Insucomb

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

Composition:

Active substances: metformin hydrochloride, glibenclamide;

One film-coated tablet of 500 mg/2.5 mg contains 500 mg of metformin hydrochloride and 2.5 mg of glibenclamide;

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

Excipients: povidone K 30, microcrystalline cellulose (type 101), sodium croscarmellose, microcrystalline cellulose (type 102), magnesium stearate;

Film coating for 500 mg/2.5 mg tablet: Opadry® II Pink 85F240091 (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, red iron oxide (E 172));

Film coating for 500 mg/5 mg tablet: Opadry® II Yellow 85F220095 (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), tartrazine aluminium lake (E 102), sunset yellow FCF aluminium lake (E 110)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

500 mg/2.5 mg tablets: round, biconvex, film-coated, pink-colored tablets with the inscription "2.5" engraved on one side;

500 mg/5 mg tablets: round, biconvex, film-coated, yellow-colored tablets with the inscription "5" engraved on one side.

Pharmacotherapeutic group.

Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Combination of oral hypoglycemic agents. Metformin and sulfonylurea derivatives. ATC code A10BD02.

Pharmacological properties.

Pharmacodynamics.

Insucomb is a combined oral hypoglycemic agent. It is a fixed-dose combination of two oral hypoglycemic agents from different pharmacological classes.

Metformin is a biguanide with antihyperglycemic effects. It reduces plasma glucose levels both in fasting state and after food intake. It does not stimulate insulin secretion and does not cause hypoglycemia through this mechanism.

Metformin acts via three pathways:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscle tissue, resulting in enhanced peripheral glucose uptake and utilization;
• delays intestinal absorption of glucose.

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

Independent of its effects on glycemia, metformin has a positive effect on lipid metabolism. This effect has been demonstrated in controlled medium- or long-term clinical trials using therapeutic doses: metformin reduces levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

This positive effect on lipid metabolism has not been observed during clinical studies of combined use of metformin and glibenclamide.

Glibenclamide is a second-generation sulfonylurea derivative with a medium elimination half-life. It stimulates insulin production by the pancreas, resulting in a rapid decrease in blood glucose levels. This action depends on the presence of functional β-cells (islets of Langerhans).

The stimulation of insulin secretion by glibenclamide in response to food intake is particularly important. Administration of glibenclamide to patients with diabetes leads to increased food-stimulated insulin secretion. Elevated insulin and C-peptide secretion persists for at least 6 months of treatment.

Metformin and glibenclamide have different mechanisms of action, but their effects are complementary. Glibenclamide stimulates insulin secretion from the pancreas, while metformin reduces cellular insulin resistance, thereby increasing insulin sensitivity in peripheral tissues (skeletal muscles) and liver.

Results from controlled, double-blind, reference-drug clinical trials in patients with type 2 diabetes inadequately controlled by monotherapy with either metformin or glibenclamide in combination with diet and exercise indicate that combination therapy provides a comprehensive effect on glucose regulation.

Special patient categories.

Children.

In a 26-week, active-controlled, double-blind clinical trial involving 167 patients aged 9 to 16 years with type 2 diabetes not adequately controlled by diet and exercise, with or without prior oral hypoglycemic therapy, fixed-dose combination therapy of metformin hydrochloride 250 mg and glibenclamide 1.25 mg did not demonstrate superior efficacy in reducing glycated hemoglobin (HbA1c) from baseline. Therefore, the medicinal product should not be used in children.

Pharmacokinetics.

Combination of metformin and glibenclamide.

The bioavailability of metformin and glibenclamide in combination is equivalent to that when one tablet of metformin and one tablet of glibenclamide are taken simultaneously. The bioavailability of metformin in combination is independent of food intake. The bioavailability of glibenclamide in combination is also independent of food intake, although the rate of glibenclamide absorption increases with food.

Metformin.

Absorption.

After oral administration, maximum plasma concentration (Cmax) of metformin is reached within 2.5 hours. The absolute bioavailability of 500 mg or 850 mg metformin tablets is approximately 50–60% in healthy volunteers. Approximately 20–30% of the orally administered, unabsorbed metformin is excreted in feces.

Metformin absorption is saturable and incomplete. The absorption pharmacokinetics of metformin are considered to be nonlinear. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. In controlled clinical trials, Cmax of metformin did not exceed 5 µg/mL, even with maximum doses.

