Gliclazide

Pharmacological properties

mechanism of action. the active substance glyclazide is an oral hypoglycemic agent, a sulfonylurea derivative, which differs from other drugs by the presence of a heterocyclic ring that contains nitrogen and has endocyclic bonds.

Gliclazide reduces plasma glucose due to stimulation of insulin secretion by β-cells of the pancreatic islets of Langerhans. An increase in the level of postprandial insulin and secretion of the C-peptide persist even after 2 years of use of the drug. In addition to these metabolic properties, gliclazide also has hemovascular properties.

Pharmacodynamic effects. Effect on insulin secretion. In patients with type II diabetes mellitus, gliclazide restores the early peak of insulin secretion in response to glucose intake and increases the second phase of insulin secretion. An increase in insulin secretion occurs in accordance with food intake or glucose load.

Hemovascular properties. Glyclazide reduces microthrombosis due to two mechanisms that can be involved in the development of complications of diabetes:

• partially inhibits platelet aggregation and adhesion, reduces the number of platelet activation markers (β-thromboglobulin, thromboxane B₂);
• affects the fibrinolytic activity of vascular endothelium (increases the activity of tPA).

Prevention of complications of type II diabetes. ADVANCE is an international multicenter randomized trial with a bifactorial design, aimed at determining the advantages of an intensive glycemic control strategy (HbA1c level ≤6.5%) based on MR Diabeton compared to the standard glycemic control and the benefits of lowering blood pressure with a fixed combination of perindopril / indapamide compared with placebo on the background of the current standard therapy (double blind comparison) regarding the effect on the main macro- and microvascular complications in patients with diabetes mellitus II type.

The primary endpoint consisted of the main macrovascular (cardiovascular death, non-lethal myocardial infarction, non-lethal stroke) and microvascular (new cases or worsening nephropathy, retinopathy) events.

11,140 patients were included in the ADVANCE study. During the 6 weeks of the period of introduction into the study, patients continued to receive their usual sugar-lowering therapy. Then, patients were randomly divided into the standard glycemic control group (n = 5569) and the Diabeton MR administration group as the basis of the strategy for intensive glycemic control (n = 5571). The strategy for intensive glycemic control was based on the appointment of MR Diabeton from the very beginning of treatment or on the appointment of MR Diabeton in addition to standard therapy (the therapy that the patient received at the time of inclusion) with a possible increase in dose to the maximum (120 mg) and then, if necessary, the addition of other hypoglycemic drugs such as metformin, acarbose, thiazolidinediones or insulin. Other sulfonylureas in the intensive glycemic control group were not used. Patients were under close medical supervision and strictly adhered to a diet.

The observation lasted 4.8 years. The result of Diabeton MR treatment, which was the basis of the strategy for intensive glycemic control (average achieved HbA1c level is 6.5%), compared with standard glycemia control (average achieved HbA1c level is 7.3%), there was a significant total decrease of 10% the relative risk of major macro- and microvascular complications (HR 0.90; 95% CI [0.82; 0.98], p = 0.013; 18.1% of patients from the intensive control group compared to 20% of patients from the standard control group ) The advantages of the strategy for intensive glycemic control with the appointment of Diabeton MR in the basis of therapy were due to:

• a significant decrease in the relative risk of major microvascular events by 14% (HR 0.86; 95% CI [0.77; 0.97], p = 0.014; 9.4% vs 10.9%);
• a significant decrease in the relative risk of new cases or progression of nephropathy by 21% (HR 0.79; 95% CI [0.66–0.93], p = 0.006; 4.1% vs 5.2%);
• a significant reduction in the relative risk of newly emerged microalbuminuria by 8% (HR 0.92; 95% CI [0.85–0.99], p = 0.030; 34.9% vs 37.9%);
• a significant decrease in the relative risk of renal events by 11% (HR 0.89; 95% CI [0.83; 0.96], p = 0.001; 26.5% vs 29.4%);

At the end of the study, 65% and 81.1% of the patients in the intensive control group (vs 28.8% and 50.2% of the standard control group) achieved the HbA1c goal of ≤6.5% and ≤7%, respectively.

90% of patients in the intensive control group took Diabeton MR (the average daily dose was 103 mg), 70% of them took the maximum daily dose of 120 mg. In the group of intensive glycemic control based on Diabeton MR, the body weight of patients remained stable.

