Diabeton® mr 60 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIABETON® MR 60 mg (DIABETON® MR 60 mg)

Composition:

Active substance: gliclazide;

One tablet contains gliclazide 60 mg;

Excipients: lactose monohydrate, hypromellose, magnesium stearate, maltodextrin, silicon dioxide colloidal anhydrous.

Pharmaceutical form. Modified-release tablets.

Main physicochemical properties: white, elongated tablets with a score line and embossing "DIA 60" on both sides. The tablets can be divided.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Blood glucose-lowering drugs, excluding insulins. Sulfonamides, urea derivatives. Gliclazide. ATC code A10BB09.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Diabeton® MR 60 mg is an oral antihyperglycemic agent. The active substance, gliclazide, is a derivative of sulfonylurea and is distinguished by the presence of a heterocyclic ring containing nitrogen and endocyclic bonds.

Gliclazide reduces plasma glucose levels by stimulating insulin secretion from pancreatic β-cells of the islets of Langerhans. Elevated postprandial insulin levels and C-peptide secretion are maintained even after 2 years of treatment. In addition to these metabolic properties, gliclazide also has hemovascular effects.

Pharmacodynamic effects.

Effect on insulin secretion. In patients with type 2 diabetes, gliclazide restores the early peak of insulin secretion in response to glucose intake and enhances the second phase of insulin secretion. Increased insulin release occurs in response to food intake or glucose loading.

Hemovascular properties. Gliclazide reduces microthrombosis through two mechanisms that may contribute to the development of diabetic complications:

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

Pharmacokinetics.

Absorption. Plasma concentrations of gliclazide progressively increase during the first 6 hours after administration, then reach a plateau level maintained from 6 to 12 hours after dosing.

Individual variations are minor.

Gliclazide is completely absorbed in the gastrointestinal tract. Food intake does not affect the rate or extent of absorption.

Distribution. Plasma protein binding of gliclazide is approximately 95%. The volume of distribution is about 30 L.

A single daily dose of Diabeton® MR 60 mg provides effective plasma concentrations of gliclazide for 24 hours.

Biotransformation. Gliclazide is primarily metabolized in the liver and excreted in urine; less than 1% of the active substance is excreted unchanged in urine. No active metabolites have been detected in plasma.

Elimination. The elimination half-life of gliclazide is approximately 12–20 hours.

Linearity/Non-linearity. With doses up to 120 mg, a linear relationship is observed between administered dose and plasma concentration.

Special patient groups.

Elderly patients. No clinically significant changes in pharmacokinetic parameters of the drug have been observed in elderly patients.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus in adults:

• reduction and control of blood glucose when it is not possible to normalize glucose levels by diet, physical exercise, and weight reduction alone.

Contraindications.

• Hypersensitivity to gliclazide or to other sulfonylurea drugs, sulfonamides, or to any component of the drug;
• type 1 diabetes;
• diabetic precoma and coma, diabetic ketoacidosis;
• severe renal or hepatic insufficiency (in such cases insulin therapy is recommended);
• treatment with miconazole;
• breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Medicinal products that 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.

Not recommended concomitant use

Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea drugs (by displacing their binding to plasma proteins and/or reducing their elimination).

It is advisable to use another anti-inflammatory agent; the patient should be warned and advised about the importance of self-monitoring. If necessary, the dose of the drug should be adjusted during and after anti-inflammatory therapy.

Alcohol increases the risk of hypoglycemic reactions (due to inhibition of compensatory mechanisms), which may lead to hypoglycemic coma. Consumption of alcohol and use of alcohol-containing medications should be avoided.

Combinations requiring caution

When used concomitantly with any of the following drugs, hypoglycemia may occur in some cases due to enhanced hypoglycemic effect: other antidiabetic agents [insulins, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists], β-blockers, fluconazole, angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril), H2-receptor antagonists, monoamine oxidase inhibitors (MAO), sulfonamides, clarithromycin, and nonsteroidal anti-inflammatory drugs.

Medicinal products that may cause hyperglycemia

Not recommended concomitant use

Danazol has a diabetogenic effect. If use of this active substance cannot be avoided, the patient should be warned and advised about the importance of monitoring glucose levels in urine and blood. Adjustment of the antidiabetic agent dose may be required during and after danazol therapy.

