GLUCOVANCE®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLUCOVANCE® (GLUCOVANCE®)

Composition:

Active substances:

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

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

Film coating: Opadry OY-L-24808: lactose monohydrate; hypromellose 15 cP; titanium dioxide (E 171); polyethylene glycol; iron oxide yellow (E 172); iron oxide red (E 172); iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated, biconvex, light orange-colored film-coated tablets with "2.5" 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

Metformin is a biguanide with an antihyperglycemic effect. It reduces glucose levels in blood plasma both in the 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 muscles, leading to enhanced peripheral glucose uptake and utilization;
• delays intestinal glucose absorption.

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

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

To date, clinical studies have not demonstrated this beneficial effect on lipid metabolism during concomitant 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 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 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 the pancreas to secrete insulin, while metformin reduces cellular resistance to insulin, thereby increasing insulin sensitivity in peripheral tissues (skeletal muscles) and liver tissue.

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 show that combination therapy has a comprehensive effect on glucose regulation.

Children
In a 26-week, actively controlled, double-blind clinical trial involving 167 patients aged 9 to 16 years with type 2 diabetes who did not achieve adequate control with diet and exercise, with or without oral hypoglycemic therapy, fixed-dose combination therapy of metformin hydrochloride 250 mg and glibenclamide 1.25 mg did not demonstrate greater efficacy in reducing glycated hemoglobin (HbA1c) levels from baseline. Therefore, Glucovance® should not be used in pediatric patients.

Pharmacokinetics

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 not affected by food intake. The bioavailability of glibenclamide in combination is also not affected by food intake; however, the rate of glibenclamide absorption increases with food.

Absorption
After oral administration, the Cmax (maximum plasma concentration) of metformin is reached at approximately 2.5 hours (tmax – time to reach maximum concentration). The absolute bioavailability of 500 mg or 850 mg metformin tablets is approximately 50–60% in healthy volunteers. After oral administration, 20–30% of unabsorbed metformin is excreted in feces.

Following oral administration, metformin absorption is saturable and incomplete. The absorption pharmacokinetics of metformin are presumed to be nonlinear. With 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, maximum plasma metformin levels (Cmax) did not exceed 5 µg/mL, even with maximum doses.

Distribution
Plasma protein binding is negligible. Metformin penetrates into erythrocytes. The maximum concentration in blood 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 from 63 to 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 that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased plasma metformin levels.

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

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

Metabolism
Glibenclamide is completely metabolized in the liver, forming two metabolites. Hepatic insufficiency 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. The terminal elimination half-life is 4–11 hours.

Biliary excretion of metabolites increases in patients with renal insufficiency, depending on the degree of renal impairment, when creatinine clearance is below 30 mL/min. When creatinine clearance exceeds 30 mL/min, renal insufficiency does not affect glibenclamide elimination.

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

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, to other components of the medicinal product, to other sulfonylurea drugs, or to sulfonamides;
• type 1 diabetes mellitus (insulin-dependent diabetes), diabetic precoma;
• any type of acute metabolic acidosis (e.g. lactic acidosis, 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;
• diseases that may cause tissue hypoxia (including 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 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.

Interactions contraindicated

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

Interactions not recommended

• Alcohol – disulfiram-like reaction (alcohol intolerance), especially with chlorpropamide, glibenclamide, glipizide, tolbutamide. Increased risk of hypoglycemic reactions (due to inhibition of compensatory responses) may lead to hypoglycemic coma (see section "Special precautions for use"). Consumption of alcohol and medicinal products containing alcohol should be avoided.
• Phenylbutazone (systemic use): enhanced hypoglycemic effect of sulfonylurea derivatives (by displacing their protein binding and/or reducing their elimination). It is recommended to use alternative nonsteroidal anti-inflammatory drugs or to warn the patient and emphasize the importance of self-monitoring of blood glucose. If necessary, the dose of the antidiabetic drug should be adjusted during and after discontinuation of anti-inflammatory agents.

