Diabeton^® MR (Tablets) Instructions for Use

ATC Code

A10BB09 (Gliclazide)

Active Substance

Gliclazide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug of the second-generation sulfonylurea group

Pharmacotherapeutic Group

Hypoglycemic agent for oral administration of the second-generation sulfonylurea group

Pharmacological Action

Gliclazide is a sulfonylurea derivative, an oral hypoglycemic drug, which differs from similar drugs by the presence of an N-containing heterocyclic ring with an endocyclic bond.

Gliclazide reduces blood glucose concentration by stimulating insulin secretion by the beta cells of the islets of Langerhans. The increase in postprandial insulin and C-peptide concentration persists after 2 years of therapy.

In addition to its effect on carbohydrate metabolism, Gliclazide has hemovascular effects.

Pharmacodynamic effects

Effect on insulin secretion

In type 2 diabetes mellitus, the drug restores the early peak of insulin secretion in response to glucose intake and enhances the second phase of insulin secretion. A significant increase in insulin secretion is observed in response to stimulation caused by food intake and glucose administration.

Hemovascular effects

Gliclazide reduces the risk of small vessel thrombosis by affecting mechanisms that may cause complications in diabetes mellitus:

• Partial inhibition of platelet aggregation and adhesion and reduction in the concentration of platelet activation factors (beta-thromboglobulin, thromboxane B₂);
• Restoration of the fibrinolytic activity of the vascular endothelium and an increase in the activity of tissue plasminogen activator.

Intensive glycemic control based on the use of gliclazide (glycated hemoglobin (HbA1c) <6.5%) significantly reduces micro- and macrovascular complications of type 2 diabetes mellitus compared to standard glycemic control.

The benefits of intensive glycemic control with gliclazide were independent of the benefits achieved with antihypertensive therapy.

Pharmacokinetics

Absorption

After oral administration, Gliclazide is completely absorbed. The plasma concentration of gliclazide increases gradually during the first 6 hours, with a plateau level maintained from 6 to 12 hours. Intra-individual variability is low.

Food intake does not affect the rate or extent of gliclazide absorption.

Distribution

Plasma protein binding is approximately 95% of gliclazide. V_d is about 30 L. Administration of gliclazide at a dose of 60 mg once daily maintains an effective plasma concentration of gliclazide for more than 24 hours.

Metabolism

Gliclazide is metabolized mainly in the liver. No active metabolites are present in plasma.

Excretion

T_1/2 averages from 12 to 20 hours. Gliclazide is excreted mainly by the kidneys, excretion occurs in the form of metabolites, less than 1% is excreted by the kidneys unchanged.

Linearity/non-linearity

The relationship between the administered dose (up to 120 mg) and AUC is linear.

Special populations

In elderly patients, no significant changes in pharmacokinetic parameters are observed.

Indications

• Type 2 diabetes mellitus with insufficient effectiveness of diet therapy, physical exercise, and weight reduction;
• Prevention of complications of diabetes mellitus: reduction of the risk of microvascular (nephropathy, retinopathy) and macrovascular complications (myocardial infarction, stroke) in patients with type 2 diabetes mellitus through intensive glycemic control.

ICD codes

Dosage Regimen

Tablets

Gliclazide is intended only for the treatment of adults.

The recommended dose of the drug should be taken orally, once a day, preferably with breakfast.

The daily dose can be 30-120 mg in a single dose.

It is recommended to swallow the tablet or half a tablet whole, without chewing or crushing the tablets.

If one or more doses are missed, a higher dose should not be taken at the next dose; the missed dose should be taken the next day. As with other hypoglycemic drugs, the dose of gliclazide in each case must be individually adjusted depending on blood glucose concentration and HbA1c.

The initial recommended dose of gliclazide is 30 mg (1/2 tablet)/day.

In case of adequate control, the drug at this dose can be used for maintenance therapy. If glycemic control is inadequate, the daily dose of gliclazide can be sequentially increased to 60 mg, 90 mg, or 120 mg.

The dose increase should be no earlier than 1 month of therapy with gliclazide at the previously prescribed dose. An exception is patients whose blood glucose concentration has not decreased after 2 weeks of therapy. In such cases, the drug dose can be increased 2 weeks after the start of administration.

The maximum recommended daily dose of gliclazide is 120 mg.

