Instructions Diabeton MR 60 mg modified-release tablets 60 mg blister No. 30
Composition
active ingredient: gliclazide;
1 tablet contains gliclazide 60 mg;
Excipients: lactose monohydrate, hypromellose, magnesium stearate, maltodextrin, colloidal anhydrous silicon dioxide.
Dosage form
Modified-release tablets.
Main physicochemical properties: white, oblong tablets with a score and embossed "DIA 60" on both sides. The tablets are divisible.
Pharmacotherapeutic group
Antidiabetic agents. Hypoglycemic agents, except insulins. Sulfonamides, urea derivatives. Gliclazide.
ATX code A10V B09.
Pharmacological properties
Pharmacodynamics
Mechanism of action.
The active ingredient gliclazide is an oral hypoglycemic agent that is a sulfonylurea derivative and differs from other drugs in the presence of a heterocyclic ring containing nitrogen and having endocyclic bonds.
Gliclazide reduces plasma glucose levels by stimulating insulin secretion by β-cells of the islets of Langerhans of the pancreas. The increase in postprandial insulin levels and C-peptide secretion persist even after 2 years of use of the drug. In addition to the above metabolic properties, gliclazide also has hemovascular properties.
Pharmacodynamic effects.
Effect on insulin secretion. In patients with type 2 diabetes, gliclazide restores the early peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. The increase in insulin secretion occurs in response to food intake or glucose loading.
Hemovascular properties. Gliclazide reduces microthrombosis through two mechanisms that may 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 the vascular endothelium (increases tPA activity).
Prevention of complications of type 2 diabetes. ADVANCE is an international multicenter randomized study with a bifactorial design aimed at determining the benefits of a strategy of intensive glycemic control (HbA1c level ≤ 6.5%) based on Diabeton MR compared to standard glycemic control and the benefits of blood pressure reduction using a fixed combination of perindopril/indapamide compared to placebo against the background of current standard therapy (double-blind comparison) in terms of the impact on major macro- and microvascular complications in patients with type 2 diabetes.
The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular (new cases or worsening of nephropathy, retinopathy) events.
The ADVANCE study enrolled 11,140 patients. During the 6-week run-in period, patients continued to receive their usual antidiabetic therapy. Patients were then randomized to receive standard glycemic control (n = 5569) or to receive Diabeton MR as the basis of an intensive glycemic control strategy (n = 5571). The intensive glycemic control strategy was based on the use of Diabeton MR from the beginning of treatment or on the use of Diabeton MR in addition to standard therapy (the therapy the patient was receiving at the time of inclusion) with a possible dose increase to the maximum (120 mg), and then, if necessary, with the addition of other antidiabetic drugs such as metformin, acarbose, thiazolidinediones or insulin. Other sulfonylureas were not used in the intensive glycemic control group. The patients were under close medical supervision and strictly followed a diet.
The observation lasted 4.8 years. The result of treatment with Diabeton MR, which was the basis of the intensive glycemic control strategy (mean achieved HbA1C level – 6.5%), compared with standard glycemic control (mean achieved HbA1C level – 7.3%) was a significant total reduction of 10% in the relative risk of major macro- and microvascular complications ((HR) 0.90, 95% Cl [0.82; 0.98] p = 0.013; 18.1% of patients in the intensive control group compared with 20% of patients in the standard control group). The advantages of the intensive glycemic control strategy with the appointment of Diabeton MR as the basis of therapy were due to:
a significant reduction 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 reduction 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 new-onset microalbuminuria by 8% (HR 0.92, 95% CI [0.85–0.99], p = 0.030; 34.9% vs. 37.9%); a significant reduction in the relative risk of renal events by 11% (HR 0.89, 95% Cl [0.83; 0.96], p = 0.001; 26.5% vs. 29.4%).
The benefits of the intensive glycemic control strategy based on Diabeton MR were independent of blood pressure reduction.