Distribution.

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than in plasma and is reached at approximately the same time. Erythrocytes likely represent a secondary distribution compartment. The mean volume of distribution (Vd) ranges between 63–276 L.

Metabolism.

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

Elimination.

Renal clearance of metformin is >400 mL/min, indicating elimination via glomerular filtration and tubular secretion. After oral administration, elimination half-life (t1/2) is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged t1/2 and increased plasma metformin levels.

Glibenclamide.

Absorption.

After oral administration, glibenclamide is rapidly absorbed (>95%). Time to maximum concentration (tmax) is 4 hours.

Distribution.

Glibenclamide is highly bound to plasma proteins (99%), which may influence interactions with certain medicinal products.

Metabolism.

Glibenclamide is completely metabolized in the liver, forming two metabolites. Hepatic impairment reduces glibenclamide metabolism and significantly slows its elimination.

Elimination.

Glibenclamide is excreted in the form of metabolites via bile (60%) and urine (40%). Complete elimination occurs within 45–72 hours. Terminal t1/2 ranges from 4 to 11 hours.

Biliary excretion of metabolites increases in patients with renal impairment, depending on the degree of renal dysfunction, when creatinine clearance is 30 mL/min. Therefore, if creatinine clearance is greater than 30 mL/min, renal impairment does not affect glibenclamide elimination.

Special patient categories.

Children.

The pharmacokinetics of glibenclamide and metformin in children do not differ from those in healthy adult volunteers of the same body weight and sex.

Clinical characteristics.

Indications.

Treatment of type 2 diabetes mellitus in adults, as a replacement therapy for two previous drugs (metformin and glibenclamide) in patients with stable and well-controlled glycemic levels.

Contraindications.

• Hypersensitivity to metformin, glibenclamide, other excipients of the medicinal product, and/or to other sulfonylurea drugs, sulfonamides.
• Type 1 diabetes mellitus (insulin-dependent diabetes).
• Diabetic precoma or coma.
• Any type of acute metabolic acidosis (e.g., lactoacidosis, diabetic ketoacidosis).
• Severe renal impairment (glomerular filtration rate (GFR) <30 mL/min).
• Acute conditions associated with a risk of developing renal dysfunction: dehydration, severe infections, shock.
• Conditions that may cause tissue hypoxia (acute illness or worsening of chronic disease), e.g., decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
• Hepatic insufficiency, acute alcohol intoxication, alcoholism.
• Porphyria.
• Pregnancy.
• Breastfeeding period.
• Concomitant use with miconazole (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Concomitant use with the following agents is contraindicated.

Glibenclamide.

Miconazole (for systemic use, oral gel). When used concomitantly, hypoglycemic effect is enhanced, possibly leading to hypoglycemic symptoms or even coma (see section "Contraindications").

Concomitant use with the following agents is not recommended.

Sulfonylurea agents (including glibenclamide).

Alcohol. Concomitant use results in disulfiram-like reaction (alcohol intolerance), particularly with chlorpropamide, glibenclamide, glipizide, and tolbutamide. Increased risk of hypoglycemic reactions (due to inhibition of compensatory mechanisms) may lead to hypoglycemic coma (see section "Special precautions"). Patients should avoid alcohol consumption and use of medicinal products containing alcohol during treatment.

Phenylbutazone (for systemic use). Concomitant use enhances the hypoglycemic effect of sulfonylurea derivatives, including glibenclamide (by displacing them from plasma protein binding and/or reducing their elimination). When using this medicinal product, it is recommended to use another nonsteroidal anti-inflammatory drug (NSAID) with fewer interactions or to warn the patient and intensify self-monitoring. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of the NSAID.

All hypoglycemic agents.

Danazol. When used concomitantly, patients should be warned about the need for increased self-monitoring of blood glucose levels. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of danazol.

Metformin.

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly during fasting, malnutrition, or hepatic insufficiency.

Iodine-containing radiographic contrast agents. The medicinal product should be discontinued before or during the procedure and not resumed earlier than 48 hours after the procedure, only after re-evaluation and confirmation of stable renal function (see sections "Special precautions" and "Dosage and administration").

Concomitant use with the following agents should be performed with caution.

All hypoglycemic agents.

Chlorpromazine. Concomitant use of high doses (100 mg chlorpromazine per day) increases blood glucose levels (due to reduced insulin secretion). Patients should be warned and intensified self-monitoring of blood glucose levels is recommended. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of neuroleptics.