When transferring to Gliclazide patients receiving other oral hypoglycemic drugs, their dose and T_1/2 should be taken into account. As a rule, no transition period is required. The initial dose of gliclazide is 30 mg and then it should be titrated depending on blood glucose concentration.

When replacing long T_1/2 sulfonylurea derivatives with gliclazide in the modified-release dosage form to avoid hypoglycemia caused by the additive effect of two hypoglycemic agents, their administration can be discontinued for several days. The initial dose of gliclazide in this case should also be 30 mg and can be increased later if necessary.

Combined use with another hypoglycemic drug

Gliclazide can be used in combination with biguanides, alpha-glucosidase inhibitors, or insulin.

In case of inadequate glycemic control, insulin therapy should be additionally prescribed with careful medical supervision.

Prevention of complications of type 2 diabetes mellitus

To achieve intensive glycemic control, the dose of gliclazide can be gradually increased to 120 mg/day in addition to diet and physical exercise until the target HbA1c concentration is achieved. In this case, monitoring of the risk of hypoglycemia should be carried out.

Special patient groups

No dose adjustment of the drug is required for patients over 65 years of age.

Results of clinical studies have shown that no dose adjustment of the drug is required in patients with mild to moderate renal impairment. Careful medical supervision is recommended.

In patients at risk of hypoglycemia (insufficient or unbalanced nutrition; severe or poorly compensated endocrine disorders – pituitary and adrenal insufficiency, hypothyroidism; withdrawal of corticosteroids after their long-term use and/or use in high doses; severe cardiovascular diseases – severe coronary artery disease, severe atherosclerosis of the carotid arteries, widespread atherosclerosis), it is recommended to start therapy with the minimum dose (30 mg) of gliclazide.

There are no data on the efficacy and safety of the drug use in children and adolescents under 18 years of age.

Adverse Reactions

The following adverse effects have been reported with the use of gliclazide.

Hypoglycemia

The most frequent adverse reaction associated with the use of gliclazide is hypoglycemia.

Like other drugs of the sulfonylurea group, Gliclazide can cause hypoglycemia in case of irregular food intake and especially if a meal is missed. Possible symptoms of hypoglycemia: headache, intense hunger, nausea, vomiting, increased fatigue, sleep disturbance, agitation, aggression, decreased concentration, slowed reaction, depression, confusion, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, feeling of helplessness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness and loss of consciousness with possible development of coma, up to death.

Adrenergic reactions may also be noted: increased sweating, “sticky” skin, anxiety, tachycardia, increased blood pressure, palpitations, arrhythmia and angina pectoris.

As a rule, the symptoms of hypoglycemia are relieved by taking carbohydrates (sugar). Taking sugar substitutes is ineffective. With other sulfonylurea derivatives, recurrences of hypoglycemia have been observed after its successful relief.

In case of a severe or prolonged episode of hypoglycemia, emergency medical care is indicated, possibly with hospitalization, even if there is an effect from taking carbohydrates.

Other side effects

Gastrointestinal abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation. Taking the drug with breakfast helps to avoid these symptoms or minimize them.

The following side effects are less common

Skin and subcutaneous tissue disorders skin rash, skin itching, urticaria, angioedema, erythema, maculopapular rash, bullous reactions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis and autoimmune bullous disorders) and, in exceptional cases, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Blood and lymphatic system disorders hematological disorders (anemia, leukopenia, thrombocytopenia, granulocytopenia) develop rarely. As a rule, these phenomena are reversible upon discontinuation of therapy.

Hepatobiliary disorders increased activity of liver enzymes (AST, ALT, ALP); in isolated cases – hepatitis. If cholestatic jaundice appears, therapy should be discontinued. These phenomena are usually reversible upon discontinuation of therapy.

Eye disorders transient visual disturbances caused by changes in blood glucose concentration may occur, especially at the beginning of therapy.

Class-specific effects inherent in sulfonylurea derivatives

The following adverse events have been observed with the use of other sulfonylurea derivatives: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia; increased activity of liver enzymes, impaired liver function (e.g., with the development of cholestasis and jaundice) and hepatitis, the manifestations of which decreased over time after discontinuation of sulfonylurea drugs, but in some cases led to life-threatening liver failure.

