Gliclazide-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

A10BB09 (Gliclazide)

Active Substance

Gliclazide (Rec.INN registered by WHO)

Dosage Form

Gliclazide-SZ

Prolonged-release tablets 60 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release tablets white or almost white, round, flat-cylindrical, with a bevel and a score on one side.

Excipients: microcrystalline cellulose 102, hypromellose (hydroxypropyl methylcellulose), colloidal silicon dioxide (aerosil), magnesium stearate.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.
30 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

Gliclazide is a sulfonylurea derivative, a hypoglycemic drug for oral administration, 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 β-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.

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 or 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), as well as 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 prolonged-release gliclazide significantly reduces micro- and macrovascular complications of type 2 diabetes mellitus compared to standard glycemic control.

Pharmacokinetics

Absorption

After oral administration, Gliclazide is completely absorbed. The concentration of gliclazide in the blood plasma increases gradually during the first 6 hours, the plateau level is maintained from 6 to 12 hours. Individual variability is low.

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

Distribution

Approximately 95% of gliclazide is bound to plasma proteins. V_d is about 30 L. Administration of the drug Gliclazide-SZ at a dose of 60 mg once a day maintains an effective concentration of gliclazide in the blood plasma for more than 24 hours.

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

Metabolism

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

Excretion

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

Pharmacokinetics in special patient groups

No significant changes in pharmacokinetic parameters are observed in elderly individuals.

Indications

• Type 2 diabetes mellitus with insufficient effectiveness of diet therapy, physical activity, and weight loss;
• Prevention of complications of type 2 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

The drug is intended only for the treatment of adults.

The drug should be taken orally, once a day, preferably with breakfast. It is recommended to swallow the prescribed dose (tablet or half a tablet) with water, without chewing or crushing. Take food after taking the drug.

The daily dose can be 30-120 mg (1/2-2 tablets) in one dose.

The maximum recommended daily dose is 120 mg (2 tablets of 60 mg).

The presence of a score on the 60 mg tablets allows the tablet to be divided and the daily dose to be taken as 30 mg (1/2 of a 60 mg tablet), or if necessary, 90 mg (1 tablet of 60 mg and 1/2 of a 60 mg tablet).

As with other hypoglycemic drugs, the dose of the drug in each case must be selected individually, depending on the blood glucose concentration and glycated hemoglobin (HbA_1c).

Changes in external factors (weight loss, lifestyle changes, stress) or improvement in blood glucose control may require a change in the dose of gliclazide.

It is not recommended to take a double dose to compensate for a missed one; take the usual dose the next day.

The duration of treatment is determined by the attending physician.

Initial dose

The initial recommended dose (including for elderly patients over 65 years of age) is 30 mg/day (1/2 tablet). 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 the drug can be sequentially increased to 60, 90, or 120 mg.

An increase in dose is possible no earlier than 1 month of therapy with the drug 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 dose of the drug can be increased 2 weeks after the start of administration.

Switching from another hypoglycemic drug to Gliclazide-SZ, prolonged-release tablets 60 mg

The drug Gliclazide-SZ, prolonged-release tablets 60 mg can be used instead of another oral hypoglycemic drug. When switching to Gliclazide-SZ in 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 should be 30 mg and then should be titrated depending on the blood glucose concentration.

When replacing long T_1/2 sulfonylurea derivatives with Gliclazide-SZ, to avoid hypoglycemia caused by the additive effect of two hypoglycemic agents, their administration can be stopped for several days. The initial dose of Gliclazide-SZ in this case is also 30 mg (1/2 of a 60 mg tablet) and can be increased if necessary, as described above.

Combined use with another hypoglycemic drug

The drug Gliclazide-SZ can be used in combination with biguanides, alpha-glucosidase inhibitors, or insulin. When used in combination with other drugs for diabetes mellitus, the dose selection is individual.

Prevention of diabetes complications

To achieve intensive glycemic control, the dose of Gliclazide-SZ can be gradually increased to 120 mg/day in addition to diet and exercise until the target HbA_1c level is reached. The risk of hypoglycemia should be kept in mind. In addition, other hypoglycemic drugs, such as metformin, an alpha-glucosidase inhibitor, a thiazolidinedione derivative, or insulin, can be added to the therapy.

