Siophor® 1000
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIOFOR® 1000 (SIOFOR® 1000)
Composition:
Active substance: metformin hydrochloride;
One film-coated tablet contains 1000 mg of metformin hydrochloride, equivalent to 780 mg of metformin;
Excipients: hypromellose (15000 mPa·s and 5 mPa·s), povidone (K 25), magnesium stearate, polyethylene glycol 6000, titanium dioxide (E 171).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: white, elongated film-coated tablets, with a "snap-tab" bevel on one side and a dividing line on the other.
Pharmacotherapeutic group. Antidiabetic agents. Blood glucose-lowering drugs excluding insulin. Biguanides. ATC code A10B A02.
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.
Metformine reduces glucose production in the liver.
Metformin enhances peripheral glucose uptake and utilization, partly by improving 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
The long-term benefits of regular blood glucose control in adult patients with type 2 diabetes mellitus were established in a prospective randomized study (UKPDS).
Analysis of data from overweight patients who were prescribed metformin hydrochloride after diet therapy failed showed:
- a 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 sulfonylurea derivatives or insulin (40.1 cases/1000 patient-years), p = 0.0034;
- a statistically significant reduction in 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);
- a statistically significant reduction in 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 sulfonylurea derivatives or insulin monotherapy — 18.9 cases/1000 patient-years (p = 0.021);
- a statistically significant reduction in 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 sulfonylurea 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 similar to that observed 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 after oral administration is 20–30%.
After oral administration, absorption of metformin hydrochloride is saturable and incomplete. Its absorption pharmacokinetics are considered to be nonlinear.
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 clinical studies, Cmax (mean maximum concentration) in plasma did not exceed 4 µg/mL even at maximum doses. Food reduces both the extent and slightly the 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
Protein binding of metformin to plasma proteins is negligible.
Metformin hydrochloride penetrates into erythrocytes. Maximum drug concentration in blood is lower than in plasma but is reached at approximately the same time.
Erythrocytes likely represent a secondary distribution compartment.
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 is > 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 who received 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 study. 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 (500 mg twice daily) for 14 days. Since dosing is individualized based on blood glucose levels, the clinical relevance of these data is limited.
Clinical characteristics.
Indications.
Type 2 diabetes mellitus when dietary therapy and physical exercise have failed, particularly in patients with excess body weight;
- as monotherapy or combined therapy together with other oral hypoglycemic agents, or together with insulin for the treatment of adults;
- as monotherapy or combined therapy with insulin for the treatment of children aged 10 years and older and adolescents.
For reducing diabetes complications in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line agent after failure of dietary therapy.
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, e.g., dehydration, severe infection, shock.
Conditions that may lead to tissue hypoxia (especially acute conditions or exacerbations of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
Hepatic impairment, acute alcohol intoxication, alcoholism.
Interaction with other medicinal products and other forms of interactions.
Concomitant use not recommended.
Ethanol.
During acute alcohol intoxication, the risk of lactic acidosis increases, especially in cases of fasting, inadequate nutrition, or hepatic impairment.
Alcohol consumption and the use of ethanol-containing medicinal products should be avoided.
Iodinated contrast agents.
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 precautions").
Intravenous administration of iodinated 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 kidney function, thereby increasing the risk of lactic acidosis, e.g., NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, ACE inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics. Careful monitoring of renal function is required at the start and during treatment with these drugs in combination with metformin.
Medicinal products capable of causing 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. The antidiabetic dose may need to be adjusted during and after discontinuation of these agents.
Organic cation transporters (OCTs)
Metformin is a substrate of both OCT1 and OCT2 transporters.
Concomitant use of metformin with:
- OCT1 inhibitors (such as verapamil) may reduce metformin efficacy;
- 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 renal elimination of metformin, leading to increased plasma concentrations of metformin;
- inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal elimination of metformin.
Therefore, special caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as plasma concentrations of metformin may increase. Dose adjustment of metformin should be considered if necessary, since OCT inhibitors/inducers may influence metformin efficacy.
Special precautions for use.
Lactic acidosis
Lactic acidosis is a rare but serious metabolic disorder, most commonly occurring in the context of acute worsening of renal function, cardio-pulmonary disease, or sepsis. Accumulation of metformin occurs in the setting of acute renal impairment and increases the risk of lactic acidosis.
In cases of dehydration (severe diarrhea or vomiting, fever, or limited fluid intake), metformin therapy should be temporarily discontinued, and patients are advised to consult a physician.
Treatment with metformin should be initiated cautiously in patients receiving concomitant medications capable of abruptly impairing renal function (e.g., antihypertensive agents, diuretics, or NSAIDs). Other risk factors for lactic acidosis include alcohol abuse, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, any conditions associated with hypoxia, and concomitant use of drugs that may cause 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. Confirmation of diagnosis is based on 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 warn patients about the risk of developing lactic acidosis and its symptoms.
