Glucophage film-coated tablets 850 mg No. 60

Instructions Glucophage film-coated tablets 850 mg No. 60

Composition

active ingredient: metformin hydrochloride;

1 film-coated tablet of 500 mg contains 500 mg of metformin hydrochloride, which corresponds to 390 mg of metformin;

1 film-coated tablet of 850 mg contains 850 mg of metformin hydrochloride, which corresponds to 662.90 mg of metformin;

1 film-coated tablet of 1000 mg contains 1000 mg of metformin hydrochloride, which corresponds to 780 mg of metformin;

excipients: povidone K 30, magnesium stearate;

film coating for tablets of 500 mg, 850 mg: hypromellose;

film coating for 1000 mg tablets: Opadry Klia (hypromellose, macrogol 400, macrogol 8000).

Dosage form

Film-coated tablets.

Main physicochemical properties:

film-coated tablets, 500 mg, 850 mg: round tablets with a biconvex surface, white in color, film-coated;

Film-coated tablets, 1000 mg: oval-shaped tablets with a biconvex surface, white in color, film-coated, with a score on both sides and engraving "1000" on one side.

Pharmacotherapeutic group

Drugs affecting the digestive system and metabolism. Antidiabetic drugs. Oral hypoglycemic agents, except insulins. Biguanides. ATC code A10B A02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic effects, both on fasting and postprandial hyperglycemia. It does not stimulate insulin secretion and does not cause a hypoglycemic effect.

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

Metformin exerts its antihyperglycemic effect through several mechanisms:

Metformin reduces hepatic glucose production, metformin facilitates peripheral glucose uptake and utilization, partly by enhancing insulin action;

Metformin alters intestinal glucose metabolism: absorption from the bloodstream is increased and absorption from food is decreased. Additional gut-related mechanisms include increased glucagon-like peptide 1 (GLP-1) release and decreased bile acid reabsorption. Metformin alters the gut microbiome;

Metformin can improve the lipid profile in patients with hyperlipidemia.

In clinical trials, patients' body weight remained stable or decreased moderately while taking metformin.

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

Pharmacokinetics.

Absorption.

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

After oral administration, the absorption of metformin is saturable and incomplete.

The absorption of metformin is assumed to be non-linear. When metformin is used at recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and are less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 μg/ml even at maximum doses.

When taken with food, the absorption of metformin is reduced and somewhat slowed down.

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

Distribution.

Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes. The maximum concentration in the blood is lower than the maximum concentration in plasma, while the time to reach it is approximately the same. Erythrocytes are most likely a secondary compartment of distribution for metformin. The mean volume of distribution (Vd) ranges from 63 to 276 liters.

Metabolism.

Metformin is excreted unchanged in the urine. Metabolites have not been identified in humans.

Breeding.

Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore the elimination half-life increases, leading to increased metformin plasma levels.

Special patient groups.

Kidney failure.

Limited data are available in patients with moderate renal impairment, so it is not possible to accurately estimate the systemic exposure of metformin in this patient group compared to patients with normal renal function. Therefore, dose adjustment is necessary according to clinical efficacy/tolerability (see section 4.2).

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-dose use are limited to one study.

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

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

Indication

Type 2 diabetes mellitus with ineffective diet therapy and exercise regimen, especially in patients with excess body weight:

as monotherapy or as part of combination therapy with other oral hypoglycemic agents or with insulin for the treatment of adults;

as monotherapy or as part of combination therapy with insulin for the treatment of children aged 10 years and older and adolescents.

To reduce the complications of diabetes in adult patients with type 2 diabetes and overweight as a first-line drug after ineffective diet therapy.

Contraindication

Hypersensitivity to metformin or any other component of the drug;

any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);

diabetic precoma;

severe renal failure (glomerular filtration rate (GFR) < 30 ml/min);

acute conditions with a risk of developing kidney dysfunction, such as: dehydration, severe infectious diseases, shock;

diseases that can lead to the development of tissue hypoxia (especially acute diseases or exacerbation of a chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;

liver failure, acute alcohol poisoning, alcoholism.

Interaction with other medicinal products and other types of interactions

Combinations that are not recommended for use.

Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in the presence of fasting, malnutrition, or liver failure.

Iodinated radiocontrast agents: Metformin should be discontinued in patients prior to or at the time of the procedure and not resumed until 48 hours after the procedure and only after renal function has been re-evaluated and stable (see sections 4.2 and 4.4).

Combinations to be used with caution. Some medicinal products, such as non-steroidal 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 adversely affect renal function, which may increase the risk of lactic acidosis. Careful monitoring of renal function is necessary when initiating treatment with the above medicinal products or when used in combination with metformin.

Drugs with hyperglycemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. During and after discontinuation of such concomitant therapy, the dose of Glucophage® should be adjusted.

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 the effectiveness of metformin;

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 the renal excretion of metformin with a subsequent increase in metformin plasma concentrations;

Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.

Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.

Application features

Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.

Patients receiving metformin should be cautiously initiated on medicinal products that may acutely impair renal function (e.g. antihypertensives, 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 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia, which may progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical attention immediately.

Lactic acidosis is characterized by diagnostic laboratory indicators: decreased blood pH (< 7.35), increased serum lactate concentration in blood plasma (> 5 mmol/L), increased anion gap, and increased lactate/pyruvate ratio.

