Siofor 1000 film-coated tablets 1000 mg No. 30

Instructions for Siofor 1000 film-coated tablets 1000 mg No. 30

Composition

active ingredient: metformin hydrochloride;

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

excipients: hypromellose (15,000 mPa·s and 5 mPa·s), povidone (K 25), magnesium stearate, polyethylene glycol 6000, titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: white, oblong, film-coated tablets with a wedge-shaped “snap-tab” recess on one side and a score line on the other.

Pharmacotherapeutic group

Antidiabetic agents. Hypoglycemic drugs, except insulins. Biguanides. ATX code A10B A02.

Pharmacological properties

Pharmacodynamics

Mechanism of action.

The action of metformin is due to three mechanisms:

1) reduction of glucose production in the liver due to inhibition of gluconeogenesis and glycogenolysis;

2) increasing muscle sensitivity to insulin, improving glucose uptake by peripheral tissues and its utilization;

3) slowing down the absorption of glucose in the intestines.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. Metformin improves the functional activity of all currently known types of glucose transporters (GLUT).

Metformin belongs to the group of biguanides, which have antihyperglycemic activity and contribute to the reduction of blood glucose levels both on an empty stomach and after eating. The drug does not stimulate insulin production, therefore it does not cause hypoglycemia.

Metformin has a beneficial effect on fat metabolism, namely, its use in therapeutic doses lowers the level of total cholesterol, low-density lipoproteins, and triglycerides.

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

Clinical efficacy and safety

A prospective randomized trial (UKPDS) established the long-term benefit of regular blood glucose monitoring in adult patients with type 2 diabetes.

Analysis of data obtained in overweight patients who were prescribed metformin hydrochloride after diet therapy had been ineffective for them showed:

a statistically significant reduction in the absolute risk of developing diabetic complications in patients who used metformin hydrochloride (29.8 cases/1000 patient-years) compared with diet therapy alone (43.3 cases/1000 patient-years), p = 0.0023, and compared with the total indicators of patients who used monotherapy with sulfonylurea derivatives and insulin (40.1 cases/1000 patient-years), p = 0.0034; a statistically significant reduction in the absolute risk of mortality associated with diabetes mellitus: metformin hydrochloride - 7.5 cases/1000 patient-years; diet therapy alone - 12.7 cases/1000 patient-years (p = 0.017); a statistically significant reduction in the absolute risk of all-cause mortality: in patients who used metformin hydrochloride - 13.5 cases/1000 patient-years compared to diet therapy alone - 20.6 cases/1000 patient-years (p = 0.011), and compared to the total indicators of patients who used monotherapy with sulfonylurea derivatives and insulin - 18.9 cases/1000 patient-years (p = 0.021); a statistically significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride - 11 cases/1000 patient-years; diet therapy alone - 18 cases/1000 patient-years (p = 0.01).

The superiority of metformin hydrochloride used as a second-line drug in combination with a sulfonylurea derivative in terms of clinical outcome has not been confirmed.

In some patients with type 1 diabetes, metformin hydrochloride has been used in combination with insulin, but the clinical benefit of such combination therapy has not been formally established.

Children and adolescents

According to controlled clinical trials in which the drug was used for 1 year in a small number of children and adolescents aged 10 to 16 years, the effectiveness of the drug in controlling blood sugar levels was about the same as in adults.

Pharmacokinetics

Absorption

After oral administration of metformin hydrochloride, Cmax (maximum plasma concentration) is reached after 2.5 hours. The absolute bioavailability of metformin hydrochloride in the dosage form of 500 mg and 850 mg tablets in healthy volunteers is 50–60%. After oral administration, the unabsorbed fraction excreted in the feces is 20–30%.

