Siophor® 850

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIOFOR® 850 (SIOFOR® 850)

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet contains 850 mg of metformin hydrochloride;

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

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white, elongated film-coated tablets with a dividing line on both sides.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Hypoglycemic agents except insulin. Biguanides. Metformin. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Metformin reduces basal hyperinsulinemia and, when used 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, partly by enhancing insulin action. Metformin alters glucose handling in the intestine: glucose uptake into the bloodstream increases, while absorption from food decreases. Additional intestinal-related mechanisms include increased release of glucagon-like peptide-1 (GLP-1) and reduced reabsorption of bile acids. Metformin alters the gut microbiome.

Metformin may improve the lipid profile in patients with hyperlipidemia.

In clinical studies, metformin use has been associated with either stable body weight or modest weight loss.

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

Clinical efficacy and safety

In a prospective randomized study (UKPDS), long-term benefits of regular blood glucose control were demonstrated in adult patients with type 2 diabetes.

Analysis of data from overweight patients who were prescribed metformin hydrochloride after diet therapy proved ineffective showed:

• statistically significant reduction in the absolute risk of developing diabetic complications in patients treated with 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 combined data from patients treated with monotherapy using sulfonylureas or 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 treated with 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 combined data from patients treated with monotherapy using sulfonylureas or 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 clinical benefit of metformin hydrochloride as a second-line agent in combination with sulfonylureas has not been confirmed.

Metformin hydrochloride has been used in combination with insulin in some patients with type 1 diabetes, but the clinical benefit of this combination therapy has not been officially established.

Children and adolescents

According to data from controlled clinical trials involving a small number of children and adolescents aged 10 to 16 years treated for 1 year, the efficacy of the drug in controlling blood glucose levels was approximately the same as in adults.

Pharmacokinetics.

Absorption

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

After oral administration, absorption of metformin hydrochloride is saturable and incomplete. Nonlinear pharmacokinetics of absorption are presumed.

At recommended doses and dosing regimens, steady-state plasma concentrations of metformin hydrochloride are achieved within 24–48 hours and generally do not exceed 1 µg/mL. In conducted studies, C_max (mean maximum concentration) in plasma did not exceed 4 µg/mL even with maximum doses. Food decreases the extent and rate of metformin absorption. After oral administration of an 850 mg metformin hydrochloride tablet, peak plasma concentration decreased by 40%, the area under the pharmacokinetic curve (AUC) decreased by 25%, and the time to peak plasma concentration increased by 35 minutes. The clinical significance of these effects has not been established.

Distribution

Plasma protein binding of metformin is negligible.

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

Erythrocytes likely represent a secondary distribution compartment.

The mean volume of distribution (V_d) ranges from 63 to 276 L.

Biotransformation

Metformin is excreted unchanged in urine. No metabolites of metformin have been identified in humans.

Elimination

Renal clearance of metformin exceeds 400 mL/min, indicating elimination via glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours.

In renal impairment, renal clearance of metformin decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and consequently increased plasma metformin levels.

Children and adolescents

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

Multiple-dose studies: data are limited to one single trial. After repeated administration of metformin hydrochloride 500 mg twice daily for 7 days in children and adolescents, maximum plasma concentration (C_max) and total exposure (AUC_0–t) were reduced by approximately 33% and 40%, respectively, compared to adult diabetic patients receiving repeated doses of 500 mg twice daily for 14 days. Since the dose is individually adjusted based on blood glucose levels, the clinical significance of these data is limited.

Clinical characteristics.

Indications.

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

For children aged 10 years and older, Siofor® 850 can be used as monotherapy or in combination with insulin.

Contraindications.

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 impairment (glomerular filtration rate (GFR) < 30 mL/min).

Acute conditions that may negatively affect kidney function, such as dehydration, severe infection, shock.

Conditions that may lead to tissue hypoxia (particularly acute conditions or exacerbations of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

Hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Concomitant use not recommended.

Ethanol.

In cases of acute alcohol intoxication, the risk of lactic acidosis increases, especially in the presence of fasting, inadequate nutrition, or hepatic impairment.

Alcohol consumption and use of ethanol-containing medicinal products should be avoided.

Contrast agents containing iodine.

Metformin must be discontinued at the time of or prior to the procedure and restarted no earlier than 48 hours after the procedure, provided that renal function has been reassessed and found to be stable (see section "Dosage and administration", "Special instructions").

Intravenous administration of iodine-containing radiographic contrast agents may cause renal impairment and, consequently, metformin accumulation, increasing the risk of lactic acidosis.

Concomitant use requiring special caution.

