Glialore

INSTRUCTIONS for medical use of the medicinal product GLIORAL® (GLIORAL®)

Composition:

active substance: gliclazide;

1 tablet contains 80 mg of gliclazide;

excipients: lactose monohydrate; corn starch; povidone; pregelatinized starch; sodium lauryl sulfate; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, flat-surfaced tablets, white to yellowish-white in color, with a score line on one side.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Hypoglycemic agents, excluding insulins. Sulfonamides, urea derivatives. Gliclazide. ATC code A10BB09.

Pharmacological Properties

Pharmacodynamics

Gliclazide is an oral hypoglycemic antidiabetic agent, a derivative of sulfonylurea, distinguished from other similar compounds by an N-containing heterocyclic ring with an endocyclic bond. In addition to its hypoglycemic effect, gliclazide reduces platelet adhesion and aggregation and enhances fibrinolytic activity. These effects are considered components of the pathogenesis of late complications of diabetes mellitus. Gliclazide enhances the secretion of pre-synthesized insulin from pancreatic β-cells, increases peripheral glucose utilization, and reduces hepatic gluconeogenesis. Increased postprandial insulin and C-peptide secretion is maintained after two years of treatment.

It also possesses antioxidant properties, which contribute to the prevention of microcirculatory disorders in insulin-independent diabetes mellitus.

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 proportion to food intake or glucose load.

Hemovascular properties. Gliclazide reduces microthrombosis through two mechanisms potentially involved in the development of diabetic complications:

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

Pharmacokinetics

Absorption.

Gliclazide is rapidly and completely absorbed after oral administration. Maximum plasma concentration is reached within 2–6 hours. Food intake does not affect the rate or extent of absorption.

Distribution.

Approximately 95% of gliclazide is bound to plasma proteins. The volume of distribution is approximately 19 L.

Biotransformation.

Gliclazide is primarily metabolized in the liver, forming inactive metabolites, and is excreted by the kidneys: less than 1% of the active substance is excreted unchanged in urine.

Elimination.

The elimination half-life of gliclazide is 10–12 hours.

Special populations.

Elderly patients

No significant changes in pharmacokinetic parameters have been observed in elderly patients.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus (non-insulin-dependent) — when blood glucose concentration cannot be controlled by diet, physical activity, or weight reduction alone.

Contraindications.

• Hypersensitivity to gliclazide or other sulfonylurea drugs;
• hypersensitivity to sulfonamides or to any component of the medicinal product;
• insulin-dependent diabetes (type 1);
• severe hepatic or renal insufficiency — in such cases, insulin therapy is recommended;
• diabetic ketoacidosis;
• precoma or diabetic coma;
• severe trauma, burns, or infectious diseases in the acute phase;
• concomitant treatment with miconazole (see section "Interaction with other medicinal products and other forms of interaction");
• concomitant treatment with quinolones;
• pregnancy and breastfeeding (see section "Use in pregnancy or breastfeeding");
• diabetes mellitus in children.

Interaction with other medicinal products and other forms of interaction.

The concomitant use of other medicinal products may enhance or reduce the blood glucose-lowering effect of gliclazide. Therefore, their use should only be considered upon consultation with a physician.

Medicinal products whose concomitant use may increase the risk of hypoglycemia

Contraindicated concomitant use

Miconazole (for systemic use, oral gel) enhances the hypoglycemic effect of gliclazide, potentially leading to symptoms of hypoglycemia or even coma.

Quinolones enhance the hypoglycemic effect, possibly causing severe, profound, and persistent hypoglycemia that is difficult to control, or even coma, particularly in elderly patients with renal insufficiency.

Not recommended concomitant use

Phenylbutazone (for systemic use) enhances the hypoglycemic effect of sulfonylurea derivatives (by displacing them from plasma protein binding and/or reducing their elimination). It is recommended to use alternative nonsteroidal anti-inflammatory drugs (NSAIDs) or to warn the patient and emphasize the importance of self-monitoring of blood glucose. If necessary, the dose of the antidiabetic agent may be adjusted during and after anti-inflammatory treatment.