At the recommended doses and schedules of metformin hydrochloride, steady-state plasma concentrations are reached within 24–48 hours and are generally less than 1 μg/ml. In studies, mean maximum plasma concentrations (Cmax) did not exceed 4 μg/ml even at maximum doses. Food reduces the extent and, to some extent, the rate of metformin absorption. After oral administration of an 850 mg metformin hydrochloride tablet, peak plasma concentrations were reduced by 40%, area under the pharmacokinetic curve (AUC) was reduced by 25%, and time to peak plasma concentrations was delayed by 35 minutes. The clinical significance of these effects has not been established.

Distribution

The binding of metformin to plasma proteins is insignificant.

Metformin hydrochloride penetrates into erythrocytes. The maximum concentration of the drug in the blood is lower than its maximum concentration in the blood plasma, but is achieved at approximately the same time.

Presumably, erythrocytes represent the second phase of division.

The mean volume of distribution (Vd) ranges from 63 to 276 liters.

Biotransformation

Metformin is excreted unchanged in the urine. Its metabolites have not been detected in humans.

Breeding

Renal clearance of metformin is >400 ml/min, indicating that it is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance is reduced in proportion to creatinine clearance, which increases its half-life and, accordingly, leads to an increase in metformin plasma levels.

Children and adolescents

Single-dose studies: In children and adolescents given a single dose of metformin hydrochloride 500 mg, pharmacokinetic parameters were similar to those in healthy adults.

Multiple-dose studies: Data are limited to one study. After repeated administration of metformin hydrochloride 500 mg twice daily for 7 days in children and adolescents, there was a reduction in maximum plasma concentration (Cmax) and total exposure (AUC0-t) of approximately 33% and 40%, respectively, compared to adult diabetic patients receiving repeated doses of 500 mg.

2 times a day for 14 days. Since the dose of the drug is selected individually based on the blood glucose content, the clinical significance of the data presented is limited.

Indication

Type 2 diabetes mellitus when diet and exercise regimen are ineffective, especially in overweight patients; 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 the active substance or to any of the excipients. Any type of acute metabolic acidosis (lactic acidosis, diabetic ketoacidosis), diabetic precoma. Severe renal failure (glomerular filtration rate (GFR) < 30 ml/min). Acute conditions that may adversely affect renal function, e.g. dehydration, severe infectious disease, shock. Diseases that may lead to tissue hypoxia (especially acute diseases or exacerbation of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock. Hepatic failure, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other types of interactions

Concurrent use is not recommended.

Ethanol.

In case of acute alcohol intoxication, the risk of lactic acidosis increases, especially in case of starvation, malnutrition, or liver failure.

Alcohol consumption and the use of ethanol-containing medications should be avoided.

Iodine-containing contrast agents.

Metformin should be discontinued for the duration of the procedure or prior to its completion and resumed no earlier than 48 hours after the procedure, provided that renal function has been monitored and that renal function is stable (see section “Method of administration and dosage”, “Special precautions for use”).

Intravenous use of iodinated radiocontrast agents may cause renal failure, and, as a result, metformin accumulation and an increased risk of lactic acidosis.

Concomitant use requiring special caution.

Medicinal products that may cause hyperglycaemia (e.g. glucocorticoids (systemic and topical) and sympathomimetics). More frequent monitoring of blood glucose levels may be necessary, especially at the beginning of treatment. If necessary, the dose of the antidiabetic agent should be adjusted during and after the withdrawal of these medicinal products.

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 efficacy of metformin; OCT1 inducers (such as rifampicin) may increase the gastrointestinal absorption and efficacy of metformin; OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with 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 co-administered 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

Lactic acidosis is a rare but serious metabolic disorder that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. Metformin accumulation occurs in the setting of acute renal failure and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhea or vomiting, fever, or limited fluid intake), metformin treatment should be temporarily discontinued and it is recommended to consult a doctor.

In patients taking metformin, treatment with drugs that can sharply worsen renal function (e.g. antihypertensive drugs, diuretics or NSAIDs) should be initiated with caution. Other risk factors for lactic acidosis include alcohol abuse, hepatic insufficiency, inadequate control of diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of drugs that can cause lactic acidosis (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions").