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 advised about the importance of monitoring blood glucose levels. Adjustment of the antidiabetic agent dose may be required during and after neuroleptic therapy.

Glucocorticoids (for systemic and local use: intra-articular, topical, and rectal preparations) and tetracosactide increase blood glucose levels with possible development of ketoacidosis (due to reduced carbohydrate tolerance). The patient should be warned and advised about the importance of monitoring blood glucose levels, especially at the beginning of treatment. Adjustment of the antidiabetic agent dose may be required during and after glucocorticoid therapy.

Intravenous: ritodrine, salbutamol, terbutaline increase blood glucose levels via β2-adrenergic effect. The patient should be advised about the importance of monitoring blood glucose levels. If necessary, the patient should be switched to insulin therapy.

St. John's wort (Hypericum perforatum) preparations reduce gliclazide concentration. The patient should be advised about the importance of monitoring blood glucose levels.

Medicinal products that may cause dysglycemia

Combinations requiring caution

Fluoroquinolones. When used concomitantly with Diabeton® MR 60 mg, the patient should be warned about the risk of dysglycemia and advised about the importance of monitoring blood glucose levels.

Combinations with warnings

Anticoagulants (e.g., warfarin, etc.). Sulfonylurea drugs may potentiate the anticoagulant effect of anticoagulants when used concomitantly. If necessary, the dose of anticoagulants may be adjusted.

Special precautions for use.

Hypoglycemia. This medicinal product should only be prescribed to patients who are able to eat regularly (including breakfast). It is important to consume carbohydrates regularly, as delayed meals, inadequate food intake, or meals low in carbohydrates increase the risk of hypoglycemia. Hypoglycemia is more likely to occur during low-calorie diets, prolonged or intense physical exertion, alcohol consumption, or when combining hypoglycemic agents.

Hypoglycemia may occur during treatment with sulfonylurea drugs (see section "Adverse reactions"). Occasionally, hypoglycemia may be severe and prolonged. In such cases, hospitalization and administration of glucose for several days may be required.

To reduce the risk of hypoglycemic episodes, individual patient characteristics should be taken into account, clear instructions provided, and the dose carefully adjusted.

Factors that increase the risk of hypoglycemia:

• patient refuses or is unable to follow medical advice (particularly relevant for elderly patients);
• inadequate or irregular nutrition, skipped meals, fasting periods, or dietary changes;
• imbalance between physical exertion and carbohydrate intake;
• renal impairment;
• severe hepatic impairment;
• drug overdose;
• 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").

Renal and hepatic impairment. The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic impairment or severe renal impairment. Hypoglycemic episodes in such patients may be prolonged and therefore require appropriate management.

Patient information

Patients and their family members should be informed about the risk of hypoglycemia, its symptoms (see section "Adverse reactions"), treatment, and conditions that may predispose to its development.

Patients should be informed about the importance of adhering to dietary recommendations, regular physical activity, and regular blood glucose monitoring.

Worsening glycemic control in patients receiving antidiabetic medications may be triggered by St. John’s wort (Hypericum perforatum) (see section "Interaction with other medicinal products and other forms of interaction"), stress, trauma, infection, or surgery. In some cases, insulin therapy may become necessary.

The hypoglycemic efficacy of any oral antidiabetic agent, including gliclazide, may diminish over time. This may result from progressive disease severity or reduced response to treatment. This phenomenon is known as secondary failure, which differs from primary failure, where drugs are ineffective from the start of treatment. Before concluding that secondary failure has occurred, the appropriateness of the prescribed dose and the patient’s adherence to dietary recommendations should be verified.

Disglycemia. Changes in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported in diabetic patients receiving concomitant therapy with fluoroquinolones, particularly in elderly patients. Therefore, careful monitoring of blood glucose levels is recommended for all patients receiving Diabeton® MR 60 mg and fluoroquinolones simultaneously.

Laboratory tests. Glycated hemoglobin levels (or fasting blood glucose) should be measured to assess glycemic control. Self-monitoring of blood glucose by patients may also be beneficial.

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, treatment with sulfonylurea agents may induce hemolytic anemia. Since gliclazide belongs to the sulfonylurea class of chemically related drugs, caution should be exercised, and alternative therapy with an agent from another class should be considered for patients with G6PD deficiency.

