Glibenclamide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLIBENCLAMIDE (GLIBENCLAMIDE)

Composition:

Active substance: glibenclamide;

One tablet contains 5 mg of glibenclamide calculated as 100% dry substance;

Excipients: lactose monohydrate, potato starch, povidone, Ponceau 4R (E 124), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: flat cylindrical tablets with a score line and beveled edge, pale pink in color. Slight marbling and specks on the surface are permissible.

Pharmacotherapeutic group.

Oral hypoglycemic agents. Sulfonamides, derivatives of sulfonylurea.

ATC code A10BB01.

Pharmacological properties.

Pharmacodynamics.

Glibenclamide exerts a hypoglycemic effect both in patients with type 2 diabetes mellitus and in healthy individuals, as it enhances insulin secretion from pancreatic β-cells through their stimulation. This effect is dependent on the glucose concentration in the environment surrounding the β-cells.

Pharmacokinetics.

After oral administration, glibenclamide is rapidly and almost completely absorbed. Concomitant food intake does not significantly affect this process. Plasma protein binding of glibenclamide exceeds 98%. Maximum serum concentration is reached within 2.5 hours and amounts to 100 ng/mL. After 8–10 hours, serum concentration decreases, depending on the administered dose, to 10–20 ng/mL. The elimination half-life is approximately 2 hours after intravenous administration and 7 hours after oral administration. However, some studies indicate that in diabetic patients this duration may be prolonged to 8–10 hours. Glibenclamide is completely metabolized in the liver into several metabolites that do not significantly contribute to the glucose-lowering effect of glibenclamide. Metabolites are excreted in urine and bile in approximately equal amounts, with complete elimination occurring within 45–72 hours. In patients with impaired liver function, elimination of glibenclamide from plasma is slowed. In patients with renal insufficiency, depending on the degree of renal dysfunction, excretion of metabolites in urine increases compensatorily. With moderate renal impairment (creatinine clearance ≥ 30 mL/min), total elimination remains unchanged, whereas accumulation is possible in severe renal insufficiency.

Clinical characteristics.

Indications.

Non-insulin-dependent diabetes mellitus in adults (type 2 diabetes mellitus), when other measures such as strict adherence to diet, reduction of excess body weight, and adequate physical activity have not led to satisfactory correction of blood glucose levels.

Contraindications.

• Hypersensitivity to the active substance, to Ponceau 4R, or to any component of the medicinal product.
• Hypersensitivity to other sulfonylurea drugs, sulfonamides, sulfonamide diuretics, or probenecid.
• In cases of diabetes mellitus requiring insulin therapy: insulin-dependent diabetes mellitus (type 1 diabetes mellitus), complete secondary failure of glimepiride therapy in type 2 diabetes mellitus, metabolic state with tendency towards acidosis, precoma or diabetic coma, post-pancreatectomy state.
• Severe impairment of liver function.
• Severe impairment of kidney function.
• Pregnancy or breastfeeding period.
• Concomitant use with bosentan.

Interaction with other medicinal products and other forms of interaction.

When glimepiride is used concomitantly with other medicinal products, its effect may be enhanced or diminished; therefore, consultation with a physician regarding the use of other drugs is recommended.

Enhancement of glimepiride effect (possible occurrence of hypoglycemic reactions) may occur when used concomitantly with: other oral antidiabetic agents and insulin, angiotensin-converting enzyme inhibitors, anabolic steroids and androgens, antidepressants (fluoxetine, MAO inhibitors), β-adrenergic blockers, quinolone derivatives, chloramphenicol, clofibrate and its analogs, coumarin derivatives, disopyramide, fenfluramine, miconazole, para-aminosalicylic acid, pentoxifylline (administered parenterally in high doses), perhexiline, pyrazolone derivatives, probenecid, salicylates, sulfonamides, tetracycline-class preparations, troxiquatol, cytostatic agents such as cyclophosphamide.

Administration of β-adrenergic receptor blockers, clonidine, guanethidine, and reserpine may reduce the perception of early symptoms of hypoglycemia.

Reduction of glimepiride effect (possible occurrence of hyperglycemic reactions) may occur when used concomitantly with: acetazolamide, β-adrenergic blockers, barbiturates, diazoxide, diuretics, glucagon, isoniazid, corticosteroids, nicotinic acid derivatives, phenothiazine derivatives, phenytoin, rifampicin, thyroid hormones, female sex hormones (gestagens, estrogens), sympathomimetics. H2-receptor blockers, clonidine, and reserpine may either reduce or enhance the glucose-lowering effect of the drug. In individual cases, pentamidine may cause severe hypoglycemia or hyperglycemia. The effect of coumarin derivatives may be either enhanced or reduced.

Bosentan: in patients receiving glimepiride concomitantly with bosentan, an increased frequency of elevated liver enzymes has been observed. Both glimepiride and bosentan inhibit the transport mechanism responsible for bile acid excretion from the cell. This leads to intracellular accumulation of bile acid salts, which have cytotoxic effects; therefore, this combination should not be used.