Diagnosis

Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia progressing to coma. If suspected symptoms occur, the patient should discontinue metformin and seek immediate medical attention. Laboratory findings such as decreased blood pH (< 7.35), increased plasma lactate (> 5 mmol/L), increased anion gap, and lactate/pyruvate ratio are considered to support the diagnosis.

Doctors should warn patients about the risk of developing and the symptoms of lactic acidosis.

Kidney function

Since metformin is excreted by the kidneys, GFR should be determined before starting treatment and monitored regularly after starting treatment (see section 4.2):

at least once a year for patients with normal kidney function; at least 2–4 times a year for patients with creatinine clearance at the lower limit of normal, as well as for elderly patients.

Metformin is contraindicated in patients with GFR < 30 ml/min, treatment with the drug should be temporarily discontinued in the presence of conditions that may affect renal function (see section "Contraindications").

Renal impairment is common in the elderly and is often asymptomatic. Particular caution should be exercised in cases where there is a risk of renal impairment, such as when using antihypertensive or diuretic agents and when starting non-steroidal anti-inflammatory drugs (NSAIDs). In such cases, it is also recommended to check renal function before starting metformin treatment.

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).

Administration of iodinated contrast agents.

Intravenous administration of X-ray contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation in the body and an increased risk of lactic acidosis. Metformin should be discontinued prior to or during the procedure and not resumed until 48 hours after the procedure, provided that renal function has been monitored and is stable (see sections 4.2 and 4.5).

Metformin hydrochloride should be discontinued for the duration of surgery under general anesthesia or with spinal or epidural anesthesia. Therapy should be resumed no earlier than 48 hours after surgery and provided that renal function has been monitored and found to be stable.

Other precautions

All patients should follow a diet with a balanced distribution of carbohydrates throughout the day. Overweight patients should follow a low-calorie diet. Standard laboratory tests for patients with diabetes should be performed regularly. Monotherapy with metformin hydrochloride does not cause hypoglycemia, but caution is recommended when the drug is used in combination with insulin and other oral antidiabetic drugs (for example, sulfonylureas or meglitinides).

Pediatric population

Before using metformin hydrochloride, the diagnosis of diabetes mellitus should be confirmed.

Type II. Metformin hydrochloride is not a substitute for diet and daily exercise, which should be performed in accordance with the recommendations. During one-year controlled clinical studies, the effect of metformin on growth and development, as well as on puberty, was not observed, but data on these indicators with longer use are missing, which is why careful monitoring of them is recommended in children receiving metformin hydrochloride, especially during the pubertal period.

Children aged 10 to 12 years

In controlled clinical trials involving children, there were only 15 children aged

10-12 years. Although the use of metformin hydrochloride in these children did not differ in efficacy and safety from use in older individuals, metformin hydrochloride should be prescribed with extreme caution to children aged 10 to 12 years.

Ability to influence reaction speed when driving vehicles or other mechanisms

Metformin hydrochloride monotherapy does not cause hypoglycemia and therefore does not affect the ability to drive or use machines. However, the patient should be informed that hypoglycemic states may occur when metformin hydrochloride is used in combination with other antidiabetic agents (insulin, sulfonylureas, meglitinides).

Use during pregnancy or breastfeeding

Pregnancy

Uncontrolled diabetes mellitus 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. Animal studies have not shown any adverse effects on pregnancy, embryonic development, childbirth or postnatal development. If pregnancy is planned or occurs, metformin therapy should be discontinued, the doctor should be informed and insulin therapy should be prescribed to maintain blood glucose levels as close to normal as possible to reduce the risk of fetal malformations.

Breastfeeding period

Metformin passes into breast milk. No adverse effects have been observed in breastfed infants/toddlers whose mothers have taken the drug. However, as data on the use of the drug in such cases are insufficient, breastfeeding is not recommended for women taking metformin. A decision on whether to discontinue breastfeeding should be made taking into account both the benefit of breastfeeding and the potential risk of adverse effects on the child.

