Glucovance®

INSTRUCTIONS
for medical use of medicinal product

GLUCOVANCE®
(GLUCOVANCE®)

Composition:

Active substances:

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

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, elongated, biconvex film-coated tablets with "5" debossed 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 A10B D02.

Pharmacological properties.

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic effect. It reduces plasma glucose levels both fasting and postprandial. It does not stimulate insulin secretion and does not cause hypoglycemia mediated by 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 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 effect on glycemia, metformin exerts a positive effect on lipid metabolism. This effect has been demonstrated in controlled medium- or long-term clinical trials using therapeutic doses: metformin reduces total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels.

During the clinical trials conducted to date, no such positive effect on lipid metabolism has been observed with the concomitant use of metformin and glibenclamide.

Glibenclamide is a second-generation sulfonylurea derivative with a medium half-life. It stimulates insulin production by the pancreas, causing 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 the sensitivity of peripheral tissues (skeletal muscles) and liver tissue to insulin.

Results from controlled, double-blind clinical trials with reference drugs for type 2 diabetes inadequately controlled by monotherapy with either metformin or glibenclamide in combination with diet and exercise showed that combined therapy had a comprehensive effect on glucose level regulation.

Children. During a 26-week, active-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 regimen 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 children.

Pharmacokinetics.

Regarding the combination.

The bioavailability of metformin and glibenclamide in combination is the same as when taken simultaneously as one tablet of metformin and one tablet of glibenclamide. The bioavailability of metformin in combination is independent of food intake. The bioavailability of glibenclamide in combination is independent of food intake, although the absorption rate of glibenclamide increases with food intake.

Regarding metformin.

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

After oral administration, absorption of metformin is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are nonlinear. With recommended doses and dosing regimens of metformin, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. In controlled clinical trials, maximum plasma levels of metformin (Cmax) 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 approximately at the same time. Erythrocytes likely represent a second 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. This indicates that metformin is eliminated via 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, thus prolonging the elimination half-life, leading to increased plasma metformin levels.

Regarding glibenclamide.

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

Distribution. Glibenclamide is highly bound to plasma proteins (99%), which may affect 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. Terminal elimination half-life is 4–11 hours.

Excretion of metabolites via bile increases in patients with renal insufficiency, depending on the degree of renal function impairment, when creatinine clearance is 30 mL/min. If creatinine clearance is greater than 30 mL/min, renal insufficiency does not affect glibenclamide elimination.

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

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to metformin, glibenclamide, other components of the drug, other sulfonylurea drugs, or sulfonamides;
• Type 1 diabetes (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 risk of renal function impairment: dehydration, severe infections, shock;
• Diseases that may cause tissue hypoxia (e.g., acute illness or worsening of chronic disease), such as 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 forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Interactions contraindicated.

Regarding glibenclamide.

• Miconazole (systemic use, oral gel): enhanced hypoglycemic effect with possible hypoglycemic symptoms or even coma (see section "Contraindications").

Interactions not recommended.

Regarding sulfonylurea drugs.

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

Regarding all antidiabetic drugs.

• Danazol: if this combination is necessary, warn the patient about the need for increased self-monitoring of blood glucose levels. If necessary, adjust the dose of the drug during and after danazol discontinuation.

Regarding metformin.

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

Iodine-containing contrast agents. The drug 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 "Dosage and administration" and "Special precautions for use").

Combinations requiring caution.

Regarding all antidiabetic drugs.

• Chlorpromazine: when taken in high doses (100 mg chlorpromazine daily), increases blood glucose levels (reduces insulin production). Warn the patient and intensify self-monitoring of blood glucose. If necessary, adjust the dose of the antidiabetic drug 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). Warn the patient and intensify self-monitoring of blood glucose. If necessary, adjust the dose of the drug during and after discontinuation of corticosteroids.
• β2-agonists: increased blood glucose levels. Warn the patient and intensify blood glucose monitoring; if necessary, switch the patient to insulin therapy.

Regarding metformin.

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

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 metformin, leading to increased plasma metformin concentrations;

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

Therefore, particular caution is recommended when co-administering these drugs with metformin, especially in patients with impaired renal function, as plasma metformin concentrations may increase. If necessary, consider adjusting the metformin dose, as OCT inhibitors/inducers may affect metformin efficacy.

Regarding glibenclamide.

• β-blockers mask some symptoms of hypoglycemia: rapid heartbeat and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemia. Patients should monitor blood glucose levels, especially at the start of treatment.
• ACE inhibitors (e.g., captopril, enalapril): reduced blood glucose levels. If necessary, adjust the dose of Glucovance® during and after discontinuation of ACE inhibitors.
• Fluconazole: prolonged half-life of sulfonylurea with possible hypoglycemic symptoms. Warn the patient and intensify self-monitoring of blood glucose. If necessary, adjust the dose of the drug during and after fluconazole discontinuation.
• Boceprevir: risk of reduced hypoglycemic effect of glibenclamide, as boceprevir reduces plasma glibenclamide concentration. Concurrent use may increase liver enzyme levels.

Patients should be warned about the need for monitoring blood glucose and liver enzyme levels. If necessary, adjust the dosage regimen.

• Bile acid sequestrants: concomitant use reduces plasma glibenclamide concentration, potentially reducing its hypoglycemic effect. This effect is absent if glibenclamide is taken at least 4 hours before the other medicinal product. It is recommended to administer Glucovance® at least 4 hours before bile acid sequestrants.

