Glucovance film-coated tablets 500 mg + 5 mg No. 30

Instructions Glucovance film-coated tablets 500 mg + 5 mg No. 30

Composition

active ingredients:

1 film-coated tablet 500 mg/5 mg contains metformin hydrochloride - 500 mg and glibenclamide - 5 mg;

excipients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate;

film coating: Opadry 31F22700: lactose monohydrate; hypromellose 15 cP, titanium dioxide (E 171); polyethylene glycol, iron oxide yellow (E 172), iron oxide red (E 172), quinoline yellow (E 104).

Dosage form

Film-coated tablets.

Main physicochemical properties: oblong, biconvex, yellow tablets, film-coated, engraved with "5" on one side.

Pharmacotherapeutic group

Drugs affecting the digestive system and metabolism. Antidiabetic drugs. Oral hypoglycemic agents, except insulins. Combination of oral hypoglycemic agents. Metformin and sulfonylurea derivatives. ATC code A10B D02.

Pharmacological properties

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after a meal. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.

Metformin works in three ways:

leads to a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;

improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization;

delays the absorption of glucose in the intestine.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).

Independently of its action on glycemia, metformin has a positive effect on lipid metabolism. This effect has been proven at therapeutic doses in controlled medium- or long-term clinical trials: metformin reduces total cholesterol, low-density lipoproteins and triglycerides.

In the course of clinical studies conducted to date, such a positive effect on lipid metabolism during the combined use of metformin and glibenclamide was not detected.

Glibenclamide is a second-generation sulfonylurea with an intermediate half-life. It stimulates insulin production by the pancreas, which causes a sharp decrease in blood glucose levels. This action depends on the presence of functioning β-cells (islets of Langerhans).

The stimulation of insulin secretion by glibenclamide in response to food intake is important. The use of glibenclamide in patients with diabetes mellitus causes an increase in insulin secretion stimulated by food intake. The increased secretion of insulin and C-peptide is maintained after at least 6 months of treatment.

Metformin and glibenclamide have different mechanisms of action, but their actions are complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cellular resistance to insulin, i.e. increases the sensitivity of peripheral tissues (skeletal muscles) and liver tissues to insulin.

The results of controlled, double-blind clinical trials with reference drugs for the treatment of type 2 diabetes mellitus, which is not adequately controlled by monotherapy with metformin or glibenclamide in combination with diet and exercise, showed that the use of combination therapy had a comprehensive effect on glucose control.

Children: In a 26-week, active-controlled, double-blind clinical study in 167 patients aged 9 to 16 years with type 2 diabetes mellitus who were inadequately controlled on diet and exercise with or without oral hypoglycaemic therapy, the fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg did not demonstrate any greater efficacy in reducing glycosylated haemoglobin (HbA1c) from baseline. Therefore, Glucovance® should not be used in children.

Pharmacokinetics.

Regarding the combination.

The bioavailability of metformin and glibenclamide in combination is the same as when taking 1 tablet of metformin and 1 tablet of glibenclamide simultaneously. The bioavailability of metformin in combination is not affected by food intake. The bioavailability of glibenclamide in combination is not affected by food intake, however, the rate of absorption of glibenclamide increases with food intake.

Regarding metformin.

After oral administration, metformin absorption is saturable and incomplete. The pharmacokinetics of metformin absorption are assumed to be non-linear. At recommended metformin doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and are less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 μg/ml even at maximum doses.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than in plasma and are reached in approximately the same time. Erythrocytes are likely to represent a second distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination. Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.

Regarding glibenclamide.

Absorption: After oral administration, glibenclamide is very rapidly absorbed (> 95%). The time to reach maximum concentration is 4 hours.

Distribution: Glibenclamide is highly bound to plasma proteins (99%), which may affect interactions with some drugs.

Metabolism: Glibenclamide is completely metabolized in the liver to form two metabolites. Hepatic insufficiency reduces the metabolism of glibenclamide and significantly slows its elimination.

Excretion. Glibenclamide is excreted in the form of metabolites with bile (60%) and urine (40%). Complete elimination occurs after 45–72 hours. The terminal half-life is 4–11 hours.

The excretion of metabolites with bile increases in patients with renal insufficiency, depending on the degree of renal impairment, if the creatinine clearance is 30 ml/min. If the creatinine clearance is more than 30 ml/min, renal insufficiency does not affect the excretion of glibenclamide.