Patients with established or suspected mitochondrial disorders
Metformin is not recommended in patients with established mitochondrial disorders, such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)) and 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 discontinued immediately and a rapid diagnostic evaluation should be performed.
Renal function
Since metformin is excreted by the kidneys, glomerular filtration rate (GFR) should be assessed before initiating treatment and monitored 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 there is a risk of impaired renal function, for example, during treatment with antihypertensive or diuretic agents or at the 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 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 radiographic 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 restarted no earlier than 48 hours after the procedure, provided renal function has been reassessed and found to be stable (see sections "Dos游戏副本 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 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. If vitamin B12 deficiency is suspected (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 tolerated and no contraindications exist, and appropriate corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.
Pediatric population
The diagnosis of type 2 diabetes mellitus should be confirmed before initiating metformin hydrochloride. 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 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.
Children aged 10 to 12 years
In controlled clinical trials involving children, only 15 children aged 10–12 years were included. Although the efficacy and safety of metformin hydrochloride in this age group 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 malformations. Animal studies have not shown adverse effects on pregnancy, embryonic 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. Adverse effects in neonates/infants breastfed by mothers taking metformin have not been observed. However, due to insufficient data on use in such cases, breastfeeding is not recommended for women taking metformin. The decision on 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 (eGFR ≥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 taken 2–3 times daily with meals or immediately after meals. After 10–15 days, the dose should be adjusted according to blood glucose levels. Gradual dose escalation improves gastrointestinal tolerability. Patients receiving high doses of metformin hydrochloride (2 or 3 g daily) may switch from taking 2 film-coated tablets of 500 mg metformin hydrochloride to 1 film-coated tablet of Glucophage® 1000.
The maximum recommended daily dose of metformin hydrochloride is 3 g, divided into 3 doses. When switching from another oral antidiabetic agent to metformin hydrochloride, the previous medication should be discontinued and treatment initiated at the above-mentioned doses.
Combination with insulin.
For better control of blood glucose levels, metformin and insulin can be used together as combination therapy. The usual initial dose is 500 mg or 850 mg of metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring results.
Elderly patients.
Due to the potential for impaired 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").
Renal impairment.
Glomerular filtration rate (eGFR) should be assessed before initiating treatment with metformin-containing products and at least 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.
| eGFR ml/min |
Total maximum daily dose (should be divided into 2–3 daily doses) |
Notes |
| 60–89 |
3000 mg |
Dose reduction may be considered due to reduced kidney function. |
| 45–59 |
2000 mg |
Before initiating metformin therapy, reassess factors that may increase the risk of lactic acidosis (see section "Precautions"). The initial dose should not exceed half of the maximum dose. |
| 30–44 |
1000 mg |
|
| <30 |
̶ |
Metformin is contraindicated. |
Children
Monotherapy or combination therapy with insulin.
Metformin 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, taken during or after a meal. After 10–15 days, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation improves gastrointestinal tolerability. The maximum recommended daily dose of metformin hydrochloride is 2 g, divided into 2–3 doses.
Instructions for use. The film-coated tablet can be divided in half by hand, either by bending it with both hands or by placing it on a flat surface with the wide, wedge-shaped indentation facing down and pressing with the thumb.
Children.
Metformin hydrochloride can be used for the treatment of children aged 10 years and older.
Overdose.
Hypoglycemia has not been observed with metformin hydrochloride doses up to 85 g; however, lactic acidosis may develop. 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 from the body.
Adverse reactions.
The following frequency categories of adverse effects were used: 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), not known (the available data do not allow assessment of the frequency).
Metabolism and nutrition disorders.
Common: Vitamin B12 deficiency/low levels (see section "Special precautions").
Very rare: lactic acidosis (see section "Special precautions").
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, the dose of metformin should be divided into 2–3 doses and taken during 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 of controlled clinical trials involving a limited number of children and adolescents aged 10–16 years treated for up to 1 year, adverse events in this population were similar in nature and severity 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 and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at https://aisf.dec.gov.ua or through the company's website https://www.berlin-chemie.ua.
Shelf life. 3 years.
Storage conditions. No special storage conditions required. Keep out of reach of children.
Packaging. 15 film-coated tablets in a blister; 2 or 4 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Berlin-Chemie AG / Menarini-von Heyden GmbH.
Manufacturer's address and place of business.
Glienicker Weg 125, 12489 Berlin, Germany / Leipziger Strasse 7-13, 01097 Dresden, Germany.
Marketing Authorization Holder.
Laboratori Guidotti S.p.A.
Address of the Marketing Authorization Holder and/or its representative.
Via Livornese, 897, 56122 La Vettola (Pisa), Italy.