Glibenclamide-zdorovya

INSTRUCTIONS FOR MEDICAL USE of the medicinal product GLIBENCLAMID-ZDOROVYE (GLIBENCLAMID-ZDOROVYE)

Composition:

Active substance: glibenclamide;

1 tablet contains 5 mg of glibenclamide;

Excipients: mannitol (E 421), povidone, calcium stearate, microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate.

Dosage form. Tablets.

Main physico-chemical properties: white or almost white tablets, flat cylindrical in shape, with beveled edges and a score line.

Pharmacotherapeutic group. Medicinal products used in diabetes. Hypoglycemic agents, excluding insulin. Sulfonylurea derivatives. Glibenclamide. 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 absorption. Plasma protein binding of glibenclamide exceeds 98%. Cmax in blood serum 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 (T½) after intravenous administration is approximately 2 hours, and after oral administration, it is 7 hours. 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, which do not significantly contribute to the blood 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 delayed. In patients with renal insufficiency, depending on the degree of renal function impairment, excretion of metabolites in urine increases compensatorily. In moderate renal impairment (creatinine clearance ≥ 30 mL/min), total elimination remains unchanged, whereas in severe renal impairment, accumulation may occur.

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 resulted in satisfactory correction of blood glucose levels.

Contraindications. Hypersensitivity to the components of the medicinal product, other sulfonylurea drugs, sulfonamides, sulfonamide diuretics, or probenecid. Cases of diabetes mellitus requiring insulin therapy: insulin-dependent diabetes mellitus (type 1 diabetes mellitus), complete secondary failure of glyburide therapy in type 2 diabetes mellitus, metabolic disturbances tending toward acidosis, precoma or diabetic coma, and post-pancreatectomy state. Severe impairment of liver function. Severe impairment of kidney function. Concomitant use with bosentan.

Interaction with other medicinal products and other forms of interaction.

The effect of the medicinal product may be enhanced or diminished when used concomitantly with other drugs; therefore, consultation with a physician is required regarding the use of other medications. Glyburide is metabolized primarily by CYP 2C9 and to a lesser extent by CYP 3A4. This should be taken into account when glyburide is administered concomitantly with inducers or inhibitors of CYP 2C9.

Hypoglycemic reactions as a manifestation of enhanced drug effect may occur with concomitant use of: oral antidiabetic agents and insulin, angiotensin-converting enzyme (ACE) inhibitors, anabolic steroids and androgens, antidepressants (such as fluoxetine, monoamine oxidase inhibitors), quinolone derivatives, chloramphenicol, clarithromycin, clofibrate and its analogs, coumarin derivatives, disopyramide, fenfluramine, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), perhexiline, pyrazolone derivatives, probenecid, salicylates, sulfinpyrazone, sulfonamides, sympatholytics (such as β-adrenoreceptor blockers), tetracycline derivatives, troxacitabine, cytostatics such as cyclophosphamide.

The use of β-adrenoreceptor blockers, clonidine, guanethidine, and reserpine may reduce the perception of early symptoms of hypoglycemia.

Hyperglycemic reactions as a manifestation of diminished drug effect may occur with concomitant use of: acetazolamide, β-adrenergic blockers, barbiturates, diazoxide, diuretics, glucagon, isoniazid, corticosteroids, laxatives (in cases of chronic abuse, see section "Special precautions"), nicotinic acid derivatives, phenothiazine derivatives, phenytoin, rifampicin, thyroid hormones, female sex hormones (progestogens, estrogens), sympathomimetics. H2-receptor blockers, clonidine, and reserpine may either diminish or enhance the blood 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 diminished.

In patients who received glyburide concomitantly with bosentan, an increased frequency of elevated liver enzymes was observed. Both glyburide and bosentan inhibit the bile salt export pump (BSEP), leading to intracellular accumulation of cytotoxic bile salts; therefore, this combination should not be used (see section "Contraindications").