Pharmacokinetics
Absorption. The concentration of gliclazide in the blood plasma increases progressively 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 administration.
Individual fluctuations are insignificant.
Gliclazide is completely absorbed from the gastrointestinal tract. Food intake does not affect the rate and extent of absorption.
Distribution: Gliclazide is approximately 95% bound to plasma proteins. The volume of distribution is approximately 30 liters.
A single daily dose of Diabeton® MR 60 mg provides an effective concentration of gliclazide in blood plasma for 24 hours.
Biotransformation: Gliclazide is metabolized mainly in the liver and excreted in the urine, less than 1% of the active substance is excreted in the urine unchanged. Active metabolites are absent in the blood plasma.
Elimination: The elimination half-life of gliclazide is approximately 12-20 hours.
Linearity/non-linearity. When using the drug in doses up to 120 mg, a linear relationship is observed between the dose taken and the concentration in the blood plasma.
Special patient groups.
Elderly patients: No clinically significant changes in the pharmacokinetics of the drug are observed in elderly patients.
Indication
Type II diabetes in adults:
lowering and controlling blood glucose when glucose levels cannot be normalized by diet, exercise and weight loss alone; preventing complications of type 2 diabetes: reducing the risk of macro- and microvascular complications, including new cases or worsening of nephropathy in patients with type 2 diabetes treated with an intensive glycemic control strategy.
Contraindication
Hypersensitivity to gliclazide or to other sulfonylureas, sulfonamides or to 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); treatment with miconazole; breastfeeding period.
Interaction with other medicinal products and other types of interactions
When prescribing drugs that may cause hypo- or hyperglycemia (see below), the patient should be warned about the need for careful monitoring of blood glucose levels during treatment. It may be necessary to adjust the dose of the hypoglycemic drug during and after treatment with these drugs.
Drugs, concomitant administration of which may increase the risk of hypoglycemia.
Concomitant use contraindicated
Miconazole (for systemic use, oral gel) enhances the hypoglycemic effect with the possible development of symptoms of hypoglycemia and even the development of coma.
Concomitant use not recommended
Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea drugs (replaces their binding to 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. Alcohol and alcohol-containing drugs should be avoided.
Combinations requiring caution
When used simultaneously with one of the following drugs, hypoglycemia may occur in some cases due to an increase in the hypoglycemic effect: other blood sugar-lowering drugs (insulins, 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, MAO inhibitors, sulfonamides, clarithromycin and non-steroidal anti-inflammatory drugs.
Drugs that may increase the risk of hyperglycemia when administered concomitantly
Concomitant use not recommended
Danazol has a diabetogenic effect.
Combinations requiring caution
Chlorpromazine (neuroleptic) when used in high doses (more than 100 mg per day) increases blood glucose levels (due to decreased insulin release).
Glucocorticoids (for systemic and local use: intra-articular, cutaneous and rectal preparations) and tetracosactide increase blood glucose levels with the possible development of ketoacidosis (reduce carbohydrate tolerance).
Intravenous: ritodrine, salbutamol, terbutaline increase blood glucose levels due to β2-agonist effect.
St. John's wort (Hypericum perforatum) preparations reduce the concentration of gliclazide. The importance of blood glucose control should be emphasized.
Drugs that can cause dysglycemia
Combinations requiring caution
Fluoroquinolones. In 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 may potentiate the anticoagulant effect of the latter. If necessary, the dose of anticoagulants may be adjusted.
Application features
Hypoglycemia. This drug should only be prescribed to patients who are able to eat regularly (including breakfast). It is important to take carbohydrates regularly, as the risk of hypoglycemia is increased when meals are taken late, in inadequate quantities, or when the meal is low in carbohydrates. Hypoglycemia is more likely to occur with a low-calorie diet, prolonged or intense exercise, alcohol consumption, or a combination of hypoglycemic drugs.