Special precautions for use.

The ability to recognize warning signs of low blood glucose levels may be diminished in patients suffering from autonomic neuropathy. Particular caution is required when administering the drug to patients with impaired kidney or liver function, or with reduced function of the thyroid gland, pituitary gland, or adrenal cortex. In elderly patients, there is a risk of prolonged hypoglycemia; therefore, glimepiride should be prescribed with special caution and their condition should be closely monitored at the beginning of treatment. In this age group, under certain conditions, it may be preferable initially to use sulfonylurea agents with a shorter duration of action. Diabetic patients with signs of cerebral sclerosis and patients with whom communication is difficult are at higher risk of developing hypoglycemia. Long intervals between meals, inadequate carbohydrate intake, unusual physical exertion, diarrhea, or vomiting may increase the risk of hypoglycemia. Alcohol, when consumed repeatedly in large amounts or used chronically, may unpredictably enhance or reduce the effect of Glimepiride. Chronic abuse of laxatives may lead to deterioration of metabolic control.

Failure to adhere to the treatment regimen, insufficient blood glucose-lowering effect of the drug, or presence of stressful conditions may lead to increased blood sugar levels. Symptoms of hyperglycemia may include intense thirst, dry mouth, frequent urination, itching, dry skin, fungal or infectious skin disorders, and reduced work capacity. In unusual stressful conditions (trauma, surgery, infectious disease accompanied by fever), metabolic control may deteriorate, leading to hyperglycemia, sometimes so significant that temporary switching to insulin therapy may be required. Patients should be informed of the urgent need to consult a physician without delay if other illnesses develop during Glimepiride treatment. Patients should also be instructed that, in case of a change in treating physician (e.g., during hospitalization, due to an accident, illness, or vacation), they should inform the new physician about their diabetes.

In patients with glucose-6-phosphate dehydrogenase deficiency, treatment with sulfonylurea agents, including glimepiride, may induce hemolytic anemia; therefore, consideration should be given to switching such patients to alternative non-sulfonylurea agents.

Glimepiride should not be used in patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The medicinal product contains the dye Ponceau 4R (E 124), which may cause allergic reactions.

Some patients may require supervision by caregivers regarding tablet intake.

Use during pregnancy or breastfeeding.

Glimepiride is contraindicated during pregnancy and breastfeeding. If possible, therapy with oral antidiabetic agents should be discontinued prior to planning pregnancy. Insulin therapy is the treatment of choice during pregnancy and breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Hypoglycemia may impair a patient's ability to concentrate and their reaction time. This may pose a risk when high attention and rapid reaction are required, such as when driving a car or operating machinery. Patients should take safety measures to avoid hypoglycemia while driving or operating machinery. This is particularly important for patients who frequently experience hypoglycemia or who lack awareness of hypoglycemia warning symptoms. In such cases, the appropriateness of driving should be carefully evaluated.

Dosage and Administration

The drug is prescribed by a physician and must be accompanied by dietary adjustments. Dosage depends on the results of metabolic monitoring (blood and urine glucose levels). Monitoring of blood and urine glucose levels is necessary when switching from another hypoglycemic agent.

Initial and subsequent dosing. Therapy should be initiated, whenever possible, at the lowest doses, especially in patients with increased susceptibility to hypoglycemia or body weight below 50 kg. The initial dose is ½ to 1 tablet of Glibenclamide (corresponding to 2.5–5 mg of glibenclamide) daily. If metabolic control is inadequate, the dose should be gradually increased at intervals of several days to one week until the required daily therapeutic dose is achieved. The maximum dose is 3 tablets of Glibenclamide (corresponding to 15 mg of glibenclamide) daily.

Switching from other antidiabetic drugs. The physician should carefully switch patients to Glibenclamide, starting at a dose of ½ tablet (2.5 mg glibenclamide) to 1 tablet (5 mg glibenclamide) daily.

Dosage adjustment. In elderly, debilitated patients, or those with malnutrition, renal or hepatic impairment, the initial and maintenance doses should be reduced due to the risk of hypoglycemia. Dose adjustments should be considered if the patient experiences weight loss or changes in lifestyle.

Combination with other antidiabetic agents. Glibenclamide may be used alone (monotherapy) or in combination with metformin. In justified cases, patients intolerant to metformin may be prescribed additional thiazolidinedione agents (rosiglitazone or pioglitazone). Glibenclamide may also be combined with oral antidiabetic drugs that do not stimulate insulin secretion from β-cells (e.g., guar gum or acarbose). In cases of secondary therapeutic failure (reduced insulin production due to β-cell exhaustion), combination therapy with insulin may be attempted. However, when endogenous insulin secretion has completely ceased, monotherapy with insulin is indicated.