The benefits of the Diabeton MR-based Glycemic Control Strategy were not dependent on a decrease in blood pressure.

Pharmacokinetics

Suction. The concentration of gliclazide in blood plasma progressively increases during the first 6 hours after administration, after which it reaches a constant level (plateau), which is maintained from the 6th to the 12th hour after application. Individual fluctuations are negligible.

Glyclazide is completely absorbed in the digestive tract. Eating does not affect the rate and extent of absorption.

Distribution. The binding of gliclazide to plasma proteins is approximately 95%. The volume of distribution is about 30 liters.

A single daily dose of the drug Diabeton MR 60 mg provides an effective concentration of glycazide in blood plasma for 24 hours.

Biotransformation. Glyclazide is metabolized mainly in the liver and excreted in the urine, less than 1% of the active substance excreted in the urine unchanged. There are no active metabolites in plasma.

T_½ gliclazide is approximately 12–20 hours

Linearity / nonlinearity. When using the drug in a dose of up to 120 mg, a linear relationship is noted between the dose taken and the concentration in the blood plasma.

Special patient groups

Elderly patients. In elderly patients, no clinically significant changes in the pharmacokinetics of the drug were noted.

Indications

Type II diabetes mellitus in adults:

• decrease and control of blood glucose levels when it is impossible to normalize glucose levels only by diet, exercise and weight loss;
• prevention of complications of type II diabetes mellitus: reducing the risk of macro- and microvascular complications, in particular new cases, or aggravation of nephropathy in patients with type II diabetes who are treated according to the strategy for intensive glycemic control.

Application

For oral use. assigned only to adults. the daily dose can vary from ½ to 2 tablets per day (from 30 to 120 mg / day). the tablet can be divided into equal doses. the daily dose should be taken once during breakfast. half a tablet or a whole tablet (tablets) should be swallowed whole (do not crush or chew).

If the patient forgot to take the pills, do not increase the dose the next day.

Like all antidiabetic drugs, Diabeton MR 60 mg requires an individual dose selection depending on the patients response to treatment (blood glucose, glycated hemoglobin HbA1c).

Initial dose and dose selection. The recommended starting dose is 30 mg (½ tablets) per day. With effective glucose control, treatment at this dose can be continued. If it is necessary to strengthen control of blood glucose levels, the daily dose can be gradually increased to 60 mg (1 tablet), 90 mg (1.5 tablets) or 120 mg (2 tablets). Increasing the dose is recommended to be carried out gradually with an interval of 1 month, except in cases where there was no decrease in blood glucose levels during 2 weeks of treatment. In this case, the dose can be increased at the end of the 2nd week of treatment.

The maximum recommended daily dose is 120 mg (2 tablets).

One tablet with a modified release of the drug Diabeton MR 60 mg is equivalent to two tablets of glycazide 30 mg with a modified release.

A tablet with a modified release of the drug Diabeton MR 60 mg can be divided, which makes it possible to use the drug at a dose of 30 mg (½ tablets) and at a dose of 90 mg (1.5 tablets).

Transfer of a patient from preparations containing 80 mg gliclazide to Diabeton MR 60 mg, modified release tablets: 1 tablet containing 80 mg gliclazide corresponds to ½ Diabeton MR 60 mg tablets. It is necessary to carefully monitor blood counts during the transfer to Diabeton MR 60 mg.

Transfer of the patient from other oral antidiabetic drugs to Diabeton MR 60 mg. When transferring to Diabeton MR, dosing and T should be taken into account_½ previous oral antidiabetic drug. A transition period is usually not required. Begin with a dose of 30 mg followed by dose adjustment (see. Initial dose and dose selection).

When transferring sulfonylureas with antidiabetic drugs with a long T½, a break in treatment for several days may be necessary in order to avoid the combined effect of the two drugs and the development of hypoglycemia. Treatment with Diabeton MR 60 mg begins with a dose of 30 mg / day (½ tablet), followed by dose adjustment in accordance with the rules described in the Initial dose and dose selection section (see above).

Concomitant use with other antidiabetic drugs: Diabeton MR 60 mg can be used in combination with biguanides, alpha-glucosidase inhibitors or insulin. If adequate control of blood glucose is not achieved in patients taking Diabeton MR 60 mg, simultaneous insulin therapy can be started under close medical supervision.