Children: The pharmacokinetics of glibenclamide and metformin in children did not differ from those in healthy adult volunteers of the same gender and body weight.

Indication

Treatment of type 2 diabetes mellitus in adults, to replace previous therapy with two drugs (metformin and glibenclamide) in patients with stable and well-controlled glycemia.

Contraindication

Hypersensitivity to metformin, glibenclamide, to other components of the drug or to other sulfonylurea drugs, to sulfonamides;

type 1 diabetes mellitus (insulin-dependent diabetes mellitus), diabetic precoma;

any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);

severe renal failure (glomerular filtration rate (GFR) < 30 ml/min);

acute conditions that occur with a risk of developing kidney dysfunction: dehydration, severe infectious diseases, shock;

diseases that can cause tissue hypoxia (in particular acute disease or worsening of chronic disease), such as decompensated heart failure, respiratory failure, recent myocardial infarction, shock;

liver failure, acute alcohol intoxication, alcoholism;

porphyria;

pregnancy and breastfeeding;

concomitant therapy with miconazole (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Contraindicated interactions.

Regarding glibenclamide.

Miconazole (for systemic use, oral gel): increased hypoglycemic effect with possible manifestations of hypoglycemia or even coma (see section "Contraindications").

Interactions that are not recommended.

Regarding sulfonylurea drugs.

Alcohol - Antabuse effect (alcohol intolerance), especially for chlorpropamide, glibenclamide, glipizide, tolbutamide. Increased risk of hypoglycemic reactions (due to inhibition of compensatory reactions) may lead to hypoglycemic coma (see section "Special instructions"). Alcohol and alcohol-containing medications should be avoided.

Phenylbutazone (for systemic use): potentiates the hypoglycemic effect of sulfonylurea derivatives (displaces their binding to plasma proteins and/or reduces their excretion). It is recommended to use other nonsteroidal anti-inflammatory drugs or warn the patient and emphasize the importance of self-monitoring of blood glucose. If necessary, the dose of the hypoglycemic drug should be adjusted during and after discontinuation of anti-inflammatory drugs.

Regarding all diabetes medications.

Danazol: If this combination is necessary, the patient should be advised to increase self-monitoring of blood glucose levels. If necessary, the dose of the drug should be adjusted during and after discontinuation of danazol.

Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in the presence of fasting, malnutrition, or liver failure.

Iodinated radiopaque agents: Patients should discontinue the drug prior to or during the examination and not resume it until 48 hours after the examination, only after re-evaluation and stable renal function (see sections “Method of administration and dosage” and “Special precautions for use”).

Combinations that should be used with caution.

Regarding all diabetes medications.

Chlorpromazine: when taking high doses (100 mg of chlorpromazine per day), an increase in blood glucose levels (reduced insulin production). The patient should be warned and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the hypoglycemic drug should be adjusted during and after discontinuation of neuroleptics.

Corticosteroids (glucocorticoids) and tetracosactides (systemic and local action): increased blood glucose levels, sometimes accompanied by ketosis (reduced carbohydrate tolerance). The patient should be warned and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the drug should be adjusted during and after the cessation of corticosteroids.

β2-agonists: increased blood glucose levels. The patient should be warned and blood glucose control should be intensified, if necessary, the patient should be transferred to insulin therapy.

Regarding metformin.

Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) II inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics, may adversely affect renal function, which may increase the risk of lactic acidosis. When initiating treatment with the above medicinal products or when used in combination with metformin, renal function should be closely monitored.

Organic cation transporters (OCT).

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

OCT1 inhibitors (such as verapamil) may reduce the effectiveness of metformin;

OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with a subsequent increase in metformin plasma concentrations;

Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.

Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.

Regarding glibenclamide.

β-blockers mask some of the symptoms of hypoglycemia: palpitations and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemia. The patient should monitor blood glucose levels, especially at the beginning of treatment.

ACE inhibitors (e.g. captopril, enalapril): decrease in blood glucose levels. If necessary, the dose of Glucovance® should be adjusted during and after discontinuation of ACE inhibitors.

Fluconazole: prolongation of the half-life of sulfonylureas with possible manifestations of hypoglycemia. The patient should be warned and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the drug should be adjusted during and after the cessation of fluconazole.