Glyburide may increase plasma concentrations of cyclosporine and thereby enhance its toxicity. Therefore, when these agents are used concomitantly, monitoring of cyclosporine plasma concentrations and dose adjustment are recommended.

Colesevelam binds glyburide and thus reduces its absorption from the gastrointestinal tract. Glyburide should be taken at least 4 hours before administration of colesevelam—under these conditions, no interaction has been observed.

Other types of interactions. Acute or chronic alcohol consumption may unpredictably enhance or diminish the hypoglycemic effect of glyburide.

Special precautions for use.

The patient must be informed that if other disorders occur during treatment with glibenclamide, immediate consultation with a physician is required, and if changing physicians, the patient should inform the new physician about the presence of diabetes mellitus (e.g. during hospitalization, after an accident, or if illness occurs during vacation).

Hypoglycemia

Patients should be made aware of the risk of hypoglycemia when using antidiabetic medications. Long intervals between meals, inadequate carbohydrate intake, unusual physical exertion, diarrhea, or vomiting increase the risk of hypoglycemia (see section "Adverse reactions"). Patients with marked signs of cerebral sclerosis and those who do not follow medical recommendations are more prone to hypoglycemia. Medications acting on the central nervous system, β-blockers, as well as autonomic neuropathy, may mask the warning symptoms of hypoglycemia.

Despite initial success in treating hypoglycemia, recurrence is possible. Therefore, patients should remain under medical supervision. Severe hypoglycemia or prolonged episodes, which can only be temporarily controlled by usual amounts of sugar, require immediate treatment (see section "Overdose").

Hyperglycemia

If the treatment regimen is not followed, if the antidiabetic effect of the medication is insufficient, or during stressful situations, blood glucose levels may rise. Symptoms of hyperglycemia may include intense thirst, dry mouth, frequent urination, itching and/or dry skin, fungal or infectious skin conditions, and reduced work capacity. In extreme stress situations (trauma, surgery, infection accompanied by fever), metabolic control may deteriorate, leading to hyperglycemia, sometimes so severe that temporary insulin therapy may be required.

Laxatives

Chronic abuse of laxatives may lead to deterioration of metabolic control.

Alcohol

Acute or chronic alcohol abuse may unpredictably enhance or weaken the drug's effect.

Impaired liver and kidney function and endocrine disorders

Particular caution is required when administering the drug to patients with impaired kidney or liver function, or reduced function of the thyroid gland, pituitary gland, or adrenal cortex.

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

In patients with G6PD deficiency, treatment with sulfonylurea drugs, including glibenclamide, may cause hemolytic anemia; therefore, the drug should be used with caution, and consideration should be given to switching to non-sulfonylurea alternative agents.

Elderly patients

Age 65 years and older is a risk factor for hypoglycemia in patients receiving sulfonylurea therapy. Hypoglycemia may be difficult to recognize in elderly patients. Initial and maintenance doses of glibenclamide should be carefully adjusted to minimize the risk of hypoglycemia (see section "Dosage and administration"). When prescribing treatment for patients in this age group, sulfonylurea drugs with a shorter duration of action should be preferred.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated during pregnancy. Since oral antidiabetic agents do not control blood glucose levels as reliably as insulin, they are not suitable for the treatment of diabetes mellitus during pregnancy. Insulin therapy is the treatment of choice during pregnancy or breastfeeding. If possible, oral antidiabetic therapy should be discontinued and replaced with insulin before planned pregnancy.

Period of breastfeeding

Since it is unknown whether the drug passes into breast milk, it is contraindicated during breastfeeding.

Breastfeeding patients should either use insulin to control diabetes or discontinue breastfeeding.

Fertility

There are no data on the effect of glibenclamide on fertility in humans.

Ability to affect reaction speed when driving or operating machinery. Hypoglycemia may impair a patient's ability to concentrate and react. This may pose a risk when driving 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 lack awareness of hypoglycemia warning symptoms. In such cases, the appropriateness of driving should be reconsidered.