Special patient groups. For elderly patients (over 65 years), the dosage regimen of the drug Diabeton MR 60 mg is the same as for patients under the age of 65 years.

For patients with mild to moderate renal failure, the dosage regimen of the drug Diabeton MR 60 mg is the same as for patients with normal renal function, but the patient should be closely monitored.

Risk factors for hypoglycemia:

• insufficient or poor nutrition;
• severe or insufficiently compensated disorders of the endocrine system (hypothyroidism, hypopituitarism and adrenocorticotropic insufficiency);
• withdrawal of long-term corticosteroid therapy and / or high-dose corticosteroid therapy;
• severe vascular disease (severe coronary heart disease, severe pathology of carotid vessels, diffuse vascular disease).

A minimum starting dose of 30 mg / day is recommended.

To prevent complications of type II diabetes. According to the ADVANCE study, it is necessary to adhere to the strategy of intensive glycemic control (HbA1c level ≤6.5%). The strategy for intensive glycemic control provides for a gradual increase in the dose of Diabeton MR 60 mg to 120 mg / day. Increasing the dose should be carried out under the control of HbA1c level in compliance with strict recommendations regarding diet and exercise, controlling the risk of hypoglycemia. Other sugar-lowering drugs, such as metformin, acarbose, thiazolidinediones or insulin, may also be added.

Contraindications

• Hypersensitivity to gliclazide or other sulfonylureas, sulfonamides or any component of the drug; type I diabetes mellitus; diabetic precoma and coma, diabetic ketoacidosis; severe hepatic or renal failure (in such cases, the use of insulin is recommended); miconazole therapy; lactation period.

Side effects

The most common adverse reaction with gliclazide is hypoglycemia.as with the use of other sulfonylurea preparations, the administration of glyclazide can cause hypoglycemia with irregular nutrition, especially if the meal is skipped. the onset of hypoglycemia may be accompanied by characteristic symptoms, such as: headache, severe hunger, nausea, vomiting, fatigue, sleep disturbance, agitation, aggressiveness, decreased concentration and attention, slowing down reactions, depression, confusion, loss of vision and speech, aphasia, tremor, paresis, sensory disturbances, dizziness, feeling of powerlessness, loss of self-control, delirium, cramps, shallow breathing, bradycardia, drowsiness and loss of consciousness, which can lead to coma and death after action.

In addition, such disorders of the adrenergic system are possible: increased sweating, clammy skin, anxiety, tachycardia, hypertension, palpitation, chest pain, arrhythmia.

Usually the symptoms of hypoglycemia disappear after taking carbohydrates (sugar). However, taking sweeteners in this case will not be effective. The experience of using other sulfonylurea preparations indicates that even in the case of the effectiveness of the measures taken, hypoglycemia may occur again.

If the episode of hypoglycemia is severe or prolonged and the patient’s condition is temporarily under control due to sugar intake, emergency medical attention or even hospitalization is necessary.

Gastrointestinal upsets, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Following the recommendations for taking the drug during breakfast will help to avoid or minimize the occurrence of these manifestations.

Undesirable effects are less commonly noted:

on the part of the skin and subcutaneous tissue: rash, itching, urticaria, angioedema, erythema, maculopapular rash, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) and very rarely a drug rash with eosinophilia and systemic symptoms (DR).

On the part of the blood system and lymphatic system, hematological disorders rarely occur and may include anemia, thrombocytopenia, leukopenia, granulocytopenia. As a rule, these phenomena disappear after treatment is canceled.

On the part of the hepatobiliary system: increased levels of liver enzymes (AlAT, AsAT, ALP), hepatitis (isolated cases). In case of cholestatic jaundice, treatment with the drug should be discontinued.

These unwanted effects usually disappear after discontinuation of the drug.

From the side of the organs of vision: temporary visual impairment can occur, especially at the beginning of treatment, in connection with a change in the level of glucose in the blood.

Reactions characteristic of the sulfonylurea class of drugs: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, increased liver enzymes and even impaired liver function (for example, with cholestasis and jaundice), hepatitis with regression after single drug withdrawal or cases with further liver failure that threatened life.

