of hypoglycemia:

• adherence to diabetic diet;
• refusal or inability to follow physician's recommendations (especially in elderly patients);
• inadequate or irregular nutrition, skipped meals, periods of fasting, and dietary changes;
• imbalance between physical exertion and carbohydrate intake;
• overdose;
• insufficient glucose or caloric intake;
• certain endocrine disorders: thyroid dysfunction, hypopituitarism, and adrenal insufficiency;
• concomitant use of certain medicinal products (see section "Interaction with other medicinal products and other forms of interaction");
• hepatic and/or renal impairment;
• alcohol consumption.

To reduce the risk of hypoglycemia, it is recommended:

• to initiate treatment of insulin-independent diabetes mellitus with diet whenever possible;
• to consider patient age and blood glucose levels;
• to adjust the gliclazide dose during the first few days of therapy according to blood and urine glucose levels throughout the day.

Dose adjustment is required in the following cases:

• occurrence of mild hypoglycemic symptoms (sweating, pallor, intense hunger, tachycardia, weakness); these symptoms are relieved by oral glucose intake, dose adjustment, and/or dietary regimen modification;
• severe hypoglycemic reactions (coma and neurological disturbances, see section "Overdose");
• loss of blood glucose control (hyperglycemia); patient under stress conditions, including fever, trauma, infections, or surgical interventions. In such cases, increasing the gliclazide dose may be necessary. If this is insufficient, gliclazide treatment should be discontinued and insulin therapy initiated.

Caution is required when administering the drug to patients with impaired liver or kidney function. Treatment should be initiated with low doses, and the patient's condition should be closely monitored. The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic or severe renal impairment. Hypoglycemic episodes in such patients may be prolonged and therefore require appropriate treatment.

Patient information. The patient and family members should be informed about risk factors and conditions that may predispose to hypoglycemia, symptoms of hypoglycemia, and methods of their management. The patient should be informed about the importance of adhering to dietary recommendations, regular physical exercise, and routine blood glucose monitoring.

Worsening glycemic control in patients receiving hypoglycemic agents may be caused by infection, fever, trauma, or surgical intervention. In some cases, insulin therapy may become necessary. The hypoglycemic efficacy of any oral antidiabetic agent, including gliclazide, may change over time. This may result from progression of disease severity or reduced response to treatment. This phenomenon is known as secondary failure, which differs from primary failure, when the drug is ineffective from the beginning of treatment. Before concluding that secondary failure has developed, the appropriateness of the prescribed dose and the patient's adherence to dietary recommendations should be verified.

Laboratory parameters: Assessment of glycemic control is recommended through measurement of glycated hemoglobin (or fasting blood glucose). Patient self-monitoring of blood glucose levels may also be helpful.

In patients with glucose-6-phosphate dehydrogenase deficiency, sulfonylurea drugs may induce hemolytic anemia. Gliclazide should be used with caution in such patients, and alternative therapy should be considered.

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

Use during pregnancy or breastfeeding.

Pregnancy. There is no experience with the use of gliclazide during pregnancy. Women should be switched from oral hypoglycemic agents to insulin during planned or actual pregnancy.

Breastfeeding. There are no data on whether the active substance is excreted in breast milk. This drug should not be used during breastfeeding due to the potential risk of neonatal hypoglycemia.

Ability to affect reaction rate while driving or operating machinery. Patients should be aware of the symptoms of hypoglycemia, be able to recognize them, and exercise caution when driving or operating machinery, especially at the beginning of treatment. At the start of therapy, especially without adequate blood glucose control, patients may experience impaired concentration.

Dosage and Administration.

For oral use. For adults only.

As with all antidiabetic agents, dosage must be individualized according to the patient's individual response to treatment.

For patients whose glucose levels are usually well controlled by diet, the drug may be prescribed for a short period in case of temporary loss of glucose control.

Patients under 65 years of age.

Initial dose. The recommended initial dose is 1 tablet per day.

Dose escalation. Depending on the patient's individual response to treatment, the dose may be increased by 1 tablet. The next dose increase should not occur earlier than 14 days after the previous one.

Maintenance therapy. The dose may range from 1 to 3 tablets per day. The standard dose is 2 tablets of the drug per day, divided into 2 doses.

Maximum daily dose – 4 tablets of the drug, divided into 2 doses.

Patients over 65 years of age.

Treatment should be initiated at a dose of 40 mg (using preparations containing the corresponding amount of gliclazide) once daily. If enhanced glucose control is required, this dose may be gradually increased. The next dose increase should not occur earlier than 14 days after the previous one and under strict monitoring of blood glucose levels.

Other high-risk patient groups.

Patients with inadequate or irregular food intake, poor general condition, or with renal or hepatic insufficiency should start treatment with the minimum dose. Dose escalation should strictly follow the recommended schedule to avoid the risk of developing hypoglycemic reactions.