Dosage and Administration

The medicinal product should be taken only as prescribed by a physician and must be accompanied by dietary adjustments. The dosage depends on the results of monitoring metabolic status (blood and urine glucose levels). Monitoring of blood and urine glucose levels is necessary when switching from another hypoglycemic agent.

Initial and subsequent administration. Therapy should be initiated with the lowest possible doses, especially in patients predisposed to hypoglycemia or with body weight below 50 kg. Initially, prescribe ½ to 1 tablet of the medicinal product (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 the medicinal product (corresponding to 15 mg of glibenclamide) per day.

Switching from other antidiabetic agents. The physician should switch the patient to this medicinal product very cautiously, starting with a dose of ½ tablet (2.5 mg glibenclamide) to 1 tablet (5 mg glibenclamide) daily.

Dose titration. In elderly patients, debilitated patients, those with inadequate nutrition, or patients with impaired renal or hepatic function, the initial and maintenance doses should be reduced due to the risk of developing hypoglycemia. Dose adjustments may also be required if the patient's body weight decreases or lifestyle changes occur.

Combination with other antidiabetic agents. The medicinal product can be used alone (monotherapy) or in combination with metformin. In individual cases, for patients intolerant to metformin, additional prescription of glitazone group agents (rosiglitazone, pioglitazone) may be indicated. The medicinal product can also be combined with oral antidiabetic agents that do not stimulate β-cell release of endogenous insulin (e.g., guar gum or acarbose). In cases of secondary failure of glibenclamide therapy (reduced insulin production due to β-cell exhaustion), combination therapy with insulin may be attempted. However, when endogenous insulin secretion is completely absent, insulin monotherapy is indicated.

The patient should consult a physician if they perceive the effect of the medicinal product to be too strong or too weak.

Patients must not discontinue treatment or alter the dose or diabetic diet without consulting a physician. If changes are necessary, the patient should consult their physician in advance.

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

The duration of treatment depends on the course of the disease. Regular monitoring of blood and urine glucose levels is required during treatment. 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).

Elderly patients. For patients aged 65 years and older, initial and maintenance doses of glibenclamide should be carefully adjusted to reduce the risk of hypoglycemia. Treatment should be initiated with the lowest possible dose and gradually increased if necessary (see section "Special precautions").

Children. Glibenclamide is not used in pediatric practice.

Overdose.

Acute, pronounced overdose of glibenclamide, such as prolonged use of slightly increased doses, may lead to severe, prolonged hypoglycemia, which can be life-threatening. In cases of overdose, careful monitoring is required until it is certain that the patient is no longer at risk. It should be noted that hypoglycemia and its clinical manifestations may recur after temporary recovery. Significant overdose and severe reactions, such as loss of consciousness and other serious neurological disturbances, should be considered emergencies requiring immediate treatment and hospitalization.

Symptoms of overdose

In cases of intentional overdose, there is a risk of prolonged hypoglycemia, with possible relapses even after several days of successful treatment. In patients with impaired consciousness, hypoglycemic coma may rapidly develop, characterized by loss of consciousness, tachycardia, moist skin, hyperthermia, motor agitation, hyperreflexia, paresis with a positive Babinski reflex.

Treatment measures in overdose

See section "Adverse reactions" for management of mild hypoglycemia.

In more severe intoxications, if the patient is conscious and not prone to seizures, gastric lavage or induction of vomiting should be performed in addition to intravenous glucose administration.

If the patient is unconscious, immediate intravenous administration of glucose is required (40–80 mL of 40% glucose solution as an injection, followed by infusion of 5–10% glucose solution).

Subsequently, 1 mg of glucagon may be administered intramuscularly or intravenously. If the patient does not regain consciousness, this measure may be repeated, and intensive therapy may subsequently be required.

Glucose solution should be administered cautiously to avoid dangerous hyperglycemia, especially in children who have accidentally ingested glibenclamide. Careful monitoring of blood glucose levels is required thereafter.

Patients who have ingested life-threatening amounts of glibenclamide require detoxification by gastric lavage and administration of activated charcoal, provided the drug was taken recently.

