Siofor 500 film-coated tablets 500 mg No. 60

Instructions Siofor 500 film-coated tablets 500 mg No. 60

Composition

active ingredient: metformin hydrochloride;

1 film-coated tablet contains: metformin hydrochloride 500 mg;

excipients: hypromellose, povidone (K 25), magnesium stearate, polyethylene glycol 6000, titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: white, round, biconvex tablets, film-coated.

Pharmacotherapeutic group

Drugs affecting the digestive system and metabolism. Antidiabetic drugs. Hypoglycemic drugs, except insulins. Biguanides. Metformin. ATC code A10B A02.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic effects on both basal and postprandial hyperglycemia. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.

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

Metformin exerts its antihyperglycemic effect through several mechanisms.

Metformin reduces glucose production in the liver.

Metformin facilitates peripheral glucose uptake and utilization, in part by enhancing insulin action. Metformin alters intestinal glucose uptake: uptake 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 may improve lipid profiles in individuals with hyperlipidemia.

In clinical trials, metformin use was associated with either stable body weight or modest weight loss.

Metformin activates adenosine monophosphate protein kinase (AMPK) and increases the transport capacity of all currently known types of membrane glucose transporters (GLUTs).

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 to diet therapy alone (43.3 cases/1000 patient-years), p = 0.0023, and compared to the total indicators of patients who used monotherapy with sulfonylurea derivatives and insulin (40.1 cases/1000 patient-years), p = 0.0034;

statistically significant reduction in the absolute risk of diabetes-related mortality: metformin hydrochloride - 7.5 cases/1000 patient-years; diet therapy alone - 12.7 cases/1000 patient-years (p = 0.017);

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);

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 sulfonylureas 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, Tmax (maximum concentration of the drug) in blood plasma is reached after 2.5 hours. The absolute bioavailability of metformin hydrochloride in the dosage form of tablets of 500 mg and 850 mg 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 plasma concentrations (Cmax) did not exceed 4 μg/ml even at maximum doses. Food reduces the extent and rate of metformin absorption. After oral administration of an 850 mg metformin hydrochloride tablet, peak plasma concentrations were reduced by 40%, the area under the pharmacokinetic curve (AUC) was reduced by 25%, and the 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 a secondary 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 exceeds 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 a single 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 administration of 500 mg twice daily for 14 days. Since the dose of the drug is selected individually based on blood glucose levels, the clinical relevance of these data is limited.

Indication

Treatment of type 2 diabetes mellitus in adults and children aged 10 years and older, especially in the presence of excess body weight, when diet therapy and physical activity are ineffective.

For children aged 10 years and over, Siofor® 500 can be used as monotherapy or in combination with insulin.

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 can negatively affect kidney function, such as dehydration, severe infectious disease, 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 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 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. The need for 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 regularly after starting treatment (see section "Method of administration and dosage"):

at least once a year – in patients with normal kidney function;

at least 2–4 times a year – in patients with creatinine clearance at the lower limit of normal, as well as in 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. Metformin hydrochloride monotherapy does not cause hypoglycemia, but caution is recommended when the drug is used in combination with insulin and other oral antidiabetic drugs (e.g. sulfonylureas or meglitinides).

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with increasing metformin dose, duration of treatment and/or in patients with 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 periodic monitoring of vitamin B12. Metformin therapy should be continued as long as tolerated and there are no contraindications, and appropriate corrective treatment for vitamin B12 deficiency should be given in accordance with current clinical guidelines.

Pediatric population

Before using metformin hydrochloride, a diagnosis of type 2 diabetes mellitus should be confirmed. Metformin hydrochloride is not a substitute for diet and daily exercise, which should be performed in accordance with the recommendations. In 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 not available, which is why careful monitoring of them is recommended in children receiving metformin hydrochloride, especially during the pubertal period.

Controlled clinical trials in children included only 15 children aged 10–12 years. Although metformin hydrochloride was not shown to be as effective or safe in these children as in older adults, metformin hydrochloride should be used with caution in children aged 10–12 years.

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, parturition or postnatal development. If pregnancy is planned or if pregnancy occurs, metformin therapy should be discontinued, the doctor should be informed and insulin therapy should be initiated 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 effects of metformin have been observed in breastfed newborns/infants 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 of the drug 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.

The ability to influence the reaction speed when driving or working with other mechanisms

Monotherapy with metformin hydrochloride does not cause hypoglycemia, therefore it 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).

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 2–3 times a day, which should be taken during or after meals. After 10–15 days, the dose should be adjusted depending on blood sugar levels. A gradual increase in the dose has a positive effect on the tolerability of the drug by the digestive tract. The maximum daily 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 started at the above doses.

To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose is one film-coated tablet 2–3 times daily, while the insulin dose should be adjusted according to blood glucose measurements.

Children aged 10 and over

Monotherapy or combination therapy compatible with insulin.

The drug Siofor® can be used in children aged 10 years and older.

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 daily dose of metformin hydrochloride is 2 g per day, divided into 2–3 doses.

Elderly patients.

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, e.g. every 3–6 months.

Children

The medicine can be used in children aged 10 years and over.

Overdose

When using metformin hydrochloride in doses up to 85 g, hypoglycemia was not observed, but lactic acidosis developed, which can also be caused by an overdose of metformin hydrochloride or concomitant risk factors. Patients with signs of lactic acidosis require immediate medical attention in a hospital setting. The most effective means of removing lactate and metformin is hemodialysis.

Side effects

When analyzing undesirable effects, the following frequency values were taken as a basis: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (available information does not allow estimating the frequency).

On the part of metabolism.

Common: Decreased level/vitamin B12 deficiency (see section "Special warnings and precautions for use").

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

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

10 film-coated tablets in a blister. 6 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Berlin-Chemie AG.

Location of the manufacturer and its business address.

Glienicker Weg 125, 12489 Berlin, Germany.

Applicant

Berlin-Chemie AG.

Applicant's location

Glienicker Weg 125, 12489 Berlin, Germany.