Hypoglycemia may occur when taking sulfonylureas (see section "Adverse reactions"). Sometimes hypoglycemia can be severe and prolonged. In this case, hospitalization and administration of glucose for several days may be necessary.
To reduce the risk of hypoglycemic episodes, it is necessary to take into account the individual characteristics of patients, provide them with clear explanations, and carefully select the dose.
Factors that increase the risk of hypoglycemia:
the patient refuses or cannot follow the doctor's recommendations (especially this applies to elderly patients); unsatisfactory, irregular nutrition, skipping meals, periods of fasting or changes in diet; imbalance between physical activity and carbohydrate intake; renal failure; severe liver failure; drug overdose; certain endocrine disorders: thyroid dysfunction, hypopituitarism and adrenal insufficiency;
simultaneous use of certain medicines (see section "Interaction with other medicines and other types of interactions").
Renal and hepatic insufficiency. The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic and severe renal insufficiency. Episodes of hypoglycemia in such patients may be prolonged and require appropriate treatment.
The patient and his family members should be informed about the risk factors and conditions that may contribute to the occurrence of hypoglycemia, about the symptoms of hypoglycemia (see section "Adverse reactions") and how to eliminate them.
The patient should be informed about the importance of following the doctor's dietary recommendations, the importance of regular physical exercise, and regular blood glucose monitoring.
Deterioration of glycemic control in patients receiving hypoglycemic drugs may be caused by: St. John's wort (Hypericum perforatum), infection, fever, trauma, or surgery. In some cases, insulin may be necessary.
The hypoglycaemic efficacy of any oral antidiabetic agent, including gliclazide, may vary over time. This may be due to progression of the disease or a decrease in response to treatment. This phenomenon is known as secondary insufficiency, which is different from primary insufficiency, when the drugs are ineffective from the very beginning of treatment. Before concluding that a patient has developed secondary insufficiency, it is necessary to check the correctness of the prescribed dose and the patient's adherence to the diet.
Dysglycemia: Blood glucose disturbances, including hypoglycemia and hyperglycemia, have been reported in diabetic patients receiving concomitant therapy with fluoroquinolones, particularly in the elderly. Therefore, careful monitoring of blood glucose levels is recommended in all patients receiving Diabeton® MR 60 mg and fluoroquinolones concomitantly.
Laboratory tests: Glycated hemoglobin (or fasting blood glucose) is recommended to assess blood glucose control. Self-monitoring of blood sugar levels by patients may also be useful.
In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, the use of sulfonylureas may cause hemolytic anemia. Since gliclazide belongs to the chemical class of sulfonylureas, caution should be exercised and consideration should be given to prescribing alternative therapy from a different class to patients with G6PD deficiency.
The drug contains lactose, therefore, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency are not recommended to take this drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
Diabeton® MR 60 mg may have a minor influence on the ability to drive or use machines. Patients should be aware of the symptoms of hypoglycemia, be able to recognize them and, if they occur, exercise caution when driving or operating machinery, especially at the beginning of treatment.
Use during pregnancy or breastfeeding
Pregnancy. Oral antidiabetic agents (including Diabeton® MR 60 mg) should not be used during pregnancy. Experience with gliclazide during pregnancy is limited (less than 300 exposed pregnancies), and there are also limited data on the use of other sulfonylureas. Animal studies have shown that gliclazide is not teratogenic.
Glucose control should be achieved before pregnancy is planned to reduce the risk of abnormalities associated with uncontrolled diabetes. When planning or immediately after pregnancy, the woman should be transferred from oral hypoglycemic drugs to insulin.
Breastfeeding. There is no data on the excretion of gliclazide or its metabolites into breast milk. Diabeton® MR 60 mg is contraindicated during breast-feeding due to the possibility of neonatal hypoglycemia. A risk to the newborn and infant cannot be excluded.
Fertility: In nonclinical studies, no effects on fertility or reproductive performance were observed in male or female rats.
Method of administration and doses
For oral use.
It is intended for adults only.
