Glibofor

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLIBOFOR® (GLIBOFOR)

Composition:

Active substances: metformin, glibenclamide;

One tablet contains metformin hydrochloride 500 mg, glibenclamide 5 mg;

Excipients: sodium starch glycolate (type A), povidone (K-30), colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating composition: Opadry Yellow 04G82949 (hypromellose, talc, titanium dioxide (E 171), polyethylene glycol 6000, propylene glycol, yellow iron oxide (E 172), D&C Yellow #10 Aluminium Lake).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, oblong-shaped, biconvex film-coated tablets with the inscription "U 24" 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 plasma glucose levels both in the fasting state and after food intake. It does not stimulate insulin secretion and does not cause hypoglycemia via this mechanism.

Metformin acts through three pathways:

• It reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• It improves insulin sensitivity in muscle tissue, leading to enhanced peripheral glucose uptake and utilization;
• It delays glucose absorption in the intestine.

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 exerts a positive effect on lipid metabolism. This effect has been demonstrated in controlled medium- to 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 an additive beneficial effect on lipid metabolism when metformin is used concomitantly with 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 is dependent on the presence of functioning beta-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, demonstrated that combination therapy provides 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 prior oral hypoglycemic therapy, fixed-dose combination therapy with metformin hydrochloride 250 mg and glibenclamide 1.25 mg did not show greater efficacy in reducing glycated hemoglobin (HbA1c) from baseline. Therefore, Glucophage® should not be used in children.

Pharmacokinetics

Regarding the combination.

The bioavailability of metformin and glibenclamide in combination is equivalent to that observed 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; however, the rate of glibenclamide absorption increases with food.

Regarding metformin.

Absorption. After oral administration of metformin, Cmax (maximum plasma concentration) is reached at approximately 2.5 hours (tmax). 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 pharmacokinetics of metformin absorption are considered nonlinear. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 mcg/mL. In controlled clinical trials, maximum plasma metformin levels (Cmax) did not exceed 5 mcg/mL, even with maximum doses.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. 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.

Excretion. 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.

Regarding glibenclamide.

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 medicinal products.

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

Excretion. Glibenclamide is excreted in the form of metabolites via bile (60%) and urine (40%). It is completely eliminated within 45–72 hours. The terminal elimination half-life 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 below 30 mL/min. Therefore, if creatinine clearance is greater than 30 mL/min, renal impairment does not significantly affect glibenclamide elimination.

Children. The pharmacokinetics of glibenclamide and metformin in children are not different from those in healthy adult volunteers of similar 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, to other components of the medicinal product or 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 or respiratory failure, recent myocardial infarction, shock;
• hepatic impairment, acute alcohol intoxication, alcoholism;
• porphyria;
• pregnancy and lactation;
• concomitant therapy with miconazole (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Interactions contraindicated.

Regarding glibenclamide.

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

Combinations not recommended.

Regarding sulfonylurea drugs.

• Alcohol — disulfiram-like reaction (alcohol intolerance), especially when combined with chlorpropamide, glibenclamide, glipizide, or tolbutamide. Increased risk of hypoglycemic reactions (due to inhibition of compensatory responses), which may lead to hypoglycemic coma (see section "Special precautions for use"). Consumption of alcohol and medicinal products containing alcohol should be avoided.
• Phenylbutazone (for systemic use): enhanced hypoglycemic effect of sulfonylurea derivatives (due to displacement from plasma protein binding and/or reduced elimination). Alternative nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended, or patients should be warned about the risks, emphasizing 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.

Regarding antidiabetic drugs in general.

• Danazol: if this combination is unavoidable, patients should be informed about the importance of intensified self-monitoring of blood glucose levels. If necessary, the dose of the antidiabetic drug should be adjusted during and after danazol treatment.

Regarding metformin.

• Alcohol: alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition, or hepatic impairment.
• Iodinated contrast agents: patients should discontinue the medicinal product before or during procedures involving iodinated contrast agents and resume only no earlier than 48 hours after the procedure and 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.

Regarding antidiabetic drugs in general.

• Chlorpromazine: when administered in high doses (100 mg chlorpromazine per day) — increased blood glucose levels (reduced insulin secretion). Patients should be advised to intensify self-monitoring of blood glucose levels. If necessary, the dose of the antidiabetic drug should be adjusted during and after discontinuation of neuroleptics.
• Corticosteroids (glucocorticoids) and tetracosactide (systemic and local use): increased blood glucose levels, sometimes accompanied by ketosis (reduced carbohydrate tolerance). Patients should be advised to intensify self-monitoring of blood glucose levels. If necessary, the dose of the antidiabetic drug should be adjusted during and after corticosteroid therapy.
• β2-agonists: increased blood glucose levels. Patients should be advised to intensify blood glucose monitoring; if necessary, patients should be switched to insulin therapy.

Regarding metformin.

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, particularly loop diuretics, may adversely affect renal function, increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products, especially in combination with metformin.

