Metamin film-coated tablets 1000 mg No. 60

Instructions for use of Metamin film-coated tablets 1000 mg No. 60

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. ATX code A10B A02.

Pharmacological properties

Pharmacodynamics.

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 due to inhibition of 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 (GLUT).

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 maximum concentration (Tmax) is approximately 2.5 hours. The absolute bioavailability 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 pharmacokinetics of metformin absorption are expected to be non-linear. At recommended metformin 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 slightly delayed.

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

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and are reached at approximately the same time. Erythrocytes are likely to represent a second distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

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.

Indication

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

- as monotherapy or combination therapy in combination with other oral hypoglycemic agents or in combination with insulin for the treatment of adults.

- as monotherapy or 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 mellitus 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.;

– 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 cases of starvation, malnutrition, or liver failure. Alcohol and medications containing alcohol should be avoided during treatment with Metamin®.

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 re-evaluation and stable renal function (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. When initiating treatment with the above medicinal products or when used in combination with metformin, renal function should be closely monitored.

Medicinal products with hyperglycaemic 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 metformin dose should be adjusted under glycemic control.

Organic cation transporters (OCTs).

Metformin is a substrate of both transporters – OTC1 and OTC2.

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 inhibitors/inducers of the ATC code 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.

In patients receiving metformin, caution should be exercised when initiating treatment with agents that may acutely impair renal function (e.g., antihypertensives, diuretics, and NSAIDs).

Other risk factors for lactic acidosis include poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency and any conditions associated with hypoxia, as well as concomitant use of medicinal products that can lead to lactic acidosis (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).

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.

Diagnostic laboratory findings include decreased blood pH (<7.35), increased serum lactate concentration (>5 mmol/L), and increased anion gap and lactate/pyruvate ratio. In the event of lactic acidosis, the patient should be hospitalized immediately (see section 4.8). The physician should warn patients about the risk and symptoms of lactic acidosis.

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.

Metformin should be discontinued prior to or during the examination and not resumed until 48 hours after the examination, 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 treatment. Metformin has not been shown to affect growth and puberty in children. However, there are no data on the effects 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. 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, maintain a balanced carbohydrate intake throughout the day, and monitor laboratory parameters. Overweight patients should continue to follow a low-calorie diet. Carbohydrate metabolism should be monitored regularly.

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 the patient has been diagnosed with an intolerance to some sugars, contact your doctor before taking this medicinal product, as the product contains lactose.

Use during pregnancy or breastfeeding

Pregnancy. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. There are limited data from the use of metformin in pregnant women, which do not indicate an increased risk of congenital anomalies. Preclinical studies have not revealed any adverse effects on pregnancy, embryonal or foetal development, labour and postnatal development. In cases of planning pregnancy, as well as in the event of pregnancy, it is recommended to use insulin, not metformin, for the treatment of diabetes to maintain blood glucose levels as close to normal as possible, in order to reduce the risk of foetal malformations.

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 compatible 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.

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

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

Combination therapy is compatible 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 thereafter. 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.

Children.

Monotherapy or combination therapy compatible with insulin.

Metamin® is intended for use 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 based on 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.

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

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

Overdose

When using the drug in a dose of up to 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 associated risks can cause the occurrence of 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.

Adverse reactions

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.

Metabolic disorders: lactic acidosis (see section "Special warnings and precautions for use").

With prolonged use of the drug, absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood serum. It is recommended to consider this possible cause of hypovitaminosis B12 if the patient has megaloblastic anemia.

From the nervous system: taste disturbance.

On the part of the digestive system: digestive system disorders, such as nausea, vomiting, diarrhea, abdominal pain, lack 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 tract, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses during or after meals.

Hepatobiliary disorders: abnormal liver function tests or hepatitis, which completely disappear after metformin withdrawal.

Skin and subcutaneous tissue disorders: allergic skin reactions including rash, erythema, pruritus, urticaria.

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.

Location of the manufacturer and address of its place of business.

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