• Danazol: if this combination is unavoidable, the patient should be warned about the need for increased self-monitoring of blood glucose levels. The dose of the antidiabetic agent should be adjusted during and after danazol treatment, if necessary.

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

• Iodinated* contrast media. 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 "Dosage and administration" and "Special precautions for use").

Combinations that should be used with caution.

• Chlorpromazine: when administered in high doses (100 mg chlorpromazine daily), increases blood glucose levels (reduces insulin production). The patient should be warned and self-monitoring of blood glucose levels intensified. If necessary, the dose of the antidiabetic agent should be adjusted during and after treatment with neuroleptics.
• Corticosteroids (glucocorticoids) and tetracosactide (systemic and local use): increased blood glucose levels, sometimes accompanied by ketosis (reduced carbohydrate tolerance). The patient should be warned and self-monitoring of blood glucose levels intensified. If necessary, the dose of the antidiabetic agent should be adjusted during and after corticosteroid therapy.
• β2-agonists: increased blood glucose levels. The patient should be warned and blood glucose monitoring intensified; if necessary, the patient should be switched to insulin therapy.

Certain medicinal products, such as nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics, may adversely affect renal function, thereby increasing the risk of lactic acidosis. At the start of treatment with these medicinal products or when used in combination with metformin, careful monitoring of renal function is required.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (e.g. verapamil) may reduce metformin efficacy;
• OCT1 inducers (e.g. rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• OCT2 inhibitors (e.g. cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformine, leading to increased plasma concentrations of metformin;
• dual inhibitors of OCT1 and OCT2 (e.g. crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

Therefore, particular caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as plasma concentrations of metformin may increase. Dose adjustment of metformin should be considered if necessary, since OCT inhibitors/inducers may affect metformin efficacy.

• β-blockers may mask certain symptoms of hypoglycemia, such as palpitations and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemic episodes. The patient should monitor blood glucose levels, especially at the beginning of treatment.

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

• Fluconazole: prolonged half-life of sulfonylureas with possible hypoglycemic manifestations. The patient should be warned and self-monitoring of blood glucose levels intensified. The dose of the medicinal product should be adjusted during and after fluconazole treatment, if necessary.
• Bosentan: risk of reduced hypoglycemic effect of glibenclamide, as bosentan decreases plasma concentrations of glibenclamide. Concomitant use may also increase liver enzyme levels.

The patient should be warned about the need for monitoring blood glucose and liver enzyme levels. Dose adjustment of the medicinal product may be necessary.

• Bile acid sequestrants: when used concomitantly, plasma concentrations of glibenclamide are reduced, potentially leading to decreased hypoglycemic effect. This effect can be avoided by administering glibenclamide at least 4 hours before the bile acid sequestrant. It is recommended to administer Glucovance® at least 4 hours before bile acid sequestrants.

Interactions to be considered.

• Desmopressin: reduced antidiuretic effect.

Special precautions for use.

Lactic acidosis
is a very rare but serious metabolic complication, most commonly occurring in the setting of acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute worsening of renal function 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 metformin is recommended, and medical advice should be sought.

Patients receiving metformin should initiate treatment cautiously with agents that may acutely impair renal function (e.g., antihypertensive drugs, 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 acid游戏副本. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin immediately and seek urgent medical attention.

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

Patients with confirmed or suspected mitochondrial disorders.
Metformin is not recommended in patients with confirmed mitochondrial disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome) or mitochondrial inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the course of the disease.

If signs or symptoms suggestive of MELAS or MIDD occur after initiating metformin, treatment with metformin should be discontinued immediately, and rapid diagnostic evaluation should be performed.

Hypoglycemia.
Glucovance® contains a sulfonylurea, and therefore patients taking this medicinal product are at risk of developing hypoglycemia. Dose titration after initiation of therapy may help prevent hypoglycemia. The drug should be prescribed to patients who maintain 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 other hypoglycemic agents.