Bosentan: risk of reduced hypoglycemic effect of glibenclamide, as bosentan reduces plasma concentrations of glibenclamide. There is a risk of increased liver enzyme levels when taken concomitantly.

The patient should be advised to monitor blood glucose and liver enzyme levels and the dosage should be adjusted if necessary.

Bile acid sequestrants: when used together, the concentration of glibenclamide in the blood plasma decreases, which may lead to a decrease in its hypoglycemic effect. This effect is absent if glibenclamide is taken in advance of the use of the other drug. It is recommended to use Glucovance® at least 4 hours before taking bile acid sequestrants.

Interactions to consider.

Regarding glibenclamide.

Desmopressin: decreased antidiuretic effect.

Application features

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.

Patients receiving metformin should be cautiously initiated on medicinal products that may acutely impair renal function (e.g. antihypertensives, diuretics and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting and any condition associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia, which may progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical attention immediately.

Diagnostic laboratory findings include decreased blood pH (< 7.35), increased serum lactate concentration (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.

Hypoglycemia. Glucovance® contains a sulfonylurea, so patients taking this medicine are prone to developing hypoglycemia. After starting therapy, titration of the dose of the drug can prevent the development of hypoglycemia. The drug should be prescribed to patients who adhere to a regular meal schedule (including breakfast). Regular carbohydrate intake is an important factor, since the risk of hypoglycemia increases in the event of late meals, insufficient or unbalanced carbohydrate intake. Hypoglycemia most often occurs in patients who adhere to a low-calorie diet, after intense or prolonged exercise, when drinking alcohol or during combination therapy with hypoglycemic agents.

Diagnosis. Symptoms of hypoglycemia: headache, hunger, nausea, vomiting, severe fatigue, sleep disturbances, anxiety, attacks of aggression, impaired concentration and reactions, depression, confusion, speech defects, visual impairment, tremor, paralysis, paresthesia, dizziness, delirium, convulsions, drowsiness, fainting, shallow breathing, bradycardia. In connection with the counterregulation caused by hypoglycemia, sweating, fear, tachycardia, arterial hypertension, palpitations, angina pectoris and arrhythmia may occur. Such symptoms may be absent in the case of slow development of hypoglycemia, autonomic neuropathy or in the case of taking β-blockers, clonidine, reserpine, guanethidine or sympathomimetics.

Treatment of hypoglycemia. In case of mild symptoms of hypoglycemia without loss of consciousness or neurological manifestations, sugar should be taken immediately. Dosage adjustment and/or dietary changes should be made. Severe hypoglycemic reactions with coma, seizures, and other neurological signs may occur, which may constitute an emergency. This requires emergency treatment with intravenous glucose when hypoglycemia is diagnosed or suspected before the patient is hospitalized.

Patient selection, dose adjustment, and appropriate patient education are important in reducing the risk of hypoglycemia. If patients experience repeated episodes of severe hypoglycemia or episodes associated with hypoglycemia awareness, other hypoglycemic treatment options should be considered.

Factors contributing to the occurrence of hypoglycemia:

simultaneous intake of alcohol, especially in combination with fasting,

refusal (especially in elderly patients) or inability of patients to follow the doctor's recommendations,

irregular eating, malnutrition, missed meals, fasting or change in diet,

improper ratio between physical exercise and carbohydrate consumption,

renal failure,

severe liver failure,

overdose of Glucovance®,

some endocrine disorders: thyroid insufficiency, pituitary and adrenal insufficiency,

simultaneous administration of certain drugs (see section "Interaction with other medicinal products and other types of interactions").

Elderly patients

Age 65 years or older has been identified as a risk factor for hypoglycemia in patients using sulfonylureas. Symptoms of hypoglycemia are difficult to recognize in elderly patients.

In order to reduce the risk of hypoglycemia, careful adjustment of the initial and maintenance dose of glibenclamide should be carried out (see section "Method of administration and dosage").

Renal and hepatic insufficiency in patients may alter the pharmacokinetics and/or pharmacodynamics of Glucovance®. If hypoglycemia occurs in this category of patients, it may become chronic and require appropriate treatment.

In particular, patients should be informed about the importance of diet, regular exercise, and glycemic control.