In cases of prolonged hypoglycemia, the patient must be observed for several days with regular monitoring of blood glucose levels and infusion therapy as needed.

Adverse Reactions

Adverse reactions are classified by frequency:

very common (≥ 1/10);
common (≥ 1/100, < 1/10);
uncommon (≥ 1/1000, < 1/100);
rare (≥ 1/10,000, < 1/1000);
very rare (< 1/10,000);
frequency not known (frequency cannot be estimated from available data).

Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with glyburide therapy.

It may be prolonged during glyburide treatment and may lead to severe hypoglycemia with coma, which can be life-threatening. In cases of very subtle presentation of hypoglycemia, such as in autonomic neuropathy or concomitant therapy with sympatholytic agents (see section "Interaction with other medicinal products and other forms of interaction"), typical warning symptoms of hypoglycemia may be diminished or absent. The clinical picture of a severe hypoglycemic attack may resemble stroke.

Possible causes of hypoglycemia are described in the section "Special precautions for use".

Hypoglycemia is defined as a drop in blood glucose levels below approximately 50 mg/dL. Signs and symptoms indicating excessive drop in blood glucose levels for the patient or those around them may include: sudden sweating, palpitations, tremor, hunger sensation, anxiety, tingling sensation in the mouth, pallor of the skin, headache, drowsiness, sleep disturbances, restlessness, unsteadiness, reversible neurological symptoms (e.g., speech and visual disturbances, signs of paralysis or sensory disturbances).

If hypoglycemia progresses, the patient may lose self-control and consciousness. Such patients usually have moist, cold skin and may be prone to seizures.

A patient with diabetes mellitus can manage mild hypoglycemia by consuming sugar or food or drinks containing high amounts of sugar. Therefore, patients should always carry 20 grams of glucose with them.

If hypoglycemia cannot be promptly corrected, a physician must be contacted immediately.

Other adverse reactions

Metabolism and nutrition disorders

Common: weight gain.
Very rare: hyponatremia, disulfiram-like reaction.

Eye disorders

Very rare: transient visual disturbances and accommodation disorders may occur due to changes in blood glucose concentration, particularly at the beginning of treatment.

Gastrointestinal disorders

Uncommon: nausea, feeling of fullness/bloating in the stomach, vomiting, abdominal pain, diarrhea, belching, metallic taste in the mouth.

These complaints are transient and generally do not require discontinuation of the medicinal product.

Hepatobiliary disorders

Very rare: transient increases in aspartate aminotransferase and alanine aminotransferase levels, alkaline phosphatase; drug-induced hepatitis; intrahepatic cholestasis, possibly due to a hyperergic-type allergic reaction of liver cells.

These disorders are reversible upon discontinuation of the drug, but may rarely lead to life-threatening liver failure.

Skin and subcutaneous tissue disorders

Uncommon: pruritus, urticaria, nodular erythema (erythema nodosum), morbilliform or maculopapular exanthema, purpura, increased photosensitivity.

These hypersensitivity reactions are reversible, but very rarely may progress to life-threatening conditions associated with dyspnea and decreased arterial pressure, leading to shock.

Very rare: life-threatening allergic vasculitis; generalized hypersensitivity reactions with skin rash, arthralgia, fever, proteinuria, and jaundice.

If skin reactions occur, immediate medical attention is required.

Blood and lymphatic system disorders

Rare: thrombocytopenia.
Very rare: leukopenia, erythrocytopenia, granulocytopenia, up to development of agranulocytosis; pancytopenia, hemolytic anemia. These changes in blood parameters are reversible upon discontinuation of the drug, but very rarely may be life-threatening.

Immune system disorders

Very rare: possible cross-allergy with sulfonamides, derivatives of sulfonamides, and probenecid.

Renal and urinary disorders

Very rare: mild diuretic effect, reversible proteinuria.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 3 years.

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

Keep out of reach of children.

Packaging. Tablets № 10×5 in blisters in a carton; № 50 in a container in a carton; № 50 in a container.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business.

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.