Diagnosis.
Symptoms of hypoglycemia include headache, hunger, nausea, vomiting, marked fatigue, sleep disturbances, restlessness, aggressive outbursts, impaired concentration and reaction, depression, confusion, speech defects, visual disturbances, tremor, paralysis, paresthesia, dizziness, delirium, seizures, somnolence, loss of consciousness, shallow breathing, bradycardia. Due to counter-regulatory responses triggered by hypoglycemia, symptoms such as sweating, anxiety, tachycardia, hypertension, palpitations, angina, and arrhythmias may also occur. These symptoms may be absent in cases of slowly developing hypoglycemia, autonomic neuropathy, or when patients are taking β-blockers, clonidine, reserpine, guanethidine, or sympathomimetics.

Treatment of hypoglycemia.
In cases of moderate hypoglycemia without loss of consciousness or neurological symptoms, immediate intake of sugar is required. Dose adjustment of the medicinal product and/or dietary modification should be ensured. Severe hypoglycemic reactions, including coma, seizures, and other neurological signs, may occur and require emergency treatment with intravenous glucose upon diagnosis or suspicion of hypoglycemia, followed by hospitalization.

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

Factors predisposing to hypoglycemia:

• Concomitant alcohol intake, especially combined with fasting,
• Inability (particularly in elderly patients) or refusal of patients to follow medical advice,
• Irregular meal intake, undernutrition, missed meals, fasting, or dietary changes,
• Inadequate balance between physical activity and carbohydrate intake,
• Renal insufficiency,
• Severe hepatic insufficiency,
• Overdose of Glucovance®,

• certain endocrine disorders: hypothyroidism, hypopituitarism, and adrenal insufficiency,

• Concomitant use of certain drugs (see section "Interaction with other medicinal products and other forms of interaction").

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

To reduce the risk of hypoglycemia, careful adjustment of initial and maintenance doses of glyburide is required (see section "Dosage and administration").

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

Patients and their families should be informed about the risk of hypoglycemia, its symptoms, treatment, and predisposing 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 dyspnea, hypothermia, and coma.

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

Imbalance of blood glucose levels.
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.

Renal function.
eGFR should be assessed before initiating treatment and regularly thereafter (see section "Dosage and administration"). Metformin is contraindicated in patients with eGFR < 30 mL/min and should be temporarily discontinued in the presence of conditions affecting renal function (see section "Contraindications").

In such cases, renal function should also be evaluated before initiating metformin therapy.

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

Glucovance® is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

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

Concomitant use of glyburide with other medicinal products.
Concomitant use of glyburide with alcohol, phenylbutazone, or danazol is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

Precautions.
Patients must follow a diet with proper distribution of carbohydrate intake throughout the day. Patients with excess body weight should adhere to a low-calorie diet.

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

Metformin may reduce serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and/or presence of patient risk factors known to cause vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin treatment should be continued as long as it is tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency provided according to current clinical guidelines.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency using sulfonylureas may lead to hemolytic anemia. Since glyburide belongs to this class, Glucovance® should be used with particular caution in patients with glucose-6-phosphate dehydrogenase deficiency, and consideration should be given to switching to alternative non-sulfonylurea therapies.

The use of this medicinal product is contraindicated in patients with congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency, as the product contains lactose.

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

Use during pregnancy or breastfeeding.

Pregnancy.
Clinical and preclinical data on the use of Glucovance® during pregnancy are lacking.

Diabetes-related risk.
Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital malformations and perinatal mortality. Glycemic control should be optimized before conception to reduce the risk of congenital anomalies.

Metformin-related risk.
Preclinical studies have not shown any adverse effects on pregnancy, embryonic or fetal development, parturition, or postnatal development. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital malformations.

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

Treatment.
Adequate blood glucose control supports normal pregnancy progression in these patients. Glucovance® should not be used for the treatment of diabetes during pregnancy.

In cases of planned pregnancy or confirmed pregnancy, 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.
Metformin is excreted in human breast milk, but no adverse effects have been observed in newborns/infants breastfed by mothers receiving metformin monotherapy. However, due to lack of data on glyburide excretion in human breast milk and the risk of hypoglycemia in the newborn, the drug 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. Glyburide did not affect fertility in animals when administered orally at doses of 100 and 300 mg/kg/day.

