Glucophage

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

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet of 500 mg contains 500 mg of metformin hydrochloride, equivalent to 390 mg of metformin;

One film-coated tablet of 850 mg contains 850 mg of metformin hydrochloride, equivalent to 662.90 mg of metformin;

One film-coated tablet of 1000 mg contains 1000 mg of metformin hydrochloride, equivalent to 780 mg of metformin;

Excipients: povidone K 30, magnesium stearate;

Film coating for 500 mg and 850 mg tablets: hypromellose;

Film coating for 1000 mg tablets: Opadry® CLA (hypromellose, polyethylene glycol 400, polyethylene glycol 8000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets of 500 mg and 850 mg: white, round, biconvex tablets, film-coated;

Film-coated tablets of 1000 mg: white, oval, biconvex tablets, film-coated, with a break line on both sides and engraved "1000" on one side.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10B A02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic activity, reducing both fasting and postprandial hyperglycemia. It does not stimulate insulin secretion and does not cause hypoglycemia.

Metformin reduces fasting hyperinsulinemia, and when used in combination with insulin, reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• Metformin reduces glucose production in the liver;
• Metformin enhances peripheral glucose uptake and utilization, partly by improving insulin sensitivity;
• Metformin alters glucose metabolism in the intestine: systemic absorption increases, while food-derived glucose absorption decreases. Additional intestinal-related mechanisms include increased release of glucagon-like peptide-1 (GLP-1) and reduced reabsorption of bile acids. Metformin alters the gut microbiome;
• Metformin may improve lipid profile in patients with hyperlipidemia.

In clinical trials, patient body weight remained stable or slightly decreased during metformin treatment.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK) and enhances the transport capacity of all types of glucose membrane transporters (GLUT).

Pharmacokinetics.

Absorption.

After oral administration, the time to reach maximum concentration (Cmax) of metformin is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin from 500 mg or 800 mg tablets is approximately 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces is 20–30%.

After oral administration, metformin absorption is saturable and incomplete.

Nonlinear absorption of metformin is expected. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. In controlled clinical studies, maximum plasma concentrations (Cmax) of metformin did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption.

After oral administration of 850 mg, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute prolongation in time to maximum plasma concentration were observed. The clinical significance of these changes is unknown.

Distribution.

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration, while time to peak is approximately the same. Erythrocytes likely serve as a secondary distribution compartment for metformin. 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, elimination half-life is approximately 6.5 hours. In patients with impaired renal function, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased plasma metformin levels.

Special patient groups.

Renal impairment.

Limited data are available in patients with moderate renal impairment; therefore, systemic exposure to metformin in this patient group compared to those with normal renal function cannot be precisely determined. Dose adjustment is required based on clinical efficacy and tolerability (see section "Dosage and administration").

Pediatric population.

In a single-dose study of 500 mg metformin hydrochloride, the pharmacokinetic profile in pediatric patients was similar to that in healthy adults.

Data on multiple dosing are limited to one study.

After repeated administration of 500 mg metformin twice daily for 7 days in pediatric patients, peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to adult patients with diabetes receiving 500 mg twice daily for 14 days.

Since the dose is individually titrated based on glycemic control, the above information has limited clinical relevance.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when diet therapy and physical activity have failed, particularly in patients with excess body weight:

• as monotherapy or in combination with other oral hypoglycemic agents or insulin for the treatment of adults;
• as monotherapy or in combination with insulin for the treatment of children aged 10 years and older and adolescents.

For reducing complications of diabetes in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line agent after failed diet therapy.

Contraindications.

• Hypersensitivity to metformin or to any other component of the drug;
• any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis);
• diabetic precoma;
• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• acute conditions associated with a risk of developing renal dysfunction, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or exacerbations of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• hepatic insufficiency, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

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

Iodinated contrast agents. Metformin should be discontinued before or during radiological procedures involving iodinated contrast media and should not be restarted earlier than 48 hours after the procedure, and only after reassessment and confirmation of stable renal function (see sections "Dosage and administration" and "Special precautions").

Combinations requiring caution. 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 negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these agents or when using them in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Glucophage® may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (such as verapamil) may reduce metformin efficacy;
• OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformin, leading to increased plasma concentrations of metformin;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal excretion 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 should be considered if necessary, since OCT inhibitors/inducers may influence metformin efficacy.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in the presence 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 attention 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 mellitus, ketosis, prolonged fasting, and any conditions 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 caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptom suggestive of lactic acidosis occurs, the patient must discontinue metformin and seek immediate medical attention.

Lactic acidosis is characterized by diagnostic laboratory findings: decreased blood pH (< 7.35), elevated serum lactate concentration in plasma (> 5 mmol/L), increased anion gap, and elevated 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 (Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes)) and maternally inherited diabetes and deafness (Maternal 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 and symptoms suggestive of MELAS or MIDD occur during metformin treatment, metformin therapy should be discontinued immediately and prompt diagnostic evaluation initiated.

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").

Cardiac function. Patients with heart failure have an increased risk of developing hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

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

Surgical procedures. Metformin 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 nutrition, and only after reassessment and confirmation of stable renal function.