Renal function: GFR should be assessed before starting treatment and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with a GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see section 4.3).

Iodinated radiopaque agents. Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Patients should discontinue metformin prior to or at the time of the procedure and not resume treatment until 48 hours after the procedure and only after renal function has been re-evaluated and stable (see sections 4.2 and 4.5).

Surgery: Metformin should be discontinued during surgery performed under general, spinal or epidural anesthesia and not resumed until 48 hours after surgery or resumption of oral nutrition and only after re-evaluation and stable renal function.

Children. Type 2 diabetes mellitus should be confirmed before starting metformin treatment. One-year controlled clinical trials have shown no effect of metformin on growth and puberty in children. However, there is no data on the effect of metformin on growth and puberty with longer-term use of metformin, so careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.

Children aged 10 to 12 years. According to the results of controlled clinical studies involving 15 children aged 10 to 12 years, the efficacy and safety of metformin in this group of patients did not differ from that in older children and adolescents. The drug should be prescribed with particular caution to children aged 10 to 12 years.

Other precautions: Patients should follow a diet with a balanced intake of carbohydrates throughout the day. Overweight patients should continue to follow a low-calorie diet. Patients' carbohydrate metabolism should be monitored regularly.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with increasing metformin dose, duration of treatment and/or if the patient has risk factors known to predispose to vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g. anaemia or neuropathy). Patients with risk factors for vitamin B12 deficiency may require monitoring of vitamin B12 levels. Metformin therapy should be continued as long as tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be provided in accordance with current clinical guidelines.

Metformin monotherapy does not cause hypoglycemia, but caution should be exercised 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, pregnancy-induced 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 effects of hyperglycemia for the mother and her baby.

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

A large amount of data on pregnant women (more than 1000 exposure outcomes) from a registry-based cohort study and published results from meta-analyses and clinical trials indicate no increased risk of congenital anomalies or foetal/neonatal toxicity following exposure to metformin during the periconceptional period and/or pregnancy.

There is some anecdotal evidence about the long-term effects of metformin on weight in children exposed in utero. Metformin does not appear to affect motor and social development in children under 4 years of age exposed in utero, although data on long-term effects are limited.

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

Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. A decision on whether to discontinue breastfeeding should be made taking into account the benefit of breastfeeding and the potential risk of adverse effects to the child.

Fertility: Metformin had no effect on animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area.

Ability to influence reaction speed when driving vehicles or other mechanisms

Metformin monotherapy does not affect the reaction speed when driving or operating other mechanisms, since the drug does not cause hypoglycemia. However, caution should be exercised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin or meglitinides) due to the risk of hypoglycemia.

Method of administration and doses

Adult patients with normal renal function (GFR ≥ 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 with or after meals.

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

Slowly increasing the dose helps reduce side effects from the digestive tract.

When treating with high doses (2000–3000 mg per day), it is possible to replace every 2 tablets of Glucophage®, 500 mg, with 1 tablet of Glucophage®, 1000 mg.

The maximum recommended dose is 3000 mg per day in 3 divided doses.

If switching from another antidiabetic agent, this agent should be discontinued and metformin should be prescribed as described above.

Combination therapy with insulin.

To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted according to blood glucose measurements.

Elderly patients may have decreased renal function, therefore the dose of metformin should be selected based on assessment of renal function, which should be performed regularly (see section "Special instructions").

Renal impairment: GFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually during treatment. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be monitored closely as frequently as possible, e.g. every 3–6 months.

Children.

Monotherapy or combination therapy with insulin.

After 10–15 days, the dose should be adjusted according to the results of serum glucose measurements. A slow increase in dose helps to reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg per day in 2–3 divided doses.

Overdose

When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can lead to lactic acidosis. Lactic acidosis is an emergency and should be treated in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.

Side effects

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms in most cases resolve on their own. To prevent the occurrence of these side effects, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2–3 doses.

Adverse effects are classified according to the 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 system organ class, adverse reactions are listed in order of decreasing clinical significance.

Metabolic disorders.

Common: Vitamin B12 deficiency/decrease (see section 4.4).

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

From the nervous system.

Common: taste disturbance.

From the digestive system.

Very common: digestive system disorders such as nausea, vomiting, diarrhea, abdominal pain, loss of appetite. Most often, these side effects occur at the beginning of treatment and in most cases disappear spontaneously. To prevent the occurrence of side effects from the digestive system, it is recommended to slowly increase the dosage and take the daily dose of the drug in 2-3 doses during or after meals.

From the liver and biliary tract.

Very rare: abnormal liver function tests or hepatitis, which completely resolve after metformin withdrawal.

On 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 pediatric population aged 10-16 years treated with metformin for 1 year, adverse reactions reported in children were similar in nature and severity to those reported in adults.

Reporting of suspected adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua/.

Expiration date

Film-coated tablets, 500 mg, 850 mg – 5 years.

Film-coated tablets, 1000 mg – 4 years.

Storage conditions

Does not require any special storage conditions. Keep out of the reach of children!

Packaging

Film-coated tablets, 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.

Film-coated tablets, 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.

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

Vacation category

According to the recipe.

Producer

Merck Sante, France/Merck Sante, France.

Merck, SL, Spain.

Address

2 rue du Pressoir Vert, 45400 Semoy, France.

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