No dose adjustment of the drug is required for patients over 65 years of age. As with the use of other drugs, caution is required.

No dose adjustment of the drug is required for patients with mild to moderate renal impairment. Thorough medical monitoring is recommended.

In patients at risk of developing hypoglycemia (insufficient or unbalanced nutrition; severe or poorly compensated endocrine disorders – pituitary and adrenal insufficiency, hypothyroidism; withdrawal of glucocorticosteroids 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 use the minimum dose (30 mg) of Gliclazide-SZ.

Data on the efficacy and safety of the drug in children and adolescents under 18 years of age are not available, use is contraindicated.

Adverse Reactions

Considering the experience with gliclazide, the possibility of the following side effects should be kept in mind.

Hypoglycemia

Like other drugs of the sulfonylurea group, the drug Gliclazide-SZ can cause hypoglycemia in case of irregular food intake and especially if a meal is missed. Possible symptoms of hypoglycemia: headache, intense feeling of hunger, nausea, vomiting, increased fatigue, sleep disturbance, irritability, agitation, decreased concentration, slow reaction, depression, confusion, visual and speech impairment, aphasia, tremor, paresis, loss of self-control, feeling of helplessness, perception disturbance, dizziness, weakness, convulsions, bradycardia, delirium, shallow breathing, drowsiness, 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. As a rule, the symptoms of hypoglycemia are relieved by the intake of carbohydrates (sugar). The intake of sugar substitutes is ineffective. Against the background of other sulfonylurea derivatives, recurrences of hypoglycemia have been noted after its successful relief.

In case of severe or prolonged hypoglycemia, emergency medical care is indicated, possibly with hospitalization, even if there is an effect from carbohydrate intake.

Urgent medical attention is also required in case of the following conditions that occurred while taking Gliclazide-SZ

• Angioedema (allergic reaction with rapid swelling of the face, lips, tongue or throat, which can cause difficulty breathing, skin rash);
• Stevens-Johnson syndrome (spreading intense painful rash on the skin and mucous membranes with blistering, peeling and detachment of the skin, ulcers in the mouth, throat, nose, eyes and genitals, fever);
• Toxic epidermal necrolysis (painful skin inflammation with many small reddish spots and blisters on the body and mucous membranes, increased body temperature, flu-like symptoms, complications such as dehydration, suppuration of inflamed skin areas, pneumonia, kidney damage, infection development are possible;
• Autoimmune skin diseases with the formation of blisters and erosions on the skin and mucous membranes, skin vulnerability and sensitivity to minor injuries (signs of autoimmune bullous disorders);
• Allergic reaction in the form of extensive skin rash, increased body temperature, enlarged lymph nodes, inflammation of internal organs, blood disorders (signs of DRESS syndrome – drug rash with eosinophilia and systemic symptoms) (in exceptional cases);
• Weakness, increased body temperature, chills, rapid heartbeat, anxiety, headaches, exhaustion of the whole body, pneumonia and blood infection are possible (signs of leukopenia, including granulocytopenia);
• Tendency to bleeding (nasal, gingival, gastrointestinal), heavy menstruation, unexplained bruising, blood in the urine (signs of thrombocytopenia);
• Yellowing of the skin, bitter taste in the mouth, pain in the right hypochondrium, dark urine, discolored stool (signs of cholestatic jaundice); inflammation of the liver, dark urine, pale stool, jaundice, increased body temperature (signs of hepatitis) (isolated cases).

Other possible adverse reactions that may occur when taking Gliclazide-SZ

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

The following side effects are less common.

From the skin and subcutaneous tissue rash, itching, urticaria, erythema, maculopapular rash.

From the hematopoietic and lymphatic systems anemia.

From the liver and biliary tract increased activity of liver enzymes (AST, ALT, ALP), hepatitis (isolated cases).

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

Side effects inherent in sulfonylurea derivatives

As with the use of other sulfonylurea derivatives, the following side effects have been noted: erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia. Increased activity of liver enzymes, impaired liver function (for example, with the development of cholestasis and jaundice) and hepatitis have been noted; manifestations decreased over time after discontinuation of sulfonylurea drugs, but in some cases led to life-threatening liver failure.