Clinical researches. Serious adverse reactions were monitored during the ADVANCE study. In the group of patients with type II diabetes mellitus, who were treated according to the strategy for the intensive control of glycemia, there were no previously undesirable reactions described. Several patients suffered severe hypoglycemia. Most episodes of hypoglycemia were observed in patients with concomitant insulin therapy.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after drug registration is important. This will allow continued monitoring of the benefit / risk ratio.Health workers are requested to report suspected adverse reactions through the national reporting system.

special instructions

Hypoglycemia. this medication should only be prescribed to those patients who are able to eat regularly (including breakfast). it is important to regularly take carbohydrates, since an increased risk of hypoglycemia occurs when food is taken late, in an inadequate amount, or if it is food low in carbohydrates. the development of hypoglycemia is more likely with a low-calorie diet, prolonged or severe physical exertion, alcohol consumption or the use of a combination of antidiabetic drugs.

When taking sulfonylurea preparations, hypoglycemia may occur (see ADVERSE EFFECTS). Sometimes hypoglycemia can be severe and prolonged. In this case, hospitalization and administration of glucose for several days may be required.

To reduce the risk of episodes of hypoglycemia, it is necessary to take into account the individual characteristics of patients, give them clear explanations and carefully select the dose.

Factors that increase the risk of hypoglycemia: the patient refuses or cannot follow the doctors recommendations (especially for elderly patients); unsatisfactory, irregular nutrition, skipping meals, periods of fasting or diet changes; imbalance between physical activity and carbohydrate intake; renal failure; severe liver failure; overdose of the drug; certain disorders of the endocrine system: impaired thyroid function, hypopituitarism and adrenal insufficiency; concomitant use of certain drugs (see INTERACTIONS).

Renal and hepatic insufficiency: the pharmacokinetics and / or pharmacodynamics of gliclazide may vary in patients with hepatic and severe renal failure. Episodes of hypoglycemia in such patients can be prolonged, therefore appropriate treatment is required. The patient and his family members should be informed about risk factors and conditions that may contribute to the onset of hypoglycemia, about the symptoms of hypoglycemia (see ADVERSE EFFECTS) and how to eliminate them.

The patient should be informed about the importance of following the doctor’s recommendations regarding diet, regular exercise and regular monitoring of blood glucose.

Worsening glycemic control in patients receiving hypoglycemic drugs may be caused by St. Johns wort (Hypericum perforatum), infection, fever, trauma, or surgery. In some cases, insulin may be necessary.

The hypoglycemic efficacy of any oral hypoglycemic, including gliclazide, may change over time. This may be a consequence of the progression of the severity of the disease or a consequence of a decrease in response to treatment. This phenomenon is known as secondary failure, which differs from primary failure when drugs are ineffective from the start of treatment. Before making a conclusion regarding the development of secondary insufficiency in a patient, it is necessary to check the correctness of the dose used and the patients diet.

Dysglycemia. Blood glucose abnormalities, including hypoglycemia and hyperglycemia, have been reported in patients with diabetes who were simultaneously receiving fluoroquinolone therapy, in particular in elderly patients. That is why all patients who take Diabeton MR 60 mg and fluoroquinolones at the same time are advised to carefully monitor their blood glucose levels.

Laboratory indicators: to assess the control of blood glucose, it is recommended to determine the level of HbA1c (or fasting blood glucose).Patient self-monitoring of blood glucose may also be beneficial.

In patients with glucose-6-phosphate dehydrogenase deficiency, the use of sulfonylureas may cause hemolytic anemia. Since gliclazide belongs to the class of sulfonylurea preparations of chemical origin, caution should be exercised and consideration should be given to the administration of another class of alternative therapy to patients with glucose-6-phosphate dehydrogenase deficiency.

The composition of the drug includes lactose, therefore, patients with rare congenital disorders of galactose tolerance, glucose and galactose malabsorption syndrome, Lapp lactase deficiency are not recommended to prescribe this drug.

Use during pregnancy or lactation. Pregnancy. Oral sugar-lowering drugs should not be used during pregnancy (including Diabeton MR 60 mg). The experience with gliclazide during pregnancy is limited (less than 300 cases in pregnant women), and data on the use of other sulfonylureas are also limited. Animal studies have shown that gliclazide has no teratogenic effect. It is advisable to avoid taking gliclazide during pregnancy.

Glucose control should be achieved before pregnancy planning to reduce the risk of abnormalities associated with uncontrolled diabetes. When planning or immediately after pregnancy is established, it is necessary to transfer a woman from oral hypoglycemic drugs to insulin.