• Organic cation transporters (OCT).

Metformin is a substrate for both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (e.g. verapamil) may reduce the efficacy of metformin;
• 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 elimination of metformin, leading to increased plasma concentrations of metformin;
• inhibitors of both OCT1 and OCT2 transporters (e.g. crizotinib, olaparib) may affect the efficacy and renal elimination of metformin.

Therefore, particular caution is recommended when co-administering these drugs with metformin, especially in patients with impaired renal function, as plasma concentrations of metformin may increase. Dose adjustment of metformin may be required, as OCT inhibitors/inducers may influence the efficacy of metformin.

Regarding glibenclamide.

• β-blockers may mask certain symptoms of hypoglycemia, such as palpitations and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemia. Patients should monitor blood glucose levels, especially at the beginning of treatment.
• ACE inhibitors (e.g. captopril, enalapril): reduced blood glucose levels. If necessary, the dose of GliboFor® should be adjusted during and after discontinuation of ACE inhibitors.
• Fluconazole: prolonged half-life of sulfonylureas with possible hypoglycemic manifestations. Patients should be advised to intensify self-monitoring of blood glucose levels. If necessary, the dose of the medicinal product should be adjusted during and after fluconazole treatment.
• Bosentan: risk of reduced hypoglycemic effect of glibenclamide, as bosentan decreases plasma concentrations of glibenclamide. Concomitant use may also increase the risk of elevated liver enzymes.

Patients should be informed about the need for monitoring blood glucose levels and liver enzyme levels. If necessary, dosage adjustment of the medicinal product should be considered.

• Bile acid sequestrants: when used concomitantly, plasma concentrations of glibenclamide are reduced, potentially leading to decreased hypoglycemic effect. This effect is avoided if glibenclamide is administered sufficiently before the other medicinal product. It is recommended to administer GliboFor® at least 4 hours before bile acid sequestrants.

Interactions to be considered.

Regarding glibenclamide.

• Desmopressin: reduced antidiuretic effect.

Special precautions for use.

Lactic acidosis. Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in 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 help should be sought.

Patients receiving metformin should initiate treatment cautiously with agents that may acutely worsen renal function (e.g., antihypertensive drugs, diuretics, and NSAIDs).

Other risk factors contributing to lactic acidosis should be considered to prevent its development: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency, or any condition associated with hypoxia, as well as 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 their 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, followed by possible development of coma. If any symptoms of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

Laboratory diagnostic features of this complication include: decreased blood pH (< 7.35), plasma lactate level above 5 mmol/L, increased anion gap, and elevated lactate/pyruvate ratio.

Hypoglycemia. Glucobor® contains a sulfonylurea, 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 adhere to a regular meal schedule (including breakfast). Regular carbohydrate intake is important, as the risk of hypoglycemia increases with delayed meals, insufficient or unbalanced carbohydrate consumption. Hypoglycemia most commonly occurs in patients on a low-calorie diet, after intense or prolonged exercise, with alcohol consumption, or during combination therapy with hypoglycemic agents.

Diagnosis. Symptoms of hypoglycemia: headache, hunger sensation, 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 sweating, fear, tachycardia, arterial hypertension, palpitations, angina pectoris, and arrhythmia may 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 drug and/or dietary correction should be ensured. Severe hypoglycemic reactions with coma, seizures, and other neurological signs may occur, potentially leading to emergency conditions. This requires urgent treatment with intravenous glucose administration upon diagnosis or suspicion of hypoglycemia, prior to patient 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,
• refusal (particularly in elderly patients) or inability of patients to follow physician recommendations,
• irregular meal intake, undernutrition, skipped meals, fasting, or dietary changes,
• inadequate balance between physical activity and carbohydrate intake,
• renal insufficiency,
• severe hepatic insufficiency,
• overdose of Glucobor®,

• certain endocrine disorders: thyroid gland dysfunction, 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 glibenclamide is required (see section "Dosage and administration").

Renal and hepatic insufficiency in patients may alter the pharmacokinetics and/or pharmacodynamics of Glucobor®. 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 and treatment, as well as 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.

In particular, patients should be informed about the importance of adhering to a proper diet, regular physical exercise, and blood glucose monitoring.

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

Renal function. eGFR should be assessed before starting 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 conditions altering renal function (see section "Contraindications"). In such cases, renal function should also be checked before restarting metformin therapy.

Cardiac function. Patients with heart failure have a higher risk of developing hypoxia and renal insufficiency. Patients with stable chronic heart failure may receive metformin with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section "Contraindications").

Iodinated contrast media. Intravenous administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Patients should discontinue metformin before or during such procedures and restart no 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 glibenclamide with other medicinal products. Concomitant intake of glibenclamide with alcohol, phenylbutazone, or danazol is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Surgical interventions. The drug should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia, and restarted no earlier than 48 hours after surgery or restoration of oral nutrition, only after re-evaluation and confirmation of stable renal function.