The daily dose can vary from 0.5 to 2 tablets (30 to 120 mg per day).
The tablet can be divided into equal doses.
The daily dose should be taken once during breakfast.
Half a tablet or whole tablet(s) should be swallowed whole (do not crush or chew).
If the patient forgets to take the tablets, the dose should not be increased the next day.
Like all hypoglycemic agents, Diabeton® MR 60 mg requires individual dose adjustment depending on the patient's response to treatment (blood glucose level, glycosylated hemoglobin HbA1c).
Initial dose and dose selection. The recommended initial dose is 30 mg (0.5 tablets) per day. With effective glucose control, treatment can be continued at this dose. If there is a need to strengthen blood glucose control, the daily dose can be gradually increased to 60 mg (1 tablet), 90 mg (1.5 tablets) or 120 mg (2 tablets). It is recommended to increase the dose gradually, with an interval of 1 month, except in cases where there is no decrease in blood glucose levels during 2 weeks of treatment. In this case, the dose can be increased at the end of the second week of treatment.
The maximum recommended daily dose is 120 mg (2 tablets).
1 modified-release tablet of Diabeton® MR 60 mg is equivalent to 2 modified-release tablets of gliclazide 30 mg.
The modified-release tablet of Diabeton® MR 60 mg can be divided, which allows the drug to be used in a dose of 30 mg (0.5 tablet) and in a dose of 90 mg (1.5 tablets).
Transferring a patient from preparations containing gliclazide 80 mg to Diabeton® MR 60 mg, modified-release tablets. 1 tablet containing gliclazide 80 mg corresponds to 0.5 tablets of Diabeton® MR 60 mg. Blood counts should be carefully monitored during transfer to Diabeton® MR 60 mg.
Transferring a patient from other oral hypoglycemic agents to Diabeton® MR 60 mg. When transferring to Diabeton® MR 60 mg, the dosage and half-life of the previous oral hypoglycemic agent should be taken into account. A transition period is usually not required. The dose should be started at 30 mg with subsequent dose adjustment (see “Initial dose and dose selection”).
When transferring from hypoglycemic sulfonylureas with a long half-life, a break in treatment for several days may be necessary to avoid the cumulative effect of the two drugs and the development of hypoglycemia. Treatment with Diabeton® MR 60 mg is started with a dose of 30 mg per day (0.5 tablets) with subsequent dose adjustment in accordance with the rules for starting treatment and selecting the dose (see above).
Concomitant use with other antidiabetic agents. Diabeton® MR 60 mg can be used in combination with biguanides, alpha-glucosidase inhibitors or insulin. If adequate blood glucose control is not achieved in patients taking Diabeton® MR 60 mg, concomitant insulin therapy can be initiated under close medical supervision.
Special patient groups.
Elderly patients. For patients over 65 years of age, the dosage regimen of Diabeton® MR 60 mg is the same as for patients under 65 years of age.
Patients with renal impairment. For patients with mild to moderate renal impairment, the dosage regimen of 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 poorly compensated endocrine disorders (hypothyroidism, hypopituitarism and adrenocorticotropic insufficiency); Withdrawal of long-term corticosteroid therapy and/or high-dose corticosteroid therapy; Severe vascular diseases (severe ischemic heart disease, severe carotid artery disease, diffuse vascular diseases).
A minimum starting dose of 30 mg per day is recommended.
For the prevention of complications of type 2 diabetes. According to the ADVANCE study, it is necessary to adhere to a strategy of intensive glycemic control (HbA1c level ≤ 6.5%). The strategy of intensive glycemic control involves a gradual increase in the dose of Diabeton® MR 60 mg to 120 mg per day. The dose increase should be carried out under the control of HbA1c levels, while adhering to strict recommendations for diet and exercise, controlling the risk of hypoglycemia. It is also possible to add other sugar-lowering drugs, such as metformin, acarbose, thiazolidinediones or insulin.