Lactation. There is no data on the penetration of gliclazide or its metabolites into breast milk. Diabeton MR 60 mg is contraindicated during breastfeeding due to the possibility of neonatal hypoglycemia. The risk to newborns and infants cannot be ruled out.

Fertility. In preclinical studies, the effect on fertility or reproductive ability of female and male rats has not been established.

Children. It is not recommended to prescribe Diabeton MR 60 mg to children due to lack of data regarding the use of the drug in this category of patients.

The ability to influence the reaction rate when driving vehicles and other mechanisms. Diabeton MR 60 mg may have little effect on the ability to drive vehicles or work with other automated systems. Patients should be aware of the symptoms of hypoglycemia, be able to recognize them and, if they occur, be careful when driving or working with other mechanisms, especially at the beginning of treatment.

Interactions

When prescribing drugs, the simultaneous use of which can cause hypo- or hyperglycemia, it is necessary to warn the patient about the need for careful monitoring of blood glucose levels during treatment. dose adjustment of a hypoglycemic drug may be necessary during and after treatment with these drugs.

Drugs that may be given at the same time as an increase in the risk of hypoglycemia

Simultaneous use contraindicated

Miconazole (for systemic use, gel for the oral cavity) enhances the hypoglycemic effect with the possible development of symptoms of hypoglycemia and even the development of coma.

Concomitant use is not recommended:

• phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylureas (replaces their connection with blood plasma proteins and / or reduces their excretion);
• alcohol increases the risk of hypoglycemic reactions (due to inhibition of compensatory reactions), which can lead to hypoglycemic coma. Avoid drinking alcohol and taking medications that contain alcohol.

Combinations that require caution: when used simultaneously with one of the following drugs, in some cases hypoglycemia may occur due to an increase in the hypoglycemic effect: other sugar-lowering drugs (insulins, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists (1 -1)), β-blockers, fluconazole, ACE inhibitors (captopril, enalapril), N antagonists₂receptors, MAO inhibitors, sulfonamides, clarithromycin and NSAIDs.

Drugs that can be given at the same time as the risk of hyperglycemia

Concomitant use is not recommended:

Danazole - has a diabetic effect.

Combinations that require caution:

• chlorpromazine (antipsychotic) when used in high doses (100 mg / day) increases the level of glucose in the blood (due to a decrease in the release of insulin);
• glucocorticoids (for systemic and local use: intraarticular, cutaneous and rectal preparations) and tetracosactides - increase blood glucose with the possible development of ketoacidosis (reduce tolerance to carbohydrates);
• iv: ritodrin, salbutamol, terbutaline increase blood glucose by β₂-agonistic effect;
• St. Johns wort preparations (Hypericum perforatum) reduce the concentration of gliclazide. The importance of controlling blood glucose should be emphasized.

Drugs That May Cause Dysglycemia

Combinations that require caution

Fluoroquinolones. In the case of simultaneous use with Diabeton MR 60 mg, the patient should be warned about the risk of dysglycemia and the importance of monitoring blood glucose levels.

Combinations to consider:

• anticoagulants (e.g. warfarin, etc.): when used simultaneously with anticoagulants, sulfonylureas can potentiate the anticoagulant effect of the latter. If necessary, the dose of anticoagulants can be adjusted.

Overdose

An overdose of sulfonylureas may cause hypoglycemia. symptoms of moderate hypoglycemia (without loss of consciousness and without neurological symptoms) must be corrected by taking carbohydrates (sugar), adjusting the dose of a hypoglycemic drug and / or diet. careful monitoring of the patients condition should be continued until the doctor makes sure that the patient is safe. severe hypoglycemia, accompanied by the development of coma, convulsions or other neurological disorders, requires emergency medical care with immediate hospitalization.

When a diagnosis of hypoglycemic coma is established or if a coma is suspected, the patient needs to rapidly inject 50 ml of concentrated glucose solution (20-30%) with further continuous administration of less concentrated glucose solution (10%) with the frequency necessary to maintain a blood glucose level of 1 g / l. It is necessary to ensure constant monitoring of the patient. Depending on the condition of the patient, the doctor decides on further monitoring.

Glyclazide has a high level of binding to plasma proteins, so the use of dialysis is ineffective.

Storage conditions

No special storage conditions are required. Keep out of the reach of children.