Contraindications

• Hypersensitivity to gliclazide and other sulfonylurea derivatives, sulfonamides;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis, diabetic precoma, diabetic coma;
• Severe renal failure or severe hepatic failure (in these cases, insulin is recommended);
• Use of miconazole;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years.

With caution

Elderly age, irregular and/or unbalanced nutrition, glucose-6-phosphate dehydrogenase deficiency, severe cardiovascular diseases, hypothyroidism, adrenal or pituitary insufficiency, mild to moderate renal failure or mild to moderate hepatic failure, long-term corticosteroid therapy, alcoholism.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of gliclazide during pregnancy are absent or limited (less than 300 pregnancy outcomes), as are data on the use of other sulfonylurea derivatives.

In laboratory animal studies, Gliclazide did not have teratogenic effects.

The use of gliclazide during pregnancy is contraindicated.

To reduce the risk of congenital malformations associated with uncontrolled diabetes mellitus, diabetes control should be achieved before conception. Oral hypoglycemic drugs are not used during pregnancy. Insulin is the drug of choice for the treatment of diabetes mellitus in pregnant women. It is recommended to replace oral hypoglycemic drugs with insulin therapy: either in advance – in case of a planned pregnancy, or immediately after pregnancy is detected.

Breastfeeding period

Currently, there are no data on the penetration of gliclazide or its metabolites into breast milk. Given the risk of hypoglycemia in the breastfed child, the drug is contraindicated for use during breastfeeding. Risk to newborns/infants cannot be excluded.

Fertility

Reproductive toxicity studies did not show an effect on fertility or reproductive function in rats of both sexes.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal insufficiency.

Results of clinical studies have shown that no dose adjustment of the drug is required in patients with mild to moderate renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Hypoglycemia

The drug can only be prescribed to patients who eat regularly (including breakfast). It is very important to maintain sufficient carbohydrate intake with food, because the risk of hypoglycemia increases with irregular or insufficient nutrition, as well as when consuming food poor in carbohydrates. Hypoglycemia develops more often with a low-calorie diet, after prolonged or vigorous physical exertion, after alcohol consumption, or when taking several hypoglycemic drugs simultaneously.

When taking sulfonylurea derivatives, including gliclazide, hypoglycemia may develop, in some cases in a severe and prolonged form, requiring hospitalization and intravenous administration of dextrose solution for several days.

To reduce the risk of hypoglycemic episodes, careful individual selection of drugs and dosage regimen is necessary, as well as providing the patient with detailed instructions.

Factors that increase the risk of hypoglycemia

• Patient’s refusal or inability (especially elderly) to follow the doctor’s prescriptions and monitor their condition;
• Insufficient and irregular nutrition, skipping meals, fasting and changing the diet;
• Imbalance between physical activity and the amount of carbohydrates taken;
• Renal failure;
• Severe hepatic failure;
• Overdose of gliclazide;
• Some endocrine disorders (thyroid diseases, pituitary and adrenal insufficiency);
• Simultaneous use of certain drugs.

Hepatic and renal failure

The pharmacokinetic and/or pharmacodynamic properties of gliclazide may be altered in patients with severe hepatic and/or renal failure. Hypoglycemia developing in such patients can be quite prolonged; in such cases, immediate appropriate therapy is necessary.

Inadequate glycemic control

Glycemic control in patients receiving hypoglycemic therapy can be influenced by the following: simultaneous use of St. John’s wort preparations, fever, trauma, infectious diseases or surgical interventions. In these conditions, it may be necessary to prescribe insulin.

In many patients, the effectiveness of oral hypoglycemic drugs, including gliclazide, tends to decrease after a long period of treatment. This effect may be due to both the progression of the disease and a decrease in the therapeutic response to the drug. This phenomenon is known as secondary drug resistance, which must be distinguished from primary resistance, in which the drug does not produce the expected clinical effect already upon first prescription. Before diagnosing secondary drug resistance in a patient, the adequacy of dose selection and the patient’s adherence to the prescribed diet should be assessed.

Dysglycemia (changes in blood glucose concentration)

Changes in blood glucose concentration, including both hypoglycemia and hyperglycemia, have been reported in patients with diabetes mellitus concurrently receiving fluoroquinolone therapy, especially in elderly patients. Thus, all patients simultaneously taking Gliclazide and fluoroquinolones are recommended to have careful monitoring of blood glucose concentration.