Alcohol increases the risk of hypoglycemic reactions (due to inhibition of compensatory mechanisms), potentially leading to hypoglycemic coma. Consumption of alcohol and alcohol-containing products should be avoided.

Combinations requiring caution

Acetylsalicylic acid, phenelzine do not enhance the hypoglycemic effect of gliclazide but may prolong its action.

Cimetidine, ranitidine, fluconazole, other antidiabetic agents, NSAIDs (especially salicylates), sulfonamides, angiotensin-converting enzyme (ACE) inhibitors (enalapril, captopril), H2-receptor antagonists, indirect anticoagulants, monoamine oxidase inhibitors (MAO), diazepam, tetracyclines, chloramphenicol, fibrates, ethanol, coumarin derivatives, disopyramide enhance the hypoglycemic effect of gliclazide, potentially leading to hypoglycemia. The use of barbiturates, glucocorticoids, diuretics, estrogens, thyroid hormones, and abuse of laxatives may reduce the effectiveness of gliclazide. Sulfonamide drugs may enhance the effect of gliclazide.

Particular caution is required with dosing of monoamine oxidase inhibitors (MAO), which enhance insulin secretion.

Concomitant use of ß-adrenergic blockers may mask the symptoms of hypoglycemia. Glioral® may be combined with insulin in non-insulin-dependent diabetes or with metformin or other biguanide derivatives (phenformin); however, in some cases, hypoglycemia may occur due to an enhanced hypoglycemic effect. It should not be combined with other sulfonylurea derivatives.

Additionally, hypoglycemia may result from interactions with other glucose-lowering agents [insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists], beta-blockers, fluconazole, ACE inhibitors (captopril, enalapril), H2-receptor antagonists, sulfonamides, clarithromycin, and nonsteroidal anti-inflammatory drugs.

Medicinal products whose concomitant use may increase the risk of hyperglycemia

Not recommended concomitant use

Danazol has a diabetogenic effect. If concomitant use cannot be avoided, the patient should be warned and the importance of self-monitoring of blood and urine glucose emphasized. If necessary, the dose of the antidiabetic agent may be adjusted during and after danazol treatment.

Combinations requiring caution

Chlorpromazine (neuroleptic), when used in high doses (over 100 mg/day), increases blood glucose levels (due to reduced insulin release). The patient should be warned, and the importance of self-monitoring of blood glucose emphasized. If necessary, the dose of the antidiabetic agent may be adjusted during and after neuroleptic treatment.

Glucocorticoids (for systemic and topical use: intra-articular, topical, rectal preparations) and tetracosactide increase blood glucose levels, possibly leading to ketoacidosis (by reducing carbohydrate tolerance). The patient should be warned, and the importance of self-monitoring of blood glucose emphasized, especially at the beginning of treatment. If necessary, the dose of the antidiabetic agent may be adjusted during and after glucocorticoid therapy.

Ritodrine, salbutamol, terbutaline (intravenous) — may increase blood glucose levels due to β2-agonist effects. Monitoring of blood glucose is essential. If necessary, transition to insulin therapy should be considered.

St. John's wort (Hypericum perforatum) reduces gliclazide concentration. Therefore, regular monitoring of blood glucose levels is important.

Medicinal products that may cause dysglycemia

Combinations requiring caution

Fluoroquinolones, when used concomitantly with gliclazide, may cause dysglycemia. The patient should be warned, and the importance of blood glucose monitoring emphasized.

Combinations to be considered

Anticoagulants (e.g., warfarin) — sulfonylurea derivatives may potentiate the anticoagulant effect of anticoagulants when used concomitantly. If necessary, the dose of anticoagulants may be adjusted.

Special precautions for use.

Glioral® should be taken in combination with dietary therapy. Alcohol must not be consumed during treatment with Glioral® due to the risk of developing pronounced hypoglycemia. The risk of hypoglycemia is also increased by irregular food intake.