Contraindications

• Hypersensitivity to gliclazide, other sulfonylurea derivatives, sulfonamides, or to the excipients that are part of the drug;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis, diabetic precoma, diabetic coma;
• Severe renal or hepatic impairment (in these cases, insulin is recommended);
• Concomitant use of miconazole (see section “Drug Interactions”);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years.

It is not recommended to use in combination with phenylbutazone or danazol (see section “Drug Interactions”).

With caution elderly age (over 65 years), irregular and/or unbalanced nutrition, glucose-6-phosphate dehydrogenase deficiency, severe cardiovascular diseases, hypothyroidism, adrenal or pituitary insufficiency, renal and/or hepatic impairment, long-term glucocorticosteroid therapy, alcoholism.

Use in Pregnancy and Lactation

Pregnancy

In case of suspected, planned or confirmed pregnancy, it is necessary to consult a doctor. The use of the drug during pregnancy is contraindicated.

Breastfeeding period

The use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

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

Use in Renal Impairment

No dose adjustment of the drug is required in patients with mild to moderate renal impairment.

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

Pediatric Use

The use of the drug is contraindicated in children under 18 years of age.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Hypoglycemia

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 (see section “Adverse Reactions”).

The drug can only be prescribed to patients whose nutrition is regular and includes breakfast. It is very important to maintain sufficient carbohydrate intake with food, because the risk of developing 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 exercise, after alcohol consumption, or when taking several hypoglycemic drugs simultaneously.

As a rule, the symptoms of hypoglycemia disappear after eating food rich in carbohydrates (e.g., sugar). It should be borne in mind that the intake of sugar substitutes does not help eliminate hypoglycemic symptoms. Experience with other sulfonylurea derivatives indicates that hypoglycemia may recur despite effective initial relief of this condition. If hypoglycemic symptoms are severe or prolonged, even if there is temporary improvement after eating carbohydrate-rich food, emergency medical care is necessary, up to hospitalization.

To avoid the development of hypoglycemia, careful individual selection of drugs and dosage regimen is necessary, as well as providing the patient with complete information about the treatment being carried out. An increased risk of developing hypoglycemia may be noted in the following cases

• Refusal or inability of the patient (especially the elderly) to follow the doctor’s prescriptions and monitor their condition;
• Insufficient and irregular nutrition, skipping meals, fasting, and changes in diet;
• Imbalance between physical activity and the amount of carbohydrates consumed;
• Renal failure;
• Severe hepatic failure;
• Overdose of the drug Gliclazide-SZ;
• Certain endocrine disorders: thyroid diseases, pituitary and adrenal insufficiency;
• Concomitant use of certain medications (see the section “Drug Interactions”).

Renal and Hepatic Impairment

In patients with hepatic and/or severe renal impairment, the pharmacokinetic and/or pharmacodynamic properties of gliclazide may change. 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 may be impaired in the following cases: fever, trauma, infectious diseases, or major surgical interventions. Under these conditions, it may be necessary to discontinue therapy with Gliclazide-SZ and prescribe insulin therapy.

Hyperglycemia

High blood glucose levels may develop if Gliclazide inadequately reduces blood glucose concentration, when the patient does not comply with the treatment regimen prescribed by the doctor, as well as with the concomitant use of preparations containing St. John’s wort (Hypericum perforatum) (see the section “Drug Interactions”), or in special stressful situations. Symptoms may include thirst, frequent urination, dry mouth, dry and itchy skin, skin infections, and reduced performance.

Discontinuation of Gliclazide-SZ may cause hyperglycemia and increase the risk of diabetes-related complications. The drug should not be discontinued without consulting a doctor.

Changes in blood glucose concentration may occur with the concomitant use of gliclazide and fluoroquinolones (see the section “Drug Interactions”).

In many patients, the effectiveness of oral hypoglycemic agents, including gliclazide, tends to decrease after a prolonged period of treatment. This effect may be due to both disease progression and a reduced therapeutic response to the drug. This phenomenon is known as secondary drug resistance, which must be distinguished from primary resistance, where the drug fails to produce the expected clinical effect from the first administration. Before diagnosing a patient with secondary drug resistance, the adequacy of dose selection and the patient’s adherence to the prescribed diet should be assessed.

Laboratory Tests

Regular determination of fasting blood glucose and glycated hemoglobin HbA_1c is recommended to assess glycemic control. In addition, regular self-monitoring of blood glucose is 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 hypoglycemic agent from another group should be considered.

