Metamin film-coated tablets 1000 mg No. 90

Instructions for use of Metamin film-coated tablets 1000 mg No. 90

Composition

active ingredient: metformin hydrochloride;

1 tablet contains metformin hydrochloride 500 mg or 850 mg or 1000 mg;

Excipients: lactose monohydrate, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose.

Dosage form

Film-coated tablets.

Main physicochemical properties:

500 mg, 850 mg tablets: white or almost white, round, biconvex, smooth tablets on both sides;

1000 mg tablets: white or almost white, oval-shaped, biconvex, smooth on both sides.

Pharmacotherapeutic group

Oral hypoglycemic agents, except insulins. Biguanides. ATC code A10B A02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after a meal. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.

Metformin works in three ways:

• leads to a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization;
• delays the absorption of glucose in the intestine.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters.

Regardless of its effect on glycemia, metformin has a positive effect on lipid metabolism: it reduces total cholesterol, low-density lipoproteins, and triglycerides.

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

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 850 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. No metabolites have been identified in humans.

Elimination. Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After an oral dose, 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).

Children.

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 in 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 setting 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 that should 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. At the beginning of treatment with the above medicinal products or when used in combination with metformin, careful monitoring of renal function is necessary.

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 Metamin® should be adjusted.

Organic cation transporters (OCTs).

Metformin is a substrate of both transporters – OST1 and OST2.

Concomitant use of metformin with:

OST1 inhibitors (such as verapamil) may reduce the effectiveness of metformin;

OST1 inducers (such as rifampicin) may increase the gastrointestinal absorption and efficacy of metformin;

OST2 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 OST1 and OST2 (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 OST 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.

In case of dehydration (severe diarrhea or vomiting, fever, or decreased fluid intake), it is recommended to temporarily discontinue metformin and seek medical attention.

Patients receiving metformin should be cautiously initiated on agents that may acutely impair renal function (e.g., antihypertensives, diuretics, and NSAIDs).

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 treatment is initiated 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 radiocontrast 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 during the study and not resume it until 48 hours after the study and only after re-evaluation and stable renal function (see sections 4.2 and 4.5).

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

Children. Type 2 diabetes mellitus should be confirmed before starting metformin therapy. 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, and therefore close 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. 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).

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine, as it contains lactose.

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.

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 three times the maximum recommended daily human dose based on body surface area.

Ability to influence reaction speed when driving vehicles or other mechanisms

Monotherapy with metformin does not affect the speed of reactions 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 meglitidines) 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 (Metamin®, film-coated tablets, 500 mg or 850 mg) 2-3 times daily during 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 Metamin®, 500 mg, with 1 tablet of Metamin®, 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 of Metformin® 2-3 times daily, while the insulin dose should be adjusted according to blood glucose measurements.

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 more frequently, e.g. every 3-6 months.

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").

Children.

Monotherapy or combination therapy with insulin.

Metamin® is used in children aged 10 years and older and adolescents. The usual starting dose is 500 mg or 850 mg of Metamin® once daily during 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.

The maximum recommended dose is 2000 mg per day, divided into 2-3 doses.

Children.

The drug Metamin® is used to treat children aged 10 years and older.

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 disappear 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 reactions observed during the use of the drug are listed below by organ system and frequency of occurrence: 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), unknown (cannot be determined based on available data).

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 use 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 of the 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

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

Tablets 500 mg, 850 mg: 10 tablets in a blister. 3, 6 or 10 blisters in a cardboard box.

1000 mg tablets: 15 tablets in a blister. 2, 4 or 6 blisters in a carton.

Vacation category

According to the recipe.

Producer

"KUSUM FARM" LLC.

Address

40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54.