Ability to influence the ability to drive and use machines.
Patients should exercise particular caution when driving or operating machinery due to the risk of hypoglycemic symptoms.

Dosage and Administration

Oral use. For adult patients only.

As with other hypoglycemic agents, the dose of Glucovance® should be individually adjusted based on the patient's metabolic response (blood glucose and HbA1c levels).

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

When switching from combination therapy with metformin and glibenclamide to Glucovance®, initiate treatment with a dose corresponding to the previous regimen. The dose should be gradually increased according to blood glucose monitoring results.

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

Gradual dose escalation helps reduce gastrointestinal side effects and prevents the development of hypoglycemia.

The maximum recommended dose is 6 tablets of Glucovance® 500 mg/2.5 mg per day.

There are no data available on concomitant use of Glucovance® with insulin.

Dosing regimen depends on individual requirements:

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

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 meals after each dose of the drug.

When used concomitantly with bile acid sequestrants, Glucovance® should be taken 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").

Renal impairment.

eGFR should be assessed before initiating therapy with metformin-containing medicinal products and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should have their renal function monitored more frequently, e.g., every 3–6 months. The maximum daily dose of metformin should be divided into 2–3 doses.

Before initiating metformin 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 required strength of the fixed-dose combination is unavailable, individual monocomponents should be used instead of the fixed-dose combination product.

In elderly patients
The dosage of the drug should be adjusted according to renal function parameters (initial dose – 1 tablet of Glucovance® 500 mg/2.5 mg). Renal function should be regularly assessed (see section "Special precautions").

Elderly patients (aged 65 years and older).
To reduce the risk of hypoglycaemia, careful adjustment of the initial and maintenance dose of glyburide is required. Treatment with the drug should be initiated at the lowest dose, gradually increasing the dose if necessary (see section "Special precautions").

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

Overdose.

Overdose may lead to the development of hypoglycaemia, as the drug contains a sulfonylurea (see section "Special precautions"). Significant overdose of metformin or the presence of concomitant risk factors may lead to the development of lactic acidosis (see section "Special precautions"). Lactic acidosis is a medical emergency requiring hospitalization. Hemodialysis is the most effective method for removing lactate and metformin from the body.

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

Due to its high protein binding, glyburide 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 effects, a gradual increase in dosage and administration of the daily dose in 2–3 divided doses are recommended. Transient visual disturbances may occur at the beginning of treatment due to a reduction in blood glucose levels.

The following adverse reactions have been reported during the use of Glucovance®. Undesirable effects are classified by frequency of occurrence as follows: 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).

Blood and lymphatic system disorders

Reversible reactions that resolve after discontinuation of treatment.

Rare: leukopenia, thrombocytopenia.

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

Metabolism and nutrition disorders

Hypoglycemia (see section "Special precautions").

Common: vitamin B12 deficiency/low levels (see section "Special precautions").

Uncommon: acute hepatic porphyria, cutaneous porphyria.

Very rare: lactic acidosis (see section "Special precautions").

Disulfiram-like reaction when alcohol is consumed.

Nervous system disorders

Common: taste disturbances.

Eye disorders

Transient visual disturbances may occur at the beginning of treatment due to a reduction in blood glucose levels.

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

Cross-reactivity to sulfonamides or their derivatives.

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

Very rare: cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitization, urticaria leading to shock, erythema.

Hepatobiliary disorders

Very rare: abnormal liver function tests or hepatitis requiring discontinuation of treatment.

Investigations

Uncommon: mild increases in serum urea and creatinine levels.

Very rare: hyponatremia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life.
3 years.

Storage conditions.
No special storage conditions required. Keep out of reach and sight of children.

Packaging.
15 tablets in a blister; 2 blisters per cardboard box.

20 tablets in a blister; 3 blisters per cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Merck Sante, France.

Manufacturer's address and place of business.
2 rue du Pressoir Vert, 45400 Semoy, France.