Some medicinal products may negatively affect renal function, thereby increasing the risk of lactic acidosis, for example: nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics. Careful monitoring of renal function is necessary at the beginning and during treatment with these drugs in combination with metformin.

Medicinal products capable of causing hyperglycemia (e.g., glucocorticoids (systemic and local use) and sympathomimetics). More frequent monitoring of blood glucose levels may be required, especially at the beginning of treatment. If necessary, the dose of the antidiabetic agent should be adjusted during and after discontinuation of these drugs.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• inhibitors of OCT1 (such as verapamil) may reduce metformin efficacy;
• inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

− inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal elimination of metformin, leading to increased plasma concentrations of metformin;

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

Therefore, special caution is recommended when co-administering these drugs with metformin, especially in patients with impaired renal function, as plasma concentrations of metformin may increase. Consideration should be given to adjusting the metformin dose, since OCT inhibitors/inducers may affect metformin efficacy.

Special precautions for use.

Lactic acidosis

Lactic acidosis is a rare but serious metabolic disorder, most commonly occurring in the setting of acute renal impairment, cardio-pulmonary disease, or sepsis. Accumulation of metformin occurs in acute renal impairment and increases the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or restricted fluid intake), treatment with metformin should be temporarily discontinued and medical advice should be sought.

Treatment with metformin in patients receiving medicinal products capable of abruptly worsening renal function (e.g., antihypertensives, diuretics, or NSAIDs) should be initiated cautiously. Other risk factors for lactic acidosis include alcohol abuse, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Diagnosis

Patients and/or caregivers should be informed about the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia progressing to coma. Suspicion of lactic acidosis should prompt immediate discontinuation of metformin and urgent medical attention. Diagnosis is confirmed by laboratory findings such as decreased blood pH (< 7.35), elevated plasma lactate levels (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Physicians should inform patients about the risk and symptoms of lactic acidosis.

Patients with established or suspected mitochondrial disorders

Metformin is not recommended in patients with established mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) or maternally inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the course of the disease.

If signs or symptoms suggestive of MELAS or MIDD occur, metformin therapy should be immediately discontinued and prompt diagnostic evaluation initiated.

Renal function

Since metformin is excreted by the kidneys, glomerular filtration rate (GFR) should be assessed before initiating treatment and regularly thereafter (see section "Dosage and administration"):

• At least once a year – in patients with normal renal function;
• At least 2–4 times a year – in patients with creatinine clearance at the lower limit of normal and in elderly patients.

Metformin is contraindicated in patients with GFR < 30 mL/min. Treatment should be temporarily discontinued in conditions that may affect renal function (see section "Contraindications").

Renal impairment frequently occurs in elderly patients and may be asymptomatic. Particular caution is required when conditions that may impair renal function arise, such as use of antihypertensive or diuretic agents or initiation of nonsteroidal anti-inflammatory drugs (NSAIDs). In such cases, renal function should also be evaluated before starting metformin therapy.

Cardiac function

Patients with heart failure have an increased risk of hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure provided cardiac and renal function are regularly monitored. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Administration of iodinated contrast agents

Intravenous administration of radiological contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued at the time of, or prior to, the procedure and should not be restarted earlier than 48 hours after the procedure, provided renal function has been reassessed and found to be stable (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures

Metformin hydrochloride should be discontinued during surgery under general anesthesia or spinal/epidural anesthesia. Therapy may be resumed no earlier than 48 hours after surgery, provided renal function has been reassessed and found to be stable.

Other precautions

All patients should follow a dietary regimen with balanced carbohydrate distribution throughout the day. Overweight patients should adhere to a low-calorie diet. Standard laboratory monitoring for diabetic patients should be performed regularly. Monotherapy with metformin hydrochloride does not cause hypoglycemia; however, caution is advised when metformin is used concomitantly with insulin or other oral antidiabetic agents (e.g., sulfonylureas or meglitinides).

Metformin may reduce serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and/or in patients with known risk factors for vitamin B12 deficiency. In case of suspected vitamin B12 deficiency (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is well tolerated and no contraindications exist, and appropriate corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.

Pediatric population

Before initiating metformin hydrochloride, a diagnosis of type 2 diabetes mellitus should be confirmed.

Metformin hydrochloride does not replace the need for diet and regular physical activity, which should be maintained according to recommendations. During one-year controlled clinical trials, no effects on growth, development, or sexual maturation were observed; however, data on long-term use are limited. Therefore, careful monitoring of these parameters is recommended in children receiving metformin hydrochloride, particularly during puberty.