Imbalance of blood glucose levels. In case of surgical interventions or other causes of decompensation of diabetes mellitus, temporary insulin therapy should be considered. Symptoms of hyperglycemia: increased urination, intense thirst, dry skin.

Renal function: GFR should be assessed before starting treatment and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with a GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

In such cases, it is also recommended to check kidney function before starting metformin treatment.

Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Patients with stable chronic heart failure may take Glucovance® provided that cardiac and renal function are regularly monitored.

Glucovance® is contraindicated in patients with acute and unstable heart failure (see section “Contraindications”).

Iodinated radiocontrast agents. Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Patients should discontinue metformin prior to or at the time of the examination and not resume metformin until 48 hours after the examination, and only after re-evaluation and stable renal function (see sections 4.2 and 4.5).

Concomitant use of glibenclamide with other medicinal products. The concomitant use of glibenclamide with alcohol, phenylbutazone or danazol is not recommended (see section “Interaction with other medicinal products and other types of interactions”).

Surgery: The drug should be discontinued during surgery performed under general, spinal, or epidural anesthesia and not resumed until 48 hours after surgery or resumption of oral nutrition, and only after re-evaluation and stable renal function.

Precautions: Patients should follow a diet, properly distributing carbohydrate intake throughout the day. Overweight patients should follow a low-calorie diet.

During therapy with the drug, regular physical exercise should be performed. Laboratory parameters (glycemia and glycosylated hemoglobin - HbA1c) should be regularly monitored.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with increasing metformin dose, duration of treatment and/or if the patient has risk factors known to predispose to vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g. anaemia or neuropathy). Patients with risk factors for vitamin B12 deficiency may require monitoring of vitamin B12 levels. Metformin therapy should be continued as long as tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be provided in accordance with current clinical guidelines.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylureas may lead to the development of hemolytic anemia. Since glibenclamide belongs to this class, Glucovance® should be used with extreme caution in patients with glucose-6-phosphate dehydrogenase deficiency and consideration should be given to switching to alternative therapy with non-sulfonylurea derivatives.

Patients with congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency are contraindicated in using the drug because it contains lactose.

Glucovance® contains less than 1 mmol sodium (23 mg) per tablet, which is not clinically significant.

Use during pregnancy or breastfeeding

Pregnancy: There are no preclinical or clinical data on the use of Glucovance® during pregnancy.

Risks associated with diabetes mellitus. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. Diabetes mellitus should be controlled at the time of conception to reduce the risk of congenital anomalies.

Risk associated with glibenclamide. Glibenclamide is contraindicated for use during pregnancy. Preclinical studies have not revealed any teratogenic effects. In the absence of teratogenic effects in animals, fetal malformations in humans are not expected, since substances that cause malformations in humans have a teratogenic effect on two animal species during research. In clinical practice, there are no relevant data on the basis of which an assessment of potential malformations or fetotoxicity is formed when glibenclamide is used during pregnancy.

Treatment: Adequate blood glucose control promotes a normal pregnancy in this category of patients. Glucovance® should not be used to treat diabetes during pregnancy.

When planning pregnancy, as well as in the event of pregnancy, it is recommended to switch from oral hypoglycemic therapy to insulin therapy to maintain blood glucose levels as close to normal as possible. It is recommended to monitor the blood glucose level in the newborn.

Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants whose mothers received metformin monotherapy. However, since there is no data on the excretion of glibenclamide in human milk and because of the risk of hypoglycemia in the newborn, the drug is contraindicated during breastfeeding.

Fertility: Metformin did not affect animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area. Glibenclamide did not affect animal fertility at oral doses of 100 and 300 mg/kg/day.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients should be particularly careful when driving or operating machinery due to the risk of developing symptoms of hypoglycemia.

Method of administration and doses

Oral. For use in adult patients only.

As with other hypoglycemic agents, the dose of Glucovance® is set individually, depending on the patient's metabolic response (glycemia level and HbA1c).

Adult patients with normal renal function (GFR ≥ 90 mL/min).

It is recommended to use Glucovance® 500 mg/5 mg in patients who do not achieve adequate glycemic control when taking lower dosages.

When replacing combination therapy with metformin and glibenclamide, treatment with Glucovance® should be initiated at doses consistent with the previous dosage. The dose should be gradually increased depending on the results of blood glucose measurements.