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

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

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and/or presence of patient factors predisposing to vitamin B12 deficiency. In case of suspected vitamin B12 deficiency (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and no contraindications exist, 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 glibenclamide belongs to this class, Glucobor® should be used with particular caution in patients with glucose-6-phosphate dehydrogenase deficiency, and consideration should be given to switching to alternative therapies not belonging to sulfonylureas.

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

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

Use during pregnancy or breastfeeding.

Pregnancy. Preclinical and clinical data on the use of Glucobor® during pregnancy are lacking.

Diabetes-related risk. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. Diabetes control at conception is necessary to reduce the risk of congenital anomalies.

Metformin-related risk. Preclinical studies did not reveal adverse effects on pregnancy, embryonic or fetal development, delivery, or postnatal development. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital anomalies.

Glibenclamide-related risk. Glibenclamide is contraindicated during pregnancy. Preclinical studies did not reveal teratogenic effects. In the absence of teratogenic effects in animals, fetal malformations in humans are not expected, as substances causing developmental defects in humans typically show teratogenic effects in two animal species during testing. In clinical practice, data sufficient to assess potential malformations or fetotoxicity associated with glibenclamide use during pregnancy are lacking.

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

In case 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. Metformin passes into human breast milk, but adverse effects have not been observed in newborns/infants breastfed by mothers receiving metformin monotherapy. However, due to lack of data on glibenclamide passage into 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. Glibenclamide did not affect fertility in animals upon oral administration at doses of 100 and 300 mg/kg/day.

Ability to influence reaction speed when driving or operating machinery.

Patients should exercise particular caution when driving or operating machinery due to the risk of developing hypoglycemia symptoms.

Method of Administration and Dosage

Oral use. For adult patients only.

As with other hypoglycemic agents, the dose of Glifor® should be individually adjusted according to individual metabolic response (blood glucose and HbA1c levels).

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

Glifor® 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, treatment with Glifor® should be initiated at doses corresponding to the previous regimen. The dose should be gradually increased based on blood glucose measurements.

Dosage adjustment (increasing by 1 tablet) should be performed every 2 weeks or longer after initiation of 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 3 tablets of Glifor® 500 mg/5 mg per day.

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

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

The dosing regimen should be individualized according to clinical requirements:

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

Tablets should be taken with meals.

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

When co-administered with bile acid sequestrants, Glifor® 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").

Patients with renal impairment. eGFR should be assessed before initiating therapy with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of progressive renal impairment and in elderly patients, renal function should be closely monitored as frequently as 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, factors that may increase the risk of lactic acidosis should be carefully evaluated (see section "Special Warnings and Precautions for Use").

If the fixed-dose combination product Glifor® does not meet the patient's therapeutic needs, individual monocomponent agents should be used instead of the fixed-dose combination.

In elderly patients, the dosage of the drug should be adjusted according to renal function parameters (initial dose — 1 tablet of metformin/glibenclamide 500 mg / 2.5 mg). Renal function should be regularly assessed (see section "Special Instructions").

Elderly patients (aged 65 years and older). To reduce the risk of hypoglycemia, careful adjustment of the initial and maintenance doses of glibenclamide is required. Treatment with the drug should be initiated at the lowest dose, gradually increasing the dose as needed (see section "Special Instructions").

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

Overdose.

Overdose may lead to the development of hypoglycemia, as the drug contains a sulfonylurea (see section "Special Instructions"). Significant metformin overdose or the presence of concomitant risk factors may lead to lactic acidosis (see section "Special Instructions"). Lactic acidosis is a medical emergency and must be treated in a hospital setting. Hemodialysis is the most effective method for removing lactate and metformin from the body.

Plasma clearance of glibenclamide may be prolonged in patients with hepatic impairment.

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

Below are the adverse reactions observed during the use of the medicinal product Glifofo®. The frequency of adverse reactions is defined according to the following categories: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Blood and lymphatic system disorders:

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

These are reversible reactions that resolve after discontinuation of treatment.

Metabolism and nutrition disorders:

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

Common – decreased levels/deficiency of vitamin B12 (see section "Special precautions for use");
Uncommon – acute hepatic porphyria, cutaneous porphyria;
Very rare – lactic acidosis (see section "Special precautions for use").

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 sulfonylurea or its derivatives;
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.

Hepatic disorders:
Abnormal liver function tests or hepatitis, requiring discontinuation of treatment.

Investigations:

Uncommon – moderate increase in serum urea and creatinine levels;
Very rare – hyponatremia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to 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 from the date of manufacture in bulk.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store in a place protected from light, at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

10 tablets in a blister. 3, 6, or 10 blisters per carton (packaging from the "in bulk" form of the manufacturer "USV Private Limited", India).

Prescription status
Prescription only.

Manufacturer
JSC "Farmak".

Manufacturer's name and address

74, Kyrylivska Street, Kyiv, 04080, Ukraine.