In cases of clinical inefficacy of Glioral® or decompensation of diabetes mellitus, insulin therapy should be initiated. During pregnancy, as well as when surgical intervention is required, treatment should be switched to insulin. Therapy should be initiated cautiously, with gradual dose escalation considering age, diet, severity of disease, physical activity, and with mandatory monitoring of blood and urine glucose levels. Hypoglycemia occurs rarely, mostly with irregular meals or concomitant alcohol consumption. Mild hypoglycemic reactions not requiring medical assistance may occur more frequently.

Hypoglycemia. This medicinal product should be prescribed only if the patient is able to maintain regular meals (including breakfast). Regular intake of carbohydrates is very important. Delayed meals, insufficient food intake, or low carbohydrate content increase the risk of hypoglycemia.

The occurrence of hypoglycemia is more likely with low-calorie or irregular diet, prolonged or intense physical exertion, alcohol consumption, or concomitant use of other hypoglycemic agents. Worsening glycemic control in patients receiving antidiabetic drugs may be caused by St. John's wort (Hypericum perforatum) or any concomitant therapy affecting glipizide metabolism.

When using sulfonylurea drugs, moderate or severe hypoglycemia may occur (see section "Adverse reactions"). In cases of severe and prolonged hypoglycemia, hospitalization and administration of glucose for several days may be necessary.

Factors increasing the risk of hypoglycemia:

• Patient refuses or is unable to follow physician recommendations (especially relevant for elderly patients);
• Poor or irregular diet, skipped meals, fasting periods, or dietary changes;
• Imbalance between physical exertion and carbohydrate intake;
• Glipizide overdose;
• Insufficient glucose or caloric intake;
• 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");
• Hepatic and/or renal insufficiency;
• Alcohol consumption.

To reduce the risk of hypoglycemia, it is recommended:

• To initiate treatment of non-insulin-dependent diabetes mellitus with diet whenever possible;
• To consider patient age and blood glucose levels;
• To adjust glipizide dosage during the first few days of therapy according to blood and urine glucose levels throughout the day.

Dosage adjustment is required in the following cases:

• Development of mild hypoglycemic symptoms (sweating, pallor, intense hunger, tachycardia, weakness); these symptoms are relieved by oral glucose intake, dose adjustment, and/or meal schedule modification;
• Severe hypoglycemic reactions (coma and neurological disturbances, see section "Overdose");
• Loss of blood glucose control (hyperglycemia); patient under stressful conditions, including fever, trauma, infections, or surgical interventions. In such cases, increasing the glipizide dose may be necessary. If this is insufficient, glipizide treatment should be discontinued and insulin initiated.

Hepatic and renal function impairment. Caution is required when administering to patients with impaired liver and kidney function. Treatment should be initiated with low doses and careful monitoring of the patient's condition. The pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic and severe renal insufficiency. Episodes of hypoglycemia in such patients may be prolonged and therefore require appropriate treatment.

Patient information. The patient and family members should be informed about risk factors and conditions that may promote hypoglycemia, symptoms of hypoglycemia, and methods of their management. The patient should be informed about the importance of adhering to physician dietary recommendations, the importance of regular physical exercise, and regular monitoring of blood glucose levels.

Worsening glycemic control in patients receiving hypoglycemic agents may be caused by infection, fever, trauma, St. John's wort intake (see section "Interaction with other medicinal products and other forms of interaction"), or surgical intervention. In some cases, insulin therapy may become necessary. The hypoglycemic efficacy of any oral antidiabetic agent, including glipizide, may change over time. This may result from progression of disease severity or reduced response to treatment. This phenomenon is known as secondary failure, which differs from primary failure, where the drug is ineffective from the beginning of treatment. Before concluding secondary failure in a patient, the appropriateness of the prescribed dose and patient adherence to diet should be verified.

Disglycemia (abnormal blood glucose levels). Abnormal blood glucose levels (hypoglycemia and hyperglycemia) have been observed in diabetic patients receiving concomitant treatment with fluoroquinolones, particularly in elderly patients. Therefore, careful monitoring of blood glucose levels is recommended in all patients receiving glipizide concomitantly with fluoroquinolones.