Patients with porphyria: Acute porphyria attacks have been reported with the use of some other sulfonylurea agents in patients with porphyria.

Excipients.

This medicinal product contains lactose. Therefore, it is not recommended for patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of gliclazide during pregnancy are lacking or limited (fewer than 300 cases in pregnant women), and data on the use of other sulfonylurea agents are also insufficient. Animal studies have shown that gliclazide has no teratogenic effects.

As a precautionary measure, it is advisable to avoid using gliclazide during pregnancy.

Glycemic control should be achieved before pregnancy is planned to reduce the risk of abnormalities associated with uncontrolled diabetes.

Insulin is the treatment of choice for managing diabetes during pregnancy; oral hypoglycemic agents are not considered appropriate.

Women should be switched from oral antidiabetic agents to insulin when pregnancy is planned or immediately after pregnancy is confirmed.

Breastfeeding. There are no data on the passage of gliclazide or its metabolites into breast milk. Diabeton® MR 60 mg is contraindicated during breastfeeding due to the risk of neonatal hypoglycemia. A risk to newborns and infants cannot be excluded.

Fertility. In preclinical studies, no effects of gliclazide on fertility or reproductive performance in male or female rats were observed.

Ability to affect reaction speed when driving or operating machinery.

Diabeton® MR 60 mg may have a minor influence on the ability to drive or operate 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.

Method of Administration and Dosage

For oral use.

Prescribed only for adults.

The daily dose may vary from 0.5 to 2 tablets (from 30 to 120 mg per day).

The tablet may be divided into equal doses.

The daily dose should be taken once daily with breakfast.

Half a tablet or a whole tablet (tablets) should be swallowed whole (do not crush or chew).

If a patient forgets to take the tablets, the dose should not be increased the next day.

As with all antidiabetic agents, Diabeton® MR 60 mg requires individual dose adjustment based on the patient's response to treatment (blood glucose levels, glycated hemoglobin HbA1c).

Initial dose and dose titration. The recommended initial dose is 30 mg (0.5 tablet) per day. If adequate blood glucose control is achieved, treatment may continue at this dose. If adequate glucose control is not achieved, the daily dose may be gradually increased to 60 mg (1 tablet), 90 mg (1.5 tablets), or 120 mg (2 tablets). Dose increases should be performed gradually, at intervals of 1 month, except in cases where no reduction in blood glucose levels is observed within 2 weeks of treatment. In such cases, the dose may be increased at the end of the second week of treatment.

Maximum recommended daily dose – 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 may be divided, allowing administration at a dose of 30 mg (0.5 tablet) or 90 mg (1.5 tablets).

Switching patients from a gliclazide 80 mg formulation to Diabeton® MR 60 mg modified-release tablets. 1 tablet containing gliclazide 80 mg corresponds to 0.5 tablet of Diabeton® MR 60 mg. Blood parameters must be carefully monitored during the switch to Diabeton® MR 60 mg.

Switching patients from another oral antidiabetic agent to Diabeton® MR 60 mg. When switching to Diabeton® MR 60 mg, the dosage and half-life of the previous oral antidiabetic agent should be taken into account. A transition period is usually not required. Treatment should start at a dose of 30 mg, followed by dose adjustment (see "Initial dose and dose titration").

When switching from a sulfonylurea antidiabetic agent with a long half-life, a treatment interruption of several days may be necessary to avoid the cumulative effect of both agents and the development of hypoglycemia. Treatment with Diabeton® MR 60 mg should be initiated at a dose of 30 mg per day (0.5 tablet), with subsequent dose adjustment according to the principles of initial treatment and dose titration (see above).

Concomitant use with other antidiabetic agents. Diabeton® MR 60 mg may 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 may be initiated under close medical supervision.

Special patient groups.

Elderly patients. The dosing regimen for patients over 65 years of age is the same as for patients under 65 years of age.

Patients with renal impairment. For patients with mild to moderate renal impairment, the dosing regimen of Diabeton® MR 60 mg is the same as for patients with normal renal function; however, such patients should be under close monitoring.

Risk factors for hypoglycemia:

• inadequate or irregular nutrition;
• severe or poorly compensated endocrine disorders (hypothyroidism, hypopituitarism, and adrenocorticotropic insufficiency);
• discontinuation of long-term corticosteroid therapy and/or therapy with high-dose corticosteroids;
• severe vascular diseases (severe ischemic heart disease, severe carotid artery disease, diffuse vascular disorders).