It is not recommended to prescribe Diabeton® MR 60 mg to children due to the lack of data on the use of the drug in this category of patients.
Overdose
Overdose of sulfonylureas can cause hypoglycemia.
Symptoms of moderate hypoglycemia (without loss of consciousness and without neurological symptoms) should be corrected by taking carbohydrates (sugar), adjusting the dose of the hypoglycemic drug and/or diet. Close monitoring of the patient should continue until the doctor is sure that the patient is safe.
Severe hypoglycemia with the development of coma, convulsions, or other neurological disorders requires emergency medical care with immediate hospitalization.
If a diagnosis of hypoglycemic coma is made or if coma is suspected, the patient should be given 50 ml of a concentrated glucose solution (20% to 30%) intravenously rapidly, followed by continuous infusion of a less concentrated glucose solution (10%) at a frequency that will maintain a blood glucose level above 1 g/l. The patient should be kept under constant observation. Depending on the patient's condition, the physician will decide on further monitoring.
Gliclazide has a high level of binding to plasma proteins, so dialysis is ineffective.
Adverse reactions
The most common adverse reaction with gliclazide is hypoglycemia. As with other sulfonylureas, gliclazide can cause hypoglycemia with irregular meals and especially if meals are missed. The occurrence of hypoglycemia may be accompanied by characteristic symptoms such as: headache, intense hunger, nausea, vomiting, fatigue, sleep disturbances, agitation, aggression, decreased concentration and attention, slowed reactions, depression, confusion, visual and speech disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, feeling of weakness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness and loss of consciousness, which can lead to coma and death.
In addition, disorders of the adrenergic system are possible: sweating, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, chest pain, arrhythmia.
Usually, the symptoms of hypoglycemia disappear after taking carbohydrates (sugar). However, taking sugar substitutes will not be effective in this case. Experience with other sulfonylureas shows that even if the measures taken are effective, hypoglycemia may occur again.
If the hypoglycemic episode is severe or prolonged and the patient's condition is temporarily under control by taking sugar, emergency medical attention or even hospitalization is necessary.
Gastrointestinal disorders, including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Following the recommendations for taking the drug with breakfast will help avoid or minimize the occurrence of these manifestations.
The following undesirable effects are less common.
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioedema, erythema, maculopapular rash, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) and very rarely - drug rash with eosinophilia and systemic symptoms (DRESS).
Blood and lymphatic system disorders: Hematological disorders are rare and may include anemia, thrombocytopenia, leukopenia, granulocytopenia. These phenomena usually disappear after discontinuation of treatment.
Hepatobiliary system: increased levels of liver enzymes (ALT, AST, alkaline phosphatase), hepatitis (isolated cases). In case of cholestatic jaundice, treatment with the drug should be discontinued.
These undesirable effects usually disappear after discontinuation of the drug.
On the part of the organs of vision: temporary visual disturbances may occur due to changes in blood glucose levels, especially at the beginning of treatment.
Reactions typical of the sulfonylurea class: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, increased liver enzymes and even liver dysfunction (e.g. with cholestasis and jaundice), hepatitis with regression after discontinuation of sulfonylurea drugs or in isolated cases with subsequent life-threatening liver failure.
Clinical studies.
The ADVANCE study monitored serious adverse reactions. No previously undescribed adverse reactions were observed in the group of patients with type 2 diabetes treated with an intensive glycemic control strategy. Several patients experienced severe hypoglycemia. Most episodes of hypoglycemia occurred in patients with concomitant insulin therapy.
Reporting of suspected adverse reactions. It is important to report suspected adverse reactions after the registration of a medicinal product. This will allow for continued monitoring of the benefit/risk balance. Healthcare professionals are requested to report suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Does not require any special storage conditions. Keep out of the reach of children.
Packaging
15 tablets in a blister (PVC/aluminium). 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Servier Industries Laboratories.
Location of the manufacturer and its business address
905 rue de Saran 45520 Guidy, France.