Cases of exacerbation of the disease have been described in patients with porphyria (a hereditary disorder of pigment metabolism with increased porphyrin content in the blood and tissues and increased excretion in urine and feces) when taking some other sulfonylurea drugs.

Information for Patients

The patient, as well as family members, should be informed about the risk of hypoglycemia, its symptoms, and the conditions that contribute to its development. The patient should be informed about the potential risks and benefits of the proposed treatment.

The patient should be explained the importance of diet adherence, the need for regular exercise, and blood glucose monitoring.

Effect on Ability to Drive and Operate Machinery

Due to the possible development of hypoglycemia when using Gliclazide-SZ, patients should be aware of the symptoms of hypoglycemia and should exercise caution while driving vehicles or performing work that requires high speed of physical and mental reactions, especially at the beginning of therapy.

Overdose

Symptoms overdose with sulfonylurea derivatives can lead to hypoglycemia (see the section “Special Instructions”).

Treatment if moderate symptoms of hypoglycemia occur without impaired consciousness or neurological symptoms, carbohydrate intake with food should be increased, the drug dose should be reduced, and/or the diet should be changed. Close medical supervision of the patient’s condition should continue until it is certain that their health is not at risk.

Severe hypoglycemic conditions accompanied by coma, convulsions, or other neurological disorders may develop. If such symptoms appear, emergency medical care and immediate hospitalization are necessary.

In case of hypoglycemic coma or suspected coma, the patient should receive an intravenous bolus of 50 ml of a 20-40% dextrose (glucose) solution. Then, a 5-10% dextrose solution is administered intravenously by drip to maintain blood glucose concentration above 1 g/L. Careful monitoring of blood glucose levels and observation of the patient should be carried out for at least the next 48 hours. After this period, depending on the patient’s condition, the attending physician decides on the need for further observation.

Dialysis is ineffective due to the pronounced binding of gliclazide to plasma proteins.

Drug Interactions

Drugs and Substances That Increase the Risk of Hypoglycemia (Potentiating the Effect of Gliclazide)

Contraindicated Combinations

Miconazole (with systemic administration and when using gel on the oral mucosa): enhances the hypoglycemic effect of gliclazide (hypoglycemia may develop, up to and including coma).

Not Recommended Combinations

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. If phenylbutazone intake is necessary, the patient should be warned about the need for glycemic control. If necessary, the dose of Gliclazide-SZ should be adjusted during and after phenylbutazone administration.

Ethanol enhances hypoglycemia by inhibiting compensatory reactions and may contribute to the development of hypoglycemic coma. It is necessary to avoid taking medicines containing ethanol and consuming alcohol.

Combinations Requiring Precautions

Taking gliclazide in combination with certain medicines: other hypoglycemic agents (insulin, acarbose, metformin, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists); beta-blockers, fluconazole; ACE inhibitors – captopril, enalapril; histamine H₂-receptor blockers; MAO inhibitors; sulfonamides; clarithromycin and NSAIDs) is accompanied by an enhanced hypoglycemic effect and risk of hypoglycemia.

Drugs That Increase Blood Glucose Levels (Weakening the Effect of Gliclazide)

Not Recommended Combinations

Danazol has a diabetogenic effect. If taking this drug is necessary, the patient is advised to have careful blood glucose monitoring. If concomitant use of the drugs is necessary, dose adjustment of the hypoglycemic agent is recommended both during danazol administration and after its discontinuation.

Combinations Requiring Precautions

Chlorpromazine (antipsychotic) in high doses (more than 100 mg/day) increases blood glucose concentration by reducing insulin secretion. Careful glycemic control is recommended. If concomitant use of the drugs is necessary, dose adjustment of the hypoglycemic agent is recommended both during antipsychotic administration and after its discontinuation.

Corticosteroids (systemic and local use: intra-articular, cutaneous, rectal administration) and tetracosactide increase blood glucose concentration with possible development of ketoacidosis (reduced carbohydrate tolerance). Careful glycemic control is recommended, especially at the start 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 concentration.

Fluctuations in blood glucose concentration may occur with the concomitant use of gliclazide and fluoroquinolones, especially in elderly patients. Regular glycemic control is recommended.

Combinations to Be Considered

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

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.