A minimal initial dose of 30 mg per day is recommended.

Children.

Diabeton® MR 60 mg is not recommended for use in children due to lack of data on its use in this patient population.

Overdose.

Overdose of sulfonylurea agents may cause hypoglycemia.

Symptoms of moderate hypoglycemia (without loss of consciousness and without neurological symptoms) should be corrected by carbohydrate intake (sugar), adjustment of the antidiabetic agent dose, and/or dietary changes. Close monitoring of the patient should continue until the physician is confident that the patient is safe.

Severe hypoglycemia may occur, leading to coma, convulsions, or other neurological disturbances, requiring emergency medical care and immediate hospitalization.

In cases of diagnosed hypoglycemic coma or suspected coma development, the patient should receive a rapid intravenous injection of 50 mL of concentrated glucose solution (20% to 30%), 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 required. The physician decides on further monitoring based on the patient's condition.

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

Adverse Reactions

The most common adverse reaction associated with gliclazide is hypoglycaemia. As with other sulphonylurea drugs, gliclazide may cause hypoglycaemia if meals are irregularly taken and particularly if a meal is missed. Possible symptoms of hypoglycaemia include: headache, intense hunger, nausea, vomiting, fatigue, sleep disturbances, restlessness, aggression, reduced concentration and attention, slowed reactions, depression, confusion, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, weakness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness and loss of consciousness, which may progress to coma and may be fatal.

In addition, symptoms related to the adrenergic system may occur: sweating, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, chest pain, arrhythmia.

Symptoms of hypoglycaemia usually resolve after ingestion of carbohydrates (sugar). However, sugar substitutes are not effective in this case. Experience with other sulphonylurea drugs indicates that even if initial measures are effective, hypoglycaemia may recur.

If a hypoglycaemic episode is severe or prolonged and the patient's condition is temporarily controlled by sugar intake, immediate medical attention or even hospitalization is required.

Other Adverse Reactions

Gastrointestinal disorders, including abdominal pain, nausea, vomiting, dyspepsia, diarrhoea, and constipation. Adherence to the recommendation to take the medicinal product with breakfast may help prevent or minimize these effects.

The following undesirable effects are observed less frequently.

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, angioneurotic oedema, erythema, maculopapular eruptions, bullous reactions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and autoimmune bullous disorders), and very rarely drug reaction with eosinophilia and systemic symptoms (DRESS).

Blood and lymphatic system disorders: haematological disorders are rare and may include anaemia, leucopenia, thrombocytopenia, granulocytopenia. These effects usually resolve after discontinuation of treatment.

Hepatobiliary disorders: increased levels of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase), hepatitis (isolated cases). If cholestatic jaundice occurs, treatment with the medicinal product should be discontinued.

The above-mentioned adverse effects usually resolve after discontinuation of the drug.

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

Reactions characteristic of the sulphonylurea class of drugs

Cases of erythrocytopenia, agranulocytosis, haemolytic anaemia, pancytopenia, allergic vasculitis, hyponatraemia, elevated liver enzymes, and even liver dysfunction (e.g. with cholestasis and jaundice) have been reported. There have also been reports of hepatitis, which regressed after discontinuation of sulphonylurea drugs, or in isolated cases progressed to life-threatening hepatic failure.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 3 years.

Storage conditions

No special storage conditions required. Keep out of reach and sight of children.

Packaging

15 tablets in a blister (PVC/aluminium). 2, 6, or 8 blisters per cardboard box.

Prescription status: Prescription only.

Manufacturer

Laboratoires Servier Industrie /
Les Laboratoires Servier Industrie.

Manufacturer's address

905 route de Saran, 45520 Gidy, France.

Manufacturer

Servier (Ireland) Industries Ltd.

Manufacturer's address

Gorey Road, Arklow, Co. Wicklow, Y14 E284, Ireland.

Marketing Authorisation Holder

Les Laboratoires Servier.

Address of Marketing Authorisation Holder

50, rue Carnot, 92284 Suresnes Cedex, France.

For any inquiries, please contact LLC "Servier Ukraine" at tel. (044) 490 3441.