In controlled clinical trials involving children, only 15 children aged 10–12 years were included. Although efficacy and safety of metformin hydrochloride in these children did not differ from that in older individuals, metformin hydrochloride should be prescribed to children aged 10–12 years with particular caution.

Use during pregnancy or breastfeeding

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital malformations and perinatal mortality. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital anomalies. Animal studies have not shown adverse effects on pregnancy, embryonal development, parturition, or postnatal development. In case of planned or confirmed pregnancy, metformin therapy should be discontinued, the physician 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 is excreted in breast milk. No effects of metformin have been observed in breastfed newborns/infants of treated mothers.

However, due to insufficient data on use in such cases, breastfeeding is not recommended for women taking metformin. The decision whether to discontinue breastfeeding should take into account both the benefits of breastfeeding and the potential risk of adverse effects of the drug on the infant.

Fertility

Metformin did not affect fertility in animals when administered at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to affect reaction speed when driving or operating machinery

Monotherapy with metformin hydrochloride does not cause hypoglycemia and therefore does not impair the ability to drive or operate machinery. However, patients should be informed that hypoglycemic episodes may occur when metformin hydrochloride is used in combination with other antidiabetic agents (e.g., insulin, sulfonylureas, meglitinides).

Dosage and Administration

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 taken 2–3 times daily with or after meals. After 10–15 days, the dose should be adjusted according to blood glucose levels. Gradual dose escalation improves gastrointestinal tolerance to the drug. The maximum daily dose of metformin hydrochloride is 3 g, divided into 3 doses. When switching from another oral antidiabetic agent to metformin hydrochloride, the previous agent should be discontinued and treatment initiated at the above-mentioned doses.

Combination with insulin.

To achieve better control of blood glucose levels, metformin and insulin may be used together as combination therapy. The usual initial dose is one film-coated tablet 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring results.

Children aged 10 years and older.

Monotherapy or combination therapy with insulin.

The medicinal product Siofor® may 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 measurements. Gradual dose escalation improves gastrointestinal tolerance. The maximum daily dose of metformin hydrochloride is 2 g, divided into 2–3 doses.

Elderly patients.

Due to the possible impairment of renal function in elderly patients, dosage should be determined based on renal function tests. Regular monitoring of renal function is required (see section "Special Warnings and Precautions for Use").

Renal impairment.

Glomerular filtration rate (GFR) should be determined before initiating treatment with metformin-containing medicinal products and at least once yearly thereafter. In patients at increased risk of worsening renal impairment, as well as in elderly patients, renal function should be monitored more frequently—every 3–6 months.

Children.

The medicinal product can be used in children aged 10 years and older.

Overdose.

Hypoglycemia was not observed with administration of metformin hydrochloride at doses up to 85 g; however, lactic acidosis developed, which may also be caused by metformin hydrochloride overdose or concomitant risk factors. Patients showing signs of lactic acidosis require immediate medical attention in a hospital setting. Hemodialysis is the most effective method for removing lactate and metformin.

Adverse Reactions

The following frequency categories are used to classify adverse events: 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), and not known (frequency cannot be estimated from the available data).

Metabolism and nutrition disorders

Common: Vitamin B12 deficiency (see section "Special warnings and precautions for use").

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

Nervous system disorders

Common: Taste disturbances.

Gastrointestinal disorders

Very common: Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite. These symptoms usually occur at the beginning of treatment and resolve spontaneously in most cases. To prevent them, metformin should be taken in divided doses of 2–3 times daily with meals or after meals. Slow dose escalation improves gastrointestinal tolerability.

Hepatobiliary disorders

Very rare: Liver function test abnormalities or hepatitis, which are reversible upon discontinuation of metformin hydrochloride.

Skin and subcutaneous tissue disorders

Very rare: Skin reactions such as erythema, pruritus, urticaria.

Children and adolescents

According to published data, post-marketing experience, and results from controlled clinical trials involving a limited number of children and adolescents aged 10–16 years treated for up to 1 year, the type and severity of adverse reactions in this population were similar to those observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 15 film-coated tablets in a blister. 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Berlin-Chemie AG.

Manufacturer's location and address of the place of business.

Glienicker Weg 125, 12489 Berlin, Germany.

Manufacturer.

Menarini von Heyden GmbH.

Manufacturer's location and address of the place of business.

Leipziger Strasse 7-13, 01097 Dresden, Germany.

Marketing Authorization Holder.

Berlin-Chemie AG.

Address of the Marketing Authorization Holder.

Glienicker Weg 125, 12489 Berlin, Germany.