Fertility

Metformin did not affect animal fertility at doses of 600 mg/kg/day, which was almost 3 times the maximum recommended daily human dose based on body surface area.

Method of administration and doses

Adults with normal renal function (GFR ≥90 mL/min).

Monotherapy and combination with other oral antidiabetic agents.

The initial dose is 1 film-coated tablet of 500 mg or 850 mg of metformin hydrochloride 2-3 times a day, which should be taken during or after meals. After 10-15 days, the dose should be adjusted depending on the blood sugar level. A gradual increase in the dose has a positive effect on the tolerability of the drug in the digestive tract. For patients taking high doses of metformin hydrochloride (2 or 3 g per day), it is possible to replace the use of 2 film-coated tablets of 500 mg of metformin hydrochloride with 1 film-coated tablet of Siofor®1000.

The maximum recommended dose of metformin hydrochloride is 3 g, divided into

3 doses. When transferring from another oral antidiabetic agent to metformin hydrochloride, the previous agent should be discontinued and then therapy should be initiated at the above doses.

Combination 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.

Due to possible renal impairment in elderly patients, the dose of the drug is determined based on renal function tests. Regular monitoring of renal function is necessary (see section "Special warnings and precautions for use").

Kidney failure

Glomerular filtration rate (GFR) should be determined before starting treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of developing further renal failure and in elderly patients, renal function should be monitored more frequently, i.e. every 3–6 months.

Children

Monotherapy or combination therapy compatible with insulin.

Siofor® 1000 can be used in children aged 10 years and over.

The usual initial daily dose is 500 mg or 850 mg of metformin hydrochloride once daily with or after meals. After 10–15 days, the dose should be adjusted based on blood glucose levels. Gradual dose increases improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g per day, divided into 2–3 doses.

Instructions for use. The film-coated tablet can be split in half with two hands or by placing it on a flat surface with the wide wedge-shaped depression facing down and pressing with your thumb.

Children

Metformin hydrochloride can be used to treat children aged 10 years and older.

Overdose

When using metformin hydrochloride in doses up to 85 g, hypoglycemia was not observed, but lactic acidosis developed. Patients with signs of lactic acidosis require immediate medical attention in a hospital setting. The most effective means for removing lactate and metformin is hemodialysis.

Adverse reactions

When analyzing undesirable effects, the following frequency values were used as a basis: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unknown (available information does not allow this effect to be estimated).

On the part of metabolism.

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

Decreased absorption of vitamin B12 and decreased serum levels have been reported with long-term use of metformin hydrochloride. This should be considered as a possible cause in patients with megaloblastic anemia.

From the nervous system.

Common: taste disturbance.

From the digestive tract.

Very common: nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These phenomena occur at the beginning of treatment and in most cases resolve spontaneously. In order to prevent them, the dose of metformin should be divided into 2-3 doses and administered during or after meals. A slow increase in the dose improves the tolerability of the drug from the digestive tract.

From the liver and biliary tract.

Very rare: liver function tests or hepatitis, reversible after discontinuation of metformin hydrochloride.

On the skin and subcutaneous fat.

Very rare: skin reactions, e.g. redness, itching, urticaria.

Children and adolescents

According to published data, post-marketing experience and the results of controlled clinical trials in which the drug was used for 1 year in a limited number of children and adolescents aged 10–16 years, the nature and severity of adverse reactions in this group were similar to those observed in adults.

Reporting of possible adverse reactions

Reporting of possible adverse reactions after the registration of a medicinal product plays an important role. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Expiration date

3 years.

Storage conditions

No special storage conditions are required. Keep out of the reach of children.

Packaging

15 film-coated tablets in a blister; 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Berlin-Chemie AG/Menarini-Von Heyden GmbH.

Location of the manufacturer and its business address

Glienicker Weg 125, 12489 Berlin, Germany/Leipziger Strasse 7-13, 01097 Dresden, Germany.