Interactions to be considered.

Regarding glibenclamide.

• Desmopressin: reduced antidiuretic effect.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring with acute worsening of renal function, cardiopulmonary disease, or sepsis. With acute worsening of renal function, metformin accumulates, increasing the risk of lactic acidosis.

In case 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 with caution when using agents that may acutely worsen renal function (e.g., antihypertensive agents, diuretics, 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 lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, potentially progressing to coma. If any symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin and seek immediate medical attention.

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

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 mitochondrial inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, potentially worsening the disease course.

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

Hypoglycemia. Glucovance® contains a sulfonylurea, so patients using this medicinal product are prone to hypoglycemia. Dose titration at the start of therapy may 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 intake. Hypoglycemia most commonly occurs in patients on a low-calorie diet, after intense or prolonged exercise, alcohol consumption, or combined therapy with hypoglycemic agents.

Diagnosis. Symptoms of hypoglycemia: headache, hunger, nausea, vomiting, severe fatigue, sleep disturbances, restlessness, aggressive episodes, 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, sweating, anxiety, tachycardia, hypertension, palpitations, angina, and arrhythmia may occur. These symptoms may be absent in cases of slow-onset hypoglycemia, autonomic neuropathy, or with concomitant use of β-blockers, clonidine, reserpine, guanethidine, or sympathomimetics.

Treatment of hypoglycemia. For mild hypoglycemic symptoms without loss of consciousness or neurological signs, immediate intake of sugar is required. Dose adjustment and/or dietary correction should be ensured. Severe hypoglycemic reactions with coma, seizures, and other neurological signs may occur, requiring emergency treatment with intravenous glucose upon diagnosis or suspicion of hypoglycemia before hospitalization.

Proper patient selection, dose adjustment, and 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 predisposing to hypoglycemia:

• concomitant alcohol intake, especially combined with fasting,
• non-compliance (especially in elderly patients) or inability of patients to follow physician recommendations,
• irregular meals, undernutrition, missed meals, fasting, or dietary changes,
• improper balance between physical activity and carbohydrate intake,
• renal insufficiency,
• severe hepatic insufficiency,
• overdose of Glucovance®,

-certain endocrine disorders: hypothyroidism, hypopituitarism, 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 using 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 Glucovance®. 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 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, coma.

Patients should be specifically informed about the importance of adhering to diet, regular physical exercise, and glycemic control.

Glucose imbalance. In case of surgical procedures or other causes of diabetes decompensation, temporary insulin therapy should be considered. Symptoms of hyperglycemia: increased urination, intense thirst, dry skin.

Renal function. GFR should be assessed before starting treatment and regularly thereafter (see section "Dosage and administration"). Metformin is contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued in conditions altering renal function (see section "Contraindications").

In such cases, renal function should also be evaluated before starting 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 functions are regularly monitored.

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

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. Metformin use 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 "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of glibenclamide with other medicinal products. Concomitant use of glibenclamide 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 resumed earlier than 48 hours after surgery or restoration of oral feeding, only after re-evaluation and confirmation of stable renal function.

Precautions. Patients should adhere to a diet, properly distribute carbohydrate intake throughout the day. Overweight patients should follow a low-calorie diet.

Regular physical exercise should be performed during therapy. 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. 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 continue 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 sulfonylurea may lead to hemolytic anemia. Since glibenclamide 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 therapy.

The drug is contraindicated in patients with congenital galactosemia, glucose-galactose malabsorption syndrome, or lactase deficiency, as it contains lactose.

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

Use during pregnancy or breastfeeding.

Pregnancy. Preclinical and clinical data on the use of Glucovance® 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 did not show negative 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 anomalies.

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

Treatment. Adequate control of blood glucose levels supports normal pregnancy progression in this patient group. Glucovance® should not be used for treating diabetes during pregnancy.

In case of planned pregnancy or onset of 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 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, nearly three times the maximum recommended human daily dose based on body surface area. Glibenclamide did not affect fertility in animals after oral administration at doses of 100 and 300 mg/kg/day.

Ability to influence reaction rate when driving or operating machinery.

Patients should exercise particular caution when driving or operating machinery due to the risk of hypoglycemia 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 (GFR ≥ 90 mL/min).

Glucovance® 500 mg/5 mg is recommended for patients in whom adequate glycemic control is not achieved with lower doses.

When replacing combined therapy with metformin and glibenclamide, initiate Glucovance® at doses corresponding to previous therapy. Gradually increase the dose based on glycemic measurements.

Dosage should be adjusted (increase by one tablet) every 2 weeks or more after starting therapy, depending on glycemic levels.

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

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

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

There are no data on concomitant therapy with Glucovance® and insulin.

Dosing regimens depend on individual requirements:

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

Tablets should be taken with meals.

Dosing regimen may be adjusted according to individual meal schedules. However, to prevent hypoglycemic episodes, carbohydrate-rich meals should be consumed after each dose.

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. GFR should be assessed before starting treatment with metformin-containing drugs and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should have 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 GFR < 60 mL/min, factors increasing the risk of lactic acidosis should be considered (see section "Special precautions for use").

When the appropriate dosage strength is unavailable, individual monocomponents should be used instead of the fixed-dose combination product.