Every 2 weeks or more after the start of therapy, it is necessary to adjust the dosage of the drug (increase the dose by 1 tablet) depending on the level of glycemia.

Gradual dose increases help reduce gastrointestinal side effects and prevent the development of hypoglycemia.

The maximum recommended dose is 3 tablets of Glucovance® 500 mg/5 mg per day.

In individual cases, the dose may be increased to 4 tablets of Glucovance® 500 mg/5 mg per day.

There are no data on the combination therapy of Glucovance® with insulin.

The dosage regimen depends on individual indications:

1 time per day: 1 tablet per day during breakfast;

2 times a day: 2 or 4 tablets per day in the morning and evening;

3 times a day: 3 tablets per day in the morning, afternoon and evening.

The tablets should be taken with meals.

The dosage regimen can be adjusted according to the individual's dietary regimen. However, to prevent hypoglycemic episodes, it is necessary to consume a carbohydrate-rich meal after each dose of the drug.

In case of concomitant use with bile acid sequestrants, it is recommended to take Glucovance® at least 4 hours before taking bile acid sequestrants to minimize the risk of reduced absorption (see section “Interaction with other medicinal products and other types of interactions”).

Renal impairment. GFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be monitored closely as frequently as possible, e.g. every 3–6 months. It is recommended that the maximum daily dose of metformin be divided into 2–3 doses.

Before initiating metformin in patients with a GFR <60 mL/min, factors that may increase the risk of lactic acidosis should be considered (see section 4.4).

In the absence of a drug of the required dosage, separate monocomponents should be used instead of a fixed-dose combination drug.

The maximum daily dose is 1000 mg.

The initial dose is no more than half the maximum dose.

In elderly patients, the dosage of the drug is adjusted depending on the parameters of renal function (initial dose - 1 tablet of the drug Glucovance® 500 mg/2.5 mg). It is necessary to regularly assess renal function (see section "Special instructions").

Elderly patients (65 years and older). In order to reduce the risk of hypoglycemia, careful adjustment of the initial and maintenance dose of glibenclamide should be carried out. Treatment with the drug should be started with a minimum dose, gradually increasing the dose if necessary (see section "Special instructions").

Children. The drug is not recommended for use in children.

Overdose

Overdose may lead to hypoglycemia, as the drug contains a sulfonylurea (see section "Special precautions for use"). A significant overdose of metformin or the presence of concomitant risk factors may lead to the development of lactic acidosis (see section "Special precautions for use"). Lactic acidosis is an emergency and should be treated in a hospital. The most effective measure for the removal of lactate and metformin from the body is hemodialysis.

Plasma clearance of glibenclamide may be prolonged in patients with liver disease.

Due to its tight protein binding, glibenclamide is not removed during hemodialysis.

Side effects

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms in most cases resolve on their own. To prevent the occurrence of these side effects, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2–3 doses. Short-term visual disturbances may develop at the beginning of treatment due to a decrease in glycemia.

The following adverse reactions have been reported with Glucovance®. Adverse reactions are classified by frequency of occurrence into the following categories: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

From the blood and lymphatic system.

Reversible reactions that disappear after discontinuation of treatment.

Rare: leukopenia, thrombocytopenia.

Very rare: agranulocytosis, hemolytic anemia, bone marrow aplasia, pancytopenia.

Metabolism.

Hypoglycemia (see section "Special warnings and precautions for use").

Common: Vitamin B12 deficiency/decrease (see section 4.4).

Uncommon: acute hepatic porphyria, porphyria cutanea.

Very rare: lactic acidosis (see section "Special warnings and precautions for use").

Disulfiram-like reaction when drinking alcohol.

From the nervous system.

Common: taste disturbance.

From the organs of vision.

Short-term visual disturbances may occur at the beginning of treatment due to a decrease in glycemia.

From the digestive tract.

Very common: digestive system disorders, including nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These side effects most often occur at the beginning of treatment and usually disappear spontaneously. To prevent the occurrence of side effects from the digestive system, it is recommended to slowly increase the dosage and use the drug 2-3 times a day.

On the skin and subcutaneous tissue.

Cross-reactivity to sulfonylurea or its derivatives.

Rare: skin reactions including pruritus, urticaria, maculopapular rash.

Very rare: cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, urticaria leading to the development of