Patients should consult their physician if they perceive the drug effect to be too strong or too weak.

Patients must not discontinue treatment or alter the dose or diabetic diet without consulting their physician.

If a change is necessary, the patient should consult their physician in advance.

Administration schedule and duration of treatment. Tablets should be taken before meals, without chewing, and with sufficient fluid (preferably one glass of water). The daily dose of up to 2 tablets should be taken before breakfast. If the daily dose exceeds 2 tablets, it is recommended to divide the total dose into one morning and one evening dose in a 2:1 ratio. It is very important to take the medication at the same time every day. If a dose is accidentally missed, the next dose should not be doubled.

The duration of treatment depends on the course of the disease. During treatment, regular monitoring of blood and urine glucose levels is required. Additionally, it is recommended to periodically assess parameters such as glycated hemoglobin (HbA1c) and/or fructosamine, as well as other indicators (e.g., blood lipid levels).

Children. Glibenclamide should not be used in children due to insufficient clinical experience.

Overdose.

Single or prolonged intake of slightly elevated doses may lead to severe, prolonged hypoglycemia, which can be life-threatening. In cases of overdose or intentional misuse, prolonged hypoglycemia is expected, although it tends to normalize after successful initial treatment. Symptoms of overdose (hypoglycemic state): sudden sweating, palpitations, tremor, hunger, restlessness, oral paraesthesia, pallor, headache, sleep disturbances (drowsiness, insomnia), anxiety, unsteadiness, reversible neurological deficits (speech and vision disturbances, paralysis, or sensory disturbances). With progressive hypoglycemia, the patient may lose consciousness (hypoglycemic coma). In such cases, the skin feels cold and moist, tachycardia is present, hyperthermia may occur, along with motor agitation, hyperreflexia, paresis, and a positive Babinski reflex; seizures may also develop.

Treatment. Mild to moderate hypoglycemia can be self-treated by consuming sugar or foods and drinks high in sugar. Therefore, patients should always carry 20 g of glucose with them. Patients should inform their physician if hypoglycemia occurs, especially after a dosage change. In cases of severe hypoglycemia, immediate medical assistance is required. In accidental poisoning, if the patient is conscious and cooperative, induce vomiting and perform gastric lavage (if there is no predisposition to seizures), followed by intravenous glucose administration. If the patient is unconscious, immediate intravenous administration of glucose is required (40–80 mL of 40% solution as an injection, followed by infusion of 5–10% glucose solution). If necessary, 1 mg of glucagon may be administered intramuscularly or intravenously. If the patient does not regain consciousness, this procedure may be repeated; prolonged intensive care may be required. In cases of prolonged hypoglycemia, the patient should be monitored for several days with regular blood glucose checks and, if necessary, continued infusion therapy.

Adverse Reactions.

Metabolism and nutrition disorders. Hypoglycemia is the most common adverse effect associated with glyburide use (detailed information is provided in the section "Overdose"), as well as weight gain. This adverse effect of glyburide therapy may be prolonged and may lead to the development of severe hypoglycemia, accompanied by hypoglycemic coma, which is life-threatening.

Eye disorders. Visual disturbances and accommodation disorders, especially at the beginning of treatment.

Gastrointestinal disorders. Nausea, bloating, vomiting, abdominal pain, diarrhea, belching, metallic taste in the mouth. These symptoms are transient and do not require discontinuation of the drug.

Hepatobiliary disorders. Transient increases in AST, ALT, and alkaline phosphatase, drug-induced hepatitis, intrahepatic cholestasis, possibly due to a hyperergic-type allergic reaction of liver cells. These disorders are reversible after discontinuation of the drug, but may lead to life-threatening liver failure.

Skin and subcutaneous tissue disorders. Itching, urticarial rash, nodular erythema, measles-like or maculopapular exanthema, purpura, photosensitivity. These hypersensitivity reactions are reversible, but very rarely may progress to life-threatening conditions associated with angioedema and hypotension, and very rarely even to shock. Generalized hypersensitivity reactions accompanied by skin rash, arthralgia, fever, proteinuria, and jaundice; life-threatening allergic vasculitis. If skin reactions occur, consult a physician.

Blood and lymphatic system disorders. Thrombocytopenia. Leukopenia, erythropenica, granulocytopenia, up to the development of agranulocytosis. In isolated cases: pancytopenia, hemolytic anemia. Anemia, eosinophilia, and aplastic anemia have been reported with sulfonamides. These blood count changes are reversible after discontinuation of the drug, but very rarely may be life-threatening.

Other adverse effects. Mild diuretic effect, reversible proteinuria, hyponatremia, disulfiram-like reaction, syndrome of inappropriate antidiuretic hormone secretion (SIADH), cross-reactivity with sulfonamides, sulfonamide derivatives, and probenecid.

Ponzo 4 R may cause allergic reactions.

Shelf life.

3 years.

Do not use the drug after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister. 5 or 10 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.