Siophor® 500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIOFOR® 500 (SIOFOR® 500)

Composition:

Active substance: metformin hydrochloride;

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

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Hypoglycemic agents except insulin. Biguanides. Metformin. ATC code A10B A02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

Metformin reduces fasting hyperinsulinemia and, when used in combination with insulin, reduces insulin requirements.

Metformin exerts its antihyperglycemic effects through several mechanisms.

Metformine reduces glucose production in the liver.

Metformin enhances peripheral glucose uptake and utilization, partly by improving insulin sensitivity. 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 individuals 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

A long-term benefit of regular blood glucose control in adult patients with type 2 diabetes was established in a prospective randomized study (UKPDS).

Analysis of data from overweight patients who were prescribed metformin hydrochloride after diet therapy failed to control their condition 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.

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

Children and adolescents

According to 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, Tmax (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 amounts to 20–30%.

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

At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and generally do not exceed 1 µg/mL. In clinical studies, Cmax (mean maximum concentration) in plasma did not exceed 4 µg/mL, even with maximum doses. Food reduces 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 reach peak plasma concentration increased by 35 minutes. The clinical significance of these effects has not been established.

Distribution

Protein binding of metformin to plasma proteins is negligible.

Metformin hydrochloride penetrates into erythrocytes. Maximum drug concentration in whole blood is lower than in plasma but is reached at approximately the same time.

Erythrocytes likely represent a secondary compartment of distribution.

The mean volume of distribution (Vd) 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 a single trial. After repeated administration of metformin hydrochloride at 500 mg twice daily for 7 days in children and adolescents, maximum plasma concentration (Cmax) and total exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to adult diabetic patients receiving the same dose regimen for 14 days. Since dosage is individually adjusted based on blood glucose levels, the clinical significance of these findings 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 diet and physical exercise have been ineffective.

For children aged 10 years and older, Siofor® 500 may 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 adversely affect kidney function, such as dehydration, severe infection, shock.

Conditions that may lead to tissue hypoxia (especially acute conditions or acute exacerbation 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 medicinal products containing ethanol should be avoided.

Iodine-containing contrast agents.

Metformin must be discontinued during the procedure or prior to the procedure and should not be restarted until at least 48 hours after the procedure, provided that renal function has been reassessed and found to be stable (see section "Dosage and administration", "Special precautions").

Intravenous administration of iodine-containing radiological contrast agents may cause renal impairment and, consequently, metformin accumulation and increased 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, particularly loop diuretics. Careful monitoring of renal function is required at the beginning and during treatment when these drugs are used in combination with metformin.

Medicinal products that may cause hyperglycemia (e.g., glucocorticoids (systemic and local administration) and sympathomimetics). More frequent monitoring of blood glucose levels may be necessary, especially at the beginning of treatment. If required, 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 excretion 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 these drugs are used concomitantly with metformin, particularly in patients with impaired renal function, as plasma concentrations of metformin may increase. Consideration should be given to adjusting the dose of metformin, 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 failure, cardio-pulmonary disease, or sepsis. Accumulation of metformin occurs during acute renal impairment and increases the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or restricted fluid intake), metformin therapy should be temporarily discontinued and patients are advised to consult a physician.

Treatment with metformin in patients receiving medications that may abruptly impair renal function (e.g., antihypertensives, diuretics, or NSAIDs) should be initiated with caution. 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 drugs that may induce lactic acidosis (see sections "Contraindications", "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. In case of suspected symptoms, the patient must discontinue metformin immediately and seek 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 maternal inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, potentially worsening the disease course.

If signs or symptoms suggestive of MELAS or MIDD occur, metformin therapy should be discontinued immediately 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 in elderly patients is common and often asymptomatic. Particular caution is required when conditions that may impair renal function arise, such as use of antihypertensive or diuretic agents, or initiation of non-steroidal anti-inflammatory drugs (NSAIDs). In such cases, renal function should also be evaluated prior to starting metformin therapy.

Cardiac function

Patients with heart failure have an increased risk of developing hypoxia and renal failure. 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 administration must be discontinued during or prior to the procedure and should not be resumed until at least 48 hours after the procedure, provided renal function has been reassessed and found to be stable (see sections "Dosage and administration", "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 evenly distributed carbohydrate intake throughout the day. Overweight patients should adhere to a low-calorie diet. Standard laboratory tests 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 treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspected vitamin B12 deficiency (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Periodic monitoring of vitamin B12 may be necessary in patients with risk factors for deficiency. Metformin therapy should be continued as long as it is 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, type 2 diabetes mellitus must be confirmed. Metformin hydrochloride does not replace the need for diet and regular physical exercise, which should be maintained as recommended. During one-year controlled clinical studies, no adverse effects of metformin 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, especially 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 anomalies and perinatal mortality. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital malformations. Animal studies have not shown any adverse effects on pregnancy, embryonal development, parturition, or postnatal development. In case of planned pregnancy or when pregnancy occurs, 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

Metformin is excreted in human breast milk. No effects of metformin have been observed in newborns/infants breastfed by mothers taking the drug.

However, due to insufficient data on use in such cases, breastfeeding is not recommended in 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 had no effect on fertility in animals at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Effect on ability to drive and use machines

Metformin hydrochloride monotherapy 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 (eGFR ≥ 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 meals or immediately after meals. After 10–15 days, the dose should be adjusted based on blood glucose levels. Gradual dose escalation improves gastrointestinal tolerability of 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 therapy initiated at the above-mentioned doses.

Combination with insulin.

To achieve better blood glucose control, 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 according to blood glucose monitoring results.

Children aged 10 years and older.

Monotherapy or combination therapy with insulin.

The medicinal product 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 meals or immediately after meals. After 10–15 days, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation improves gastrointestinal tolerability. The maximum daily dose of metformin hydrochloride is 2 g, divided into 2–3 doses.

Elderly patients.

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

Renal impairment.

The glomerular filtration rate (eGFR) should be determined before initiating treatment with metformin-containing medicinal products and at least once annually 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 following administration of metformin hydrochloride in 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

In the analysis of adverse effects, the following frequency categories are used: 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 (the available data do not allow estimation of the frequency).

Metabolic disorders

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

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

Nervous system disorders

Common: taste disturbances.

Gastrointestinal disorders

Very common: nausea, vomiting, diarrhea, abdominal pain, loss of appetite. These events usually occur at the beginning of treatment and resolve spontaneously in most cases. To prevent these symptoms, the dose of metformin should be divided into 2–3 doses and administered during or after meals. Gradual dose escalation improves gastrointestinal tolerability.

Hepatic and biliary disorders

Very rare: disturbances in liver function tests or hepatitis, which are reversible after 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 marketing authorization 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. 10 film-coated tablets in a blister. 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Berlin-Chemie AG.

Manufacturer's address.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Berlin-Chemie AG.

Address of the Marketing Authorization Holder.

Glienicker Weg 125, 12489 Berlin, Germany.