Corticosteroids (glucocorticoids), tetracosactide (systemic and local use). Concomitant use increases blood glucose levels, sometimes accompanied by ketosis (due to reduced carbohydrate tolerance). Patients should be warned and intensified monitoring of blood glucose levels is recommended. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of corticosteroids.

β2-agonists. Concomitant use increases blood glucose levels. Patients should be warned and blood glucose monitoring should be intensified; if necessary, patients should be switched to insulin therapy.

Metformin.

NSAIDs, including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics. Concomitant use increases the risk of lactic acidosis (due to the negative impact of these drugs on kidney function). Careful monitoring of renal function is required when starting concomitant therapy with these agents.

Organic cation transporters (OCT).

Metformin is a substrate for both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

inhibitors of OCT1 (e.g., verapamil) – may reduce metformin efficacy;

inducers of OCT1 (e.g., rifampicin) – may increase gastrointestinal absorption and enhance metformin effect;

inhibitors of OCT2 (e.g., cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) – may reduce renal excretion of metformin, leading to increased plasma metformin concentration;

inhibitors of both OCT1 and OCT2 (e.g., crizotinib, olaparib) – may affect metformin efficacy and renal excretion.

Particular caution is required when using the hypoglycemic agent concomitantly with these drugs, especially in patients with impaired renal function, as plasma metformin concentration may increase. Dose adjustment of metformin may be necessary, as OCT inhibitors/inducers may affect metformin efficacy.

Glibenclamide.

β-blockers. These drugs may mask symptoms of hypoglycemia such as palpitations and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemic episodes. Blood glucose monitoring is required during concomitant use, especially at the beginning of treatment.

ACE inhibitors (e.g., captopril, enalapril). Concomitant use reduces blood glucose levels. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of ACE inhibitors.

Fluconazole. Concomitant use prolongs the t1/2 of sulfonylureas, potentially leading to hypoglycemia. Patients should be warned and intensified self-monitoring of blood glucose levels is recommended. If necessary, the dose of the hypoglycemic agent should be adjusted during and after discontinuation of fluconazole.

• Bosentan.* Concomitant use may reduce the hypoglycemic effect of glibenclamide, as bosentan decreases plasma glibenclamide concentrations. There is also a risk of increased liver enzyme levels.

Patients should be warned about the need for monitoring blood glucose and liver enzyme levels. Dose adjustment of the hypoglycemic agent may be required.

• Bile acid sequestrants.* Concomitant use reduces plasma glibenclamide concentrations, potentially reducing its hypoglycemic effect. This effect can be avoided if glibenclamide is taken at least 4 hours before bile acid sequestrants. It is recommended to administer the medicinal product at least 4 hours before taking bile acid sequestrants.

Concomitant use with the following agents should be considered.

Glibenclamide.

Desmopressin. Concomitant use reduces the antidiuretic effect of desmopressin.

Special precautions for use.

Risk of lactic acidosis.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in acute renal impairment, cardiopulmonary disease, or sepsis. Acute renal impairment leads to metformin accumulation, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of the medicinal product is recommended, and medical advice should be sought.

Patients receiving metformin should initiate treatment with caution when using medicinal products that may acutely worsen renal function (e.g., antihypertensive agents, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, any conditions associated with hypoxia, and concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic signs of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

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

Risk of hypoglycemia.

The medicinal product contains glibenclamide (a sulfonylurea derivative), so patients using this product are at risk of developing hypoglycemia. Dose titration of the antidiabetic agent after initiation of treatment may help prevent hypoglycemia. The medicinal product should be administered to patients who follow a regular meal schedule (including breakfast). Regular carbohydrate intake is important, as the risk of hypoglycemia increases with delayed meals, insufficient, or unbalanced carbohydrate intake. Hypoglycemia most commonly occurs in patients on a low-calorie diet, after intense or prolonged physical exercise, with alcohol consumption, or during combination therapy with hypoglycemic agents.