Children. Prior to initiating metformin therapy, a confirmed diagnosis of type 2 diabetes mellitus must be established. One-year controlled clinical studies have shown no effect of metformin on growth and sexual maturation in children. However, there are no data on the long-term effects of metformin on growth and sexual maturation; therefore, careful monitoring of these parameters is recommended in children receiving metformin, especially during puberty.

Children aged 10 to 12 years. Controlled clinical studies involving 15 children aged 10 to 12 years showed that the efficacy and safety of metformin in this patient group were comparable to those in older children and adolescents. The drug should be prescribed with particular caution to children aged 10 to 12 years.

Other precautions. Patients must adhere to a diet with evenly distributed carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Regular monitoring of carbohydrate metabolism parameters is necessary.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and/or the 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 be continued as long as it is tolerated and not contraindicated, while appropriate corrective treatment for vitamin B12 deficiency should be provided according to current clinical guidelines.

Metformin monotherapy does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides).

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse outcomes of hyperglycemia for both mother and child.

Metformin crosses the placenta in amounts that may be as high as maternal concentrations.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from cohort studies based on registries and published meta-analyses and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure during the periconception period and/or during pregnancy.

There are some unconfirmed data on the long-term effects of metformin on the weight of children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed in utero, although data on long-term outcomes are limited.

If clinically necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an alternative to insulin.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should take into account the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility. Metformin had no effect on fertility in animal studies at doses of 600 mg/kg/day, which is nearly three times the maximum recommended human daily dose based on body surface area.

Ability to influence reaction speed when driving or operating machinery.

Metformin monotherapy does not affect reaction speed when driving or operating machinery, as the drug does not cause hypoglycemia. However, caution is required when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Dosage and Administration

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

Monotherapy or combination therapy with other oral hypoglycemic agents.

The usual starting dose is 500 mg or 850 mg (Glucophage®, film-coated tablets, 500 mg or 850 mg) 2–3 times daily, taken during or after meals.

After 10–15 days, the dose should be adjusted according to serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

When high doses are used (2000–3000 mg per day), each 2 tablets of Glucophage® 500 mg may be replaced by 1 tablet of Glucophage® 1000 mg.

The maximum recommended daily dose is 3000 mg, divided into 3 doses.

When switching from another antidiabetic agent, discontinue the previous agent and initiate metformin as described above.

Combination therapy with insulin.

Metformin and insulin may be used in combination to achieve better blood glucose control. The usual starting dose is 500 mg or 850 mg of metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring.

In elderly patients, renal function may be reduced; therefore, metformin dosage should be adjusted based on assessment of renal function, which should be performed regularly (see section "Special Instructions").

Renal impairment. eGFR should be evaluated before initiating treatment with metformin-containing medicinal products and at least annually during treatment. Patients at increased risk of progressive renal impairment and elderly patients should have their renal function closely monitored as frequently as every 3–6 months.

Children.

Monotherapy or combination therapy with insulin.

Glucophage® can be used in children aged 10 years and older and in adolescents. The usual starting dose is 500 mg or 850 mg of Glucophage® once daily, taken during or after a meal.

After 10–15 days, the dose should be adjusted based on serum glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg daily, given in 2–3 divided doses.

Overdose.

Administration of 85 g of the drug did not result in hypoglycemia. However, in this case, lactic acidosis developed. Significant overdose of metformin or concomitant risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency requiring hospital treatment. Hemodialysis is the most effective procedure for removing lactate and metformin from the body.

Adverse Reactions

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhoea, 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.

Adverse effects are classified by frequency of occurrence into the following categories:

Very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

Within each organ system class, adverse reactions are listed in order of decreasing clinical significance.

Metabolism disorders

Common: decreased levels/vitamin B12 deficiency (see section "Special precautions for use").

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

From the nervous system

Common: taste disturbances.

From the gastrointestinal system

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite. These adverse effects most often occur at the beginning of treatment and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse effects, a gradual increase in dosage is recommended, along with administration of the daily dose in 2–3 divided doses during or after meals.

From the liver and biliary system

Very rare: liver function test abnormalities or hepatitis, which completely resolve after discontinuation of metformin.

From the skin and subcutaneous tissue

Very rare: skin reactions including erythema, pruritus, urticaria.

Children

In published and post-marketing data and controlled clinical trials in a limited paediatric population aged 10–16 years who received metformin for 1 year, reported adverse effects in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after a medicinal product's registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life

Tablets, film-coated, 500 mg, 850 mg – 5 years.

Tablets, film-coated, 1000 mg – 4 years.

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

Packaging.

Tablets, film-coated, 500 mg: 15 tablets in a blister; 2 or 4 blisters in a cardboard box. 20 tablets in a blister; 3 blisters in a cardboard box.

Tablets, film-coated, 850 mg: 15 tablets in a blister; 2 or 4 blisters in a cardboard box. 20 tablets in a blister; 3 blisters in a cardboard box.

Tablets, film-coated, 1000 mg: 15 tablets in a blister; 2 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer:

Merck Sante, France / Merck Sante, France.

Merck, SL, Spain / Merck, SL, Spain.

Manufacturer's address and location of business activity:

2 rue du Pressoir Vert, 45400 Semoy, France / 2 rue du Pressoir Vert, 45400 Semoy, France.

Poligono Merck, 08100 Mollet del Valles (Barcelona), Spain / Poligon Merck, 08100 Mollet del Valles (Barcelona), Spain.