Laboratory tests

For the assessment of glycemic control, regular determination of HbA1c concentration or fasting venous blood glucose concentration is recommended. Regular self-monitoring of blood glucose concentration is also advisable.

Sulfonylurea derivatives can cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Since Gliclazide is a sulfonylurea derivative, caution should be exercised when prescribing it to patients with glucose-6-phosphate dehydrogenase deficiency. The possibility of prescribing a drug not from the sulfonylurea derivative group should be considered.

Patients with porphyria

Cases of exacerbation of porphyria with the use of some other sulfonylurea derivatives in patients with porphyria have been described.

Effect on the Ability to Drive Vehicles and Operate Machinery

Gliclazide has no or negligible influence on the ability to drive vehicles and operate machinery.

However, patients should be informed about the symptoms of hypoglycemia and should exercise caution while driving or operating machinery, especially at the beginning of therapy.

Drug Interactions

Drugs and Substances That Increase the Risk of Hypoglycemia

Concomitant use is contraindicated

Miconazole (when administered systemically and when gel is applied to the oral mucosa): enhances the hypoglycemic effect of gliclazide with the possible development of hypoglycemia up to a comatose state.

Combinations not recommended for use

Phenylbutazone (systemic administration) enhances the hypoglycemic effect of sulfonylurea derivatives (displaces them from plasma protein binding and/or slows their elimination from the body).

It is preferable to use another anti-inflammatory drug or to warn the patient about the risk of hypoglycemia and to emphasize the importance of self-monitoring of blood glucose levels.

The dose of gliclazide should be adjusted if necessary during phenylbutazone administration and after its discontinuation.

Ethanol enhances hypoglycemia (by inhibiting compensatory reactions), which may contribute to the development of hypoglycemic coma.

It is necessary to avoid alcohol consumption or taking medicines containing ethanol.

Drug combinations requiring special attention and caution

The following medicinal products may enhance the hypoglycemic effect and contribute to the development of hypoglycemia: other hypoglycemic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists); beta-blockers, fluconazole; ACE inhibitors (captopril, enalapril), histamine H₂-receptor blockers; MAO inhibitors; sulfonamides; clarithromycin and NSAIDs.

Drugs That Increase Blood Glucose Levels

Combinations not recommended for use

Danazol has a diabetogenic effect.

If the use of this drug is necessary, the patient is advised to pay attention to the importance of monitoring blood and urine glucose.

If concomitant use of the drugs is necessary, dose adjustment of the hypoglycemic agent is recommended both during danazol administration and after its discontinuation.

Drug combinations requiring special attention and caution

Chlorpromazine (antipsychotic) in high doses (more than 100 mg/day) increases blood glucose levels by reducing insulin secretion.

The patient should be warned about this and attention should be paid to the importance of monitoring blood glucose levels.

If concomitant use of the drugs is necessary, dose adjustment of the hypoglycemic agent is recommended both during the antipsychotic administration and after its discontinuation.

Corticosteroids (systemic and local application – intra-articular, cutaneous, rectal administration) and tetracosactide: increase blood glucose levels with possible development of ketosis (reduced carbohydrate tolerance).

The patient should be warned about the need for careful monitoring of blood glucose levels, especially at the beginning of treatment.

If concomitant use of the drugs is necessary, dose adjustment of the hypoglycemic agent may be required both during corticosteroid administration and after their discontinuation.

Ritodrine, salbutamol, terbutaline (IV administration) beta₂-adrenergic agonists contribute to an increase in blood glucose levels.

The patient’s attention should be drawn to the importance of monitoring blood glucose levels.

If necessary, it is recommended to switch the patient to insulin therapy.

St. John’s Wort preparations the exposure of gliclazide decreases with concomitant use of St. John’s Wort preparations.

It is necessary to draw the patient’s attention to the importance of monitoring blood glucose levels.

Drugs That May Cause Dysglycemia (Change in Blood Glucose Levels)

Drug combinations requiring special attention and caution

Fluoroquinolones in case of concomitant use of gliclazide and a fluoroquinolone, patients should be warned about the risk of dysglycemia and the importance of monitoring blood glucose levels.

Combinations that should be taken into account

Anticoagulants (e.g., warfarin): sulfonylurea derivatives may enhance the effect of anticoagulants when used concomitantly.

Dose adjustment of the anticoagulant may be required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.