Symptoms of hypoglycemia: headache, hunger, nausea, vomiting, marked fatigue, sleep disturbances, restlessness, episodes of aggression, impaired concentration and reactions, depression, confusion, speech defects, visual disturbances, tremor, paralysis, paresthesia, dizziness, delirium, seizures, drowsiness, unconsciousness, shallow breathing, bradycardia. Due to counter-regulatory responses triggered by hypoglycemia, symptoms such as increased sweating, fear, tachycardia, arterial hypertension, palpitations, angina pectoris, and arrhythmia may also occur. These symptoms may be absent in cases of slowly developing hypoglycemia, autonomic neuropathy, or when taking β-blockers, clonidine, reserpine, guanethidine, or sympathomimetics.

Treatment of hypoglycemia: in cases of moderate hypoglycemia without loss of consciousness or neurological symptoms, sugar should be taken immediately. Dose adjustment of the hypoglycemic agent and/or dietary correction are required. Severe hypoglycemic reactions with coma, seizures, and other neurological signs may occur and can lead to emergency conditions. These require urgent treatment with intravenous glucose administration upon diagnosis or suspicion of hypoglycemia, prior to hospitalization.

Careful patient selection, dose adjustment, and proper patient instructions are crucial for reducing the risk of hypoglycemia. If patients experience recurrent episodes of severe hypoglycemia or episodes associated with unawareness of hypoglycemic symptoms, alternative hypoglycemic treatment options should be considered.

Factors contributing to hypoglycemia:

• concomitant alcohol intake, especially combined with fasting;
• non-compliance (particularly in elderly patients) or inability of patients to follow physician recommendations;
• irregular eating patterns, undernutrition, missed meals, fasting, or dietary changes;
• imbalance between physical activity and carbohydrate intake;
• renal insufficiency;
• severe hepatic insufficiency;
• overdose of the medicinal product;
• certain endocrine disorders: hypothyroidism, hypopituitarism, and adrenal insufficiency;
• concomitant use of certain medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Use in elderly patients.

Age 65 years and older has been identified as a risk factor for hypoglycemia in patients taking sulfonylurea agents. Hypoglycemia symptoms may be difficult to recognize in elderly patients.

To reduce the risk of hypoglycemia, careful adjustment of the initial and maintenance dose of the hypoglycemic agent is required (see section "Method of administration and dosage").

Use in patients with renal or hepatic impairment.

The pharmacokinetics and/or pharmacodynamics of the medicinal product may be altered in such patients. If hypoglycemia occurs in this patient group, it may become chronic and require appropriate treatment.

Patients and their families should be informed about the risk of hypoglycemia, its symptoms and treatment, and contributing factors. The risk of lactic acidosis should also be considered in the presence of nonspecific symptoms such as muscle cramps, gastrointestinal disturbances, abdominal pain, severe asthenia, acidotic dysparena, hypothermia, or coma.

Patients should be specifically informed about the importance of adhering to dietary recommendations, regular physical exercise, and blood glucose monitoring.

Risk of blood glucose imbalance.

In cases of surgical procedures or other causes of diabetes decompensation, temporary insulin therapy should be considered. Symptoms of hyperglycemia include increased urination, intense thirst, and dry skin.

Effect on kidneys.

eGFR should be assessed before initiating treatment and regularly during therapy (see section "Method of administration and dosage"). The medicinal product is contraindicated in patients with eGFR <30 mL/min and should be temporarily discontinued in the presence of conditions altering renal function (see section "Contraindications"). In such cases, renal function should also be evaluated before initiating treatment.

Effect on the heart.

Patients with heart failure have an increased risk of hypoxia and renal insufficiency. Patients with stable chronic heart failure may use the medicinal product provided cardiac and renal function are regularly monitored.

The medicinal product is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Risk of decreased plasma vitamin B12 levels.

Metformin may reduce vitamin B12 levels, potentially leading to deficiency. The risk of vitamin B12 deficiency increases with higher metformin doses, longer treatment duration, and in patients with risk factors for vitamin B12 deficiency. In suspected deficiency (e.g., in patients with megaloblastic anemia or newly developed neuropathy), plasma vitamin B12 levels should be checked, and current clinical guidelines for testing and treating vitamin B12 deficiency should be followed. Patients with risk factors for vitamin B12 deficiency should undergo periodic monitoring of vitamin B12 levels. Metformin therapy should continue as long as it is well tolerated and not contraindicated, with corrective treatment for vitamin B12 deficiency administered according to current clinical guidelines.

Concomitant administration of iodine-containing contrast agents.

Intravascular administration of iodine-containing contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. The medicinal product should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, only after re-evaluation and confirmation of stable renal function (see sections "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

Concomitant use with other medicinal products.