Laboratory parameters: Assessment of glycated hemoglobin levels (or fasting blood glucose) is recommended for evaluating blood glucose control. Self-monitoring of blood glucose by patients may also be beneficial.

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, sulfonylurea drugs may induce hemolytic anemia. Since glipizide belongs to the sulfonylurea class of chemical origin, caution should be exercised, and alternative therapy with a drug from another class should be considered for patients with G6PD deficiency.

Patients with porphyria: Cases of acute porphyria have been reported with the use of certain other sulfonylurea drugs in patients with porphyria.

Due to the presence of lactose in the formulation, Glioral® is not recommended for patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Experience with glipizide use during pregnancy is absent or limited (less than 300 pregnancy outcomes). There is limited data on other sulfonylurea derivatives.

In animal studies, glipizide has shown reproductive toxicity.

As a precautionary measure, the use of Glioral® during pregnancy is not recommended.

Achieving glycemic control before conception is recommended to reduce the risk of congenital anomalies associated with uncontrolled diabetes.

Oral hypoglycemic agents are not suitable for use during pregnancy — insulin is the drug of first choice for diabetes treatment during pregnancy. In cases of planned pregnancy or when pregnancy occurs, women should be switched from oral hypoglycemic agents to insulin.

Breastfeeding. There are no data on whether the active substance or its metabolites are excreted in breast milk. This medicinal product should not be used during breastfeeding due to the risk of neonatal hypoglycemia. Risk to the newborn/infant cannot be excluded.

Fertility. In animal studies, no effect on fertility or reproductive function was observed.

Ability to affect reaction speed when driving or operating machinery.

Glipizide has no or negligible influence on the ability to drive vehicles or operate machinery. However, patients should be aware of hypoglycemia symptoms, able to recognize them, and exercise caution when driving or operating machinery, especially at the beginning of treatment (see section "Special precautions for use"). At the start of therapy, in the absence of adequate blood glucose control, patients may experience impaired concentration.

Method of Administration and Dosage

Adults.

For oral use. The therapeutic daily dose is 40–320 mg. The dose should be individualized according to the patient's response to treatment. The initial dose is 40–80 mg once daily (½–1 tablet) taken with breakfast. The dose should then be gradually increased until adequate glycemic control is achieved. The single dose should not exceed 160 mg (2 tablets). Daily doses exceeding 160 mg should be divided into two doses taken with the main meals.

In obese patients who do not respond adequately to glipizide treatment, additional therapy should be initiated.

Switching from another oral antidiabetic agent to Glioral®, 80 mg tablets

Other oral antidiabetic agents may be replaced with the medicinal product Glioral® in tablet form.

When switching to Glioral® tablets, the dosage and half-life of the previous antidiabetic agent should be taken into account.

A transition period is usually not required. The initial dose is 40–80 mg (½–1 tablet). The dose should be adjusted according to changes in the patient's blood glucose levels, as described above.

When switching from glucose-lowering agents such as sulfonylurea derivatives with long elimination half-life, a short break in treatment (several days) may be necessary to avoid an additive effect of the two medicinal products, which could lead to hypoglycemia.

Combination therapy with other antidiabetic agents

Glioral® tablets may be used in combination with biguanides, alpha-glucosidase inhibitors, or insulin.

If there is an inadequate response to Glioral® tablets, concomitant insulin therapy may be considered under close medical supervision.

Special patient populations.

Elderly patients (aged 65 years and older)

Plasma clearance of gliclazide is not altered; therefore, the dosing regimen for Glioral® is the same as for adults. However, due to the increased risk of hypoglycemia in patients aged 65 years and older, caution should be exercised when prescribing sulfonylureas.

Patients with renal impairment

Patients with mild to moderate renal impairment may be treated with the same dosing regimen as patients with normal renal function, provided they are closely monitored. These data have been confirmed by clinical study results.