Patients previously treated with other oral antidiabetic agents.

As with other sulfonylurea antidiabetic agents, this drug may be substituted for another antidiabetic agent without a transition period. When switching from another sulfonylurea agent with a longer elimination half-life (e.g., chlorpropamide) to this drug, the patient should be under close supervision (for more than several weeks) to avoid an additive effect of the two agents and the development of hypoglycemia.

Children. Gliclazide, like other sulfonylurea derivatives, is not recommended for the treatment of diabetes mellitus in children.

Overdose. Overdose of sulfonylurea agents may cause hypoglycemia. Symptoms of moderate hypoglycemia (without loss of consciousness and without neurological symptoms) should be corrected by administration of carbohydrates (sugar), preferably in the form of a solution, along with adjustment of the antidiabetic drug dose and/or diet. If hypoglycemia cannot be promptly corrected, intravenous administration of glucose by a physician or intramuscular injection of glucagon is required. Close monitoring of the patient should continue until the physician is confident that the patient is out of danger.

Severe hypoglycemia leading to coma, seizures, or other neurological disturbances requires immediate medical intervention and urgent hospitalization.

In case of diagnosed hypoglycemic coma or suspected coma development, the patient should be rapidly administered 50 mL of concentrated glucose solution (20–30%) intravenously, followed by continuous infusion of a less concentrated glucose solution (10%) at a rate sufficient to maintain blood glucose levels above 1 g/L. Continuous monitoring of the patient is essential. The physician decides on further management based on the patient's condition.

Gliclazide is highly protein-bound in plasma; therefore, dialysis is ineffective.

Adverse Reactions

Based on the experience with gliclazide and other sulfonylurea derivatives, the undesirable effects listed below may occur.

Hypoglycemia. Like other sulfonylurea drugs, gliclazide may cause hypoglycemia, especially with irregular eating habits or when a meal has been skipped. Hypoglycemia may be accompanied by characteristic symptoms such as intense hunger, headache, nausea, vomiting, increased fatigue, sleep disturbances, agitation, difficulty concentrating and attention, slowed reactions, depression, confusion, speech and vision disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, weakness, loss of self-control, delirium, seizures, shallow breathing, bradycardia, drowsiness, and loss of consciousness, which may progress to coma and fatal outcome.

In addition, signs of adrenergic counter-regulation may occur, including increased sweating, clammy skin, anxiety, aggressiveness, tachycardia, hypertension, palpitations, angina attack, and arrhythmia.

Symptoms of hypoglycemia usually resolve after ingestion of carbohydrates (sugar). However, artificial sweeteners are ineffective. Experience with other sulfonylurea drugs indicates that hypoglycemic episodes may recur, even if initial corrective measures were effective.

If a hypoglycemic episode is severe or prolonged, the patient requires emergency medical care or hospitalization, even if the condition appears temporarily controlled by sugar intake.

Other undesirable effects.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Adhering to the recommendation to take the drug during breakfast may help prevent or minimize these manifestations.

The following adverse effects are observed less frequently.

Skin and subcutaneous tissue disorders: pruritus, erythema, Stevens–Johnson syndrome, toxic epidermal necrolysis, urticaria, rash, including maculopapular and bullous eruptions.

Blood and lymphatic system disorders (rare): anemia, leukopenia, thrombocytopenia, granulocytopenia, erythropenia, pancytopenia, agranulocytosis, allergic vasculitis. These reactions usually resolve after discontinuation of the drug. Data confirming a direct causal relationship between these disorders and gliclazide intake are lacking.

Hepatobiliary disorders: increased liver enzyme levels (ALT, AST, alkaline phosphatase). There are reports of isolated cases of liver failure (with cholestasis and jaundice), and hepatitis, which regressed after discontinuation of sulfonylurea drugs. If jaundice occurs, treatment with the drug should be discontinued.

These adverse effects usually resolve after discontinuation of the drug.

Eye disorders: transient visual disturbances may occur, particularly at the beginning of treatment, due to changes in blood glucose levels.

Immune system disorders: angioneurotic edema, drug rash with eosinophilia and systemic symptoms (DRESS).

Reactions typical of the sulfonylurea class of drugs include cases of erythropenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzymes, and even impaired liver function (e.g., with cholestasis, jaundice), hepatitis that regresses after discontinuation of sulfonylurea drugs, or, in rare cases, progressive life-threatening liver failure.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets|tablets| 80 mg, № 10×3, № 30 in blisters in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY «CORPORATION «ZDOROVIYA».

LIMITED LIABILITY COMPANY «FARMEKS GROUP».

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.

(LIMITED LIABILITY COMPANY «CORPORATION «ZDOROVIYA»)

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenko Street, 100.

(Limited Liability Company «FARMEKS GROUP»)