The medicinal product is not recommended to be used concomitantly with alcohol, phenylbutazone, or danazol (see section "Interaction with other medicinal products and other forms of interaction").

Use during surgical procedures.

The medicinal product should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and not resumed earlier than 48 hours after surgery or restoration of oral feeding, only after re-evaluation and confirmation of stable renal function.

Use in patients with glucose-6-phosphate dehydrogenase deficiency.

Due to the presence of glibenclamide, treatment of such patients may lead to hemolytic anemia. The medicinal product should be used with particular caution in patients with glucose-6-phosphate dehydrogenase deficiency, and switching to alternative non-sulfonylurea agents should be considered.

Precautionary measures.

Patients should follow a diet and properly distribute carbohydrate intake throughout the day. Patients with excess body weight should adhere to a low-calorie diet.

Regular physical exercise should be performed during treatment. Laboratory parameters (blood glucose and glycated hemoglobin – HbA1c) should be monitored regularly.

Precautions regarding excipients.

The 500 mg/5 mg dosage form contains aluminium lake of tartrazine (E 102) and aluminium lake of yellow FCF (E 110), which may cause allergic reactions.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical and preclinical data on the use of the glibenclamide/metformin combination during pregnancy are lacking.

Risk associated with diabetes.

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

Risk associated with metformin.

Preclinical studies have not shown adverse effects on pregnancy, embryonal or fetal development, parturition, or postnatal development. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital anomalies.

Risk associated with glibenclamide.

Glibenclamide is contraindicated during pregnancy. Preclinical studies have not shown teratogenic effects. In the absence of teratogenicity in animals, fetal malformations in humans are not expected, as substances causing developmental defects in humans typically show teratogenic effects in two animal species. In clinical practice, there are no adequate data to assess potential fetal malformations or fetotoxicity associated with glibenclamide use during pregnancy.

Treatment.

Adequate blood glucose control supports normal pregnancy progression in these patients. The medicinal product should not be used during pregnancy. In cases of planned pregnancy or if pregnancy occurs, transition from oral hypoglycemic therapy to insulin therapy is recommended to maintain blood glucose levels as close to normal as possible. Blood glucose monitoring in the newborn is recommended.

Breastfeeding period.

Metformin passes into human breast milk, but adverse reactions have not been observed in newborns/infants breastfed by mothers on metformin monotherapy. However, due to lack of data on glibenclamide excretion into human breast milk and the risk of hypoglycemia in the newborn, the medicinal product is contraindicated during breastfeeding.

Fertility.

Metformin did not affect fertility in animals at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area. Glibenclamide did not affect fertility in animals following oral administration at doses of 100 and 300 mg/kg/day.

Ability to affect reaction speed when driving or operating machinery.

Patients should exercise particular caution when driving or operating machinery during treatment due to the risk of hypoglycemic symptoms.

Method of Administration and Dosage

The medicinal product is intended for oral use in adult patients.

As with other hypoglycemic agents, the dosage of the medicinal product should be individually adjusted based on individual metabolic response (glycemia levels and HbA1c).

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

The medicinal product in the dosage strength of 500 mg/5 mg is recommended for patients in whom adequate glycemic control is not achieved with lower doses.

When switching from combination therapy with metformin and glibenclamide, initiate treatment with the medicinal product at doses corresponding to the previous dosage regimen. The dose should be gradually increased according to glycemia measurements.

Dosage adjustments (increasing the dose by 1 tablet) should be made every 2 weeks or more after initiation of therapy, depending on glycemia levels.

Gradual dose escalation helps reduce gastrointestinal adverse reactions and prevents the development of hypoglycemia.

The maximum recommended daily dose is 6 tablets of the medicinal product in the 500 mg/2.5 mg strength and 3 tablets in the 500 mg/5 mg strength.

In individual cases, the dose may be increased up to 4 tablets per day of the medicinal product in the 500 mg/5 mg strength.

There are no data on concomitant therapy with insulin.

The dosing regimen should be individually tailored according to clinical indications:

• 1 time daily: 1 tablet daily with breakfast;
• 2 times daily: 2 or 4 tablets daily in the morning and evening;
• 3 times daily: 3, 5, or 6 tablets daily in the morning, afternoon, and evening.

The tablets should be taken with meals.