Patients at risk of hypoglycemia

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

A minimum initial dose of 40–80 mg per day is recommended.

Children

Gliclazide, like other sulfonylurea derivatives, is not recommended for the treatment of diabetes mellitus in children. The safety and efficacy of Glioral® in children have not been established. Data are lacking.

Overdose.

Overdose of sulfonylurea agents may cause hypoglycemia. In case of symptoms of moderate hypoglycemia (without loss of consciousness and without neurological symptoms), administration of carbohydrates (sugar), preferably as a solution, is required, along with dose adjustment of the antidiabetic agent and/or diet. If hypoglycemia cannot be promptly corrected, intravenous administration of glucose by a physician or intramuscular injection of glucagon should be performed. Close monitoring of the patient should continue until the physician is confident the patient is out of danger.

Severe hypoglycemia leading to coma, seizures, or other neurological disturbances requires emergency medical intervention with immediate hospitalization.

In cases of diagnosed hypoglycemic coma or suspected coma development, the patient should be promptly administered 50 mL of concentrated glucose solution (20–30%) intravenously, 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 management based on the patient’s condition.

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

Adverse Reactions

Based on the experience with gliclazide and other sulfonylurea derivatives, the undesirable effects listed below may occur.

Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with gliclazide use. As with other sulfonylurea drugs, administration of gliclazide may lead to hypoglycemia, particularly in cases of irregular eating habits, especially if a meal is missed. Hypoglycemia may present with characteristic symptoms such as intense hunger, headache, nausea, vomiting, increased fatigue, sleep disturbances, excitement, aggressiveness, difficulty concentrating and attention deficit, slowed reaction time, depression, confusion, impaired consciousness, visual and speech disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, feeling of weakness, loss of self-control, delirium, seizures, shallow breathing, bradycardia, drowsiness, loss of consciousness, which may progress to coma and potentially result in death.

Additionally, signs of adrenergic counter-regulation may occur, including excessive sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina attack, and arrhythmia.

Typically, symptoms of hypoglycemia resolve after ingestion of carbohydrates (sugar). However, artificial sweeteners are ineffective. Experience with other sulfonylurea drugs indicates that hypoglycemic episodes may recur, even if initial corrective measures were effective.

If a hypoglycemic episode is severe or prolonged, the patient requires immediate medical attention or hospitalization, even if symptoms are temporarily controlled by sugar intake.

Other adverse effects.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation. Adherence to recommendations regarding administration of the drug during breakfast may help prevent or minimize these manifestations.

Less frequently observed adverse effects:

Skin and subcutaneous tissue disorders: pruritus, erythema, Stevens-Johnson syndrome, autoimmune bullous disorders, toxic epidermal necrolysis, urticaria, rash, including maculopapular and bullous rash.

Blood and lymphatic system disorders (rare): hyponatremia, anemia, leukopenia, thrombocytopenia, granulocytopenia, erythropenia, pancytopenia, agranulocytosis, allergic vasculitis. These manifestations usually resolve upon discontinuation of the drug. There is no confirmed direct causal relationship between these disorders and gliclazide administration.

Hepatobiliary disorders: elevated liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase). Isolated cases of liver failure (with cholestasis and jaundice), and hepatitis with regression after discontinuation of sulfonylurea drugs have been reported. If jaundice occurs, treatment with the drug should be discontinued.

These adverse effects generally resolve after discontinuation of the drug.

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

Immune system disorders: angioneurotic edema, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Reactions characteristic of the sulfonylurea drug class: cases of erythropenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, elevated liver enzymes, and even impaired liver function (e.g., with cholestasis, jaundice), cases of hepatitis with regression after discontinuation of sulfonylurea drugs, or, in isolated cases, progressive life-threatening liver failure.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 5 years.

Do not use the medicinal product after the expiry date.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging. Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Galenika A.D. Belgrade.

Manufacturer's address and place of business.

Batajnichki drum b.b., 11080 Belgrade-Zemun, Serbia.