The dosing schedule may be adjusted according to individual meal patterns. However, to prevent hypoglycemic episodes, it is necessary to consume carbohydrate-rich food after each administration of the medicinal product.

When co-administered with bile acid sequestrants, it is recommended to take the medicinal product at least 4 hours before bile acid sequestrants to minimize the risk of reduced absorption (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Patients with renal impairment.

Renal function (eGFR) should be assessed before initiating treatment and at least annually thereafter. Patients at increased risk of progressive renal impairment, as well as elderly patients, should undergo more frequent monitoring of renal function, for example every 3–6 months. The maximum daily dose should be divided into 2–3 daily doses.

Prior to initiating treatment in patients with eGFR <60 mL/min, consider factors that may increase the risk of lactic acidosis (see section "Special Warnings and Precautions for Use").

If the medicinal product is not available in the required dosage strength, individual monocomponents should be used instead of the fixed-dose combination product.

eGFR (mL/min)	Metformin	Glibenclamide
60-89	Maximum daily dose – 3000 mg. In case of renal function decline, dose reduction should be considered.	No dose reduction required.
45-59	Maximum daily dose – 2000 mg. Initial dose should not exceed half of the maximum dose.	Maximum daily dose – 10.5 mg.
30-44	Maximum daily dose – 1000 mg. Initial dose should not exceed half of the maximum dose.	Maximum daily dose – 10.5 mg. Use of glibenclamide is not recommended due to risk of hypoglycemia.
< 30	Combination of glibenclamide with metformin is contraindicated.

Elderly patients

Dosage of the medicinal product should be adjusted according to renal function parameters (initial dose – 1 tablet of 500 mg/2.5 mg). Renal function should be regularly assessed (see section "Special instructions").

To reduce the risk of developing hypoglycemia, careful adjustment of the initial and maintenance dose of glibenclamide is required (see section "Dosage and administration"). Treatment should be initiated with the minimum dose, gradually increasing the dose if necessary (see section "Special instructions").

Children

The medicinal product is not recommended for use in children.

Overdose

Overdose may lead to the development of hypoglycemia, as the medicinal product contains a sulfonylurea (see section "Special instructions"). Significant overdose of metformin or presence of concomitant risk factors may lead to the development of lactic acidosis (see section "Special instructions"). Lactic acidosis is a medical emergency requiring hospital treatment. The most effective method for removing 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 effectively removed by hemodialysis.

Adverse Reactions.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously in most cases. To prevent the occurrence of these adverse reactions, a gradual increase in dosage is recommended, as well as administration of the daily dose in 2–3 divided doses. Transient visual disturbances may occur at the beginning of treatment due to decreased glycemia.

Frequency of adverse reactions: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000).

Blood and lymphatic system disorders:

Rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, hemolytic anemia, bone marrow aplasia, pancytopenia.

Reactions are reversible and disappear after discontinuation of treatment.

Metabolism and nutrition disorders:

Common – vitamin B12 deficiency/low levels (see section "Special precautions"); uncommon – acute hepatic porphyria, skin porphyria; very rare – lactic acidosis (see section "Special precautions").

Hypoglycemia may occur (see section "Special precautions").

Disulfiram-like reaction may occur with alcohol consumption.

Nervous system disorders:

Common – taste disturbances.

Eye disorders:

Transient visual disturbances may occur at the beginning of treatment due to decreased glycemia.

Gastrointestinal disorders:

Very common – gastrointestinal disturbances, including nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse reactions most frequently occur at the beginning of treatment and usually resolve spontaneously. To prevent gastrointestinal adverse reactions, a gradual increase in dosage and administration of the drug 2–3 times daily are recommended.

Skin and subcutaneous tissue disorders:

Rare – skin reactions, including pruritus, urticaria, maculopapular rash; very rare – cutaneous or visceral allergic vasculitis, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitization, urticaria leading to shock, erythema.

Cross-reactivity to sulfonamides or their derivatives may occur.

Hepatobiliary disorders:

Very rare – liver function abnormalities or hepatitis requiring discontinuation of treatment.

Investigations:

Uncommon – moderate increase in plasma urea and creatinine levels; very rare – hyponatremia.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

15 tablets per blister; 2 or 4 blisters per cardboard box, or 20 tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.Ш./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

LLC «UORLД MEDICIN», Ukraine /
WORLD MEDICINE, LLC, Ukraine.