Metamin® sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METAMINÒSR (METAMINÒSR)

Composition:

Active substance: metformin hydrochloride (metformin hydrochloride);

One tablet contains 500 mg of metformin hydrochloride;

Excipients: microcrystalline cellulose, ethylcellulose, hypromellose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical characteristics: white, oval-shaped tablets, smooth on both sides.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Metformin is a biguanide with an antihyperglycemic effect. It reduces glucose levels in blood plasma both in the fasting state and after food intake. It does not stimulate insulin secretion and does not cause hypoglycemia mediated by this mechanism.

Metformin acts via three pathways:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, resulting in enhanced peripheral glucose uptake and utilization;
• delays intestinal absorption of glucose.

Metformin hydrochloride stimulates intracellular glycogen synthesis by affecting glycogen synthase. It increases the transport capacity of all known types of glucose membrane transporters (GLUT).

Pharmacodynamic effects.

The main effect of metformin hydrochloride, apart from its hypoglycemic action, is stabilization or slight reduction in body weight.

Independent of its effect on glycemia, immediate-release metformin tablets demonstrate a positive effect on lipid metabolism. In particular, they reduce total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. This effect has not been observed with extended-release tablets, likely due to evening administration. Consequently, an increase in triglyceride levels may occur.

Clinical efficacy.

Reduction of risk or delay in onset of type 2 diabetes mellitus.

The Diabetes Prevention Program (DPP) in adults was a multicenter, randomized, controlled clinical trial evaluating the effectiveness of lifestyle intervention or metformin in preventing or delaying the onset of type 2 diabetes mellitus. Inclusion criteria included age ≥25 years, BMI ≥24 kg/m² (≥22 kg/m² for Asian Americans), and impaired glucose tolerance plus fasting plasma glucose levels of 95–125 mg/dL (or ≤125 mg/dL for American Indians). Participants were assigned to intensive lifestyle intervention, 2×850 mg metformin plus standard lifestyle changes, or placebo plus standard lifestyle changes.

Baseline characteristics of DPP participants (n=3,234 over 2.8 years) were as follows: mean age 50.6±10.7 years, fasting plasma glucose 106.5±8.3 mg/dL, 2-hour plasma glucose after oral glucose load 164.6±17.0 mg/dL, and BMI 34.0±6.7 kg/m². Intensive lifestyle intervention and metformin significantly reduced the risk of developing type 2 diabetes compared to placebo: 58% (95% CI 48–66%) and 31% (95% CI 17–43%), respectively.

The benefit of lifestyle intervention over metformin was greater in older patients.

Patients who benefited most from metformin treatment were aged 45 years or older, with BMI ≥35 kg/m², baseline 2-hour glucose levels of 9.6–11.0 mmol/L, baseline HbA1c ≥6.0%, or a history of gestational diabetes. To prevent diabetes over three years, 6.9 participants needed to be treated in the lifestyle group and 13.9 in the metformin group. The time to reach a cumulative diabetes incidence of 50% was delayed by approximately three years in the metformin group compared to placebo.

Diabetes Prevention Program Outcomes Study (DPPOS) is a long-term follow-up of the DPP, including more than 87% of the original DPP participants for continued long-term observation.

Among DPPOS participants (n=2776), the cumulative incidence of diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the lifestyle intervention group. Overall incidence rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and lifestyle groups, respectively. Compared to placebo, the risk of diabetes was reduced by 18% in the metformin group (hazard ratio (HR) 0.82, 95% CI 0.72–0.93; p=0.001) and by 27% in the lifestyle group (HR 0.73, 95% CI 0.65–0.83; p<0.0001). There were no significant differences between groups regarding the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy. However, among participants who did not develop diabetes during DPP/DPPOS, the prevalence of microvascular complications was 28% lower than in those who developed diabetes (hazard ratio 0.72, 95% CI 0.63–0.83; p<0.0001). There are no comparative data on the effect of metformin on macrovascular complications in patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) and/or elevated HbA1c.

Known risk factors for type 2 diabetes from published literature include: Mongoloid or Negroid ethnicity, age over 40 years, dyslipidemia, hypertension, obesity or overweight, age, family history (first-degree relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus.

A prospective randomized trial (UKPDS) demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes receiving immediate-release metformin hydrochloride as first-line therapy after diet failure. Analysis of outcomes in overweight patients treated with metformin hydrochloride after diet failure showed:

• significant reduction in absolute risk of any diabetes-related complication: 29.8 events/1000 patient-years in the metformin hydrochloride group vs. 43.3 events/1000 patient-years in the diet-only group (p=0.0023), and vs. 40.1 events/1000 patient-years in the combined therapy group (sulfonylurea plus insulin monotherapy) (p=0.0034);
• significant reduction in absolute risk of diabetes-related mortality: 7.5 events/1000 patient-years with metformin hydrochloride vs. 12.7 events/1000 patient-years with diet alone (p=0.017);
• significant reduction in absolute risk of all-cause mortality: 13.5 events/1000 patient-years in the metformin hydrochloride group vs. 20.6 events/1000 patient-years in the diet-only group (p=0.011), and vs. 18.9 events/1000 patient-years in the combined sulfonylurea and insulin monotherapy group (p=0.021);
• significant reduction in absolute risk of myocardial infarction: 11 events/1000 patient-years with metformin hydrochloride vs. 18 events/1000 patient-years with diet alone (p=0.01).

For metformin hydrochloride used as second-line therapy in combination with sulfonylurea, clinical benefit has not been demonstrated.

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

Pharmacokinetics.

Absorption.

After oral administration of metformin hydrochloride extended-release tablets, metformin absorption is significantly delayed compared to immediate-release tablets. The time to reach maximum concentration (Tmax) is 7 hours (Tmax for immediate-release tablets is 2.5 hours).

At steady state, as with immediate-release tablets, maximum concentration (Cmax) and area under the curve (AUC) increase disproportionately relative to the administered dose.

The AUC after a single 2000 mg oral dose of metformin hydrochloride in extended-release tablets is comparable to the AUC observed after 1000 mg metformin hydrochloride in immediate-release tablets administered twice daily.

Variability in Cmax and AUC among individuals taking extended-release tablets is comparable to that observed with immediate-release tablets.

After administration of extended-release tablets in the fasting state, a 30% reduction in AUC was observed (Cmax and Tmax remained unchanged).

Absorption of metformin from extended-release tablets is not affected by food composition. No accumulation occurs with repeated dosing up to 2000 mg metformin hydrochloride as extended-release tablets.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached approximately at the same time. Erythrocytes likely represent a secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism.

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

Elimination.

Renal clearance of metformin is >400 mL/min, indicating that metformin 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 decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased metformin plasma levels.

Special patient populations.

Renal impairment.

Limited data are available for patients with moderate renal impairment; therefore, it is not possible to precisely assess systemic exposure to metformin in this patient group compared to those with normal renal function. Dose adjustment is required based on clinical efficacy and tolerability (see section "Dosage and administration").

Clinical characteristics.

Indications.

• Reduction of risk or delay in onset of type 2 diabetes mellitus in adult patients with overweight and with IGT* and/or IFG*, and/or elevated HbA1C levels who have:
  • high risk of developing overt (manifest) type 2 diabetes mellitus (see section "Pharmacodynamics");
  • progressive disturbances in carbohydrate metabolism despite lifestyle modifications over a period of 3 to 6 months.

Treatment with Metamin®SR should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Concurrently with initiation of metformin, lifestyle modifications should be continued, except in cases where the patient is unable to make such changes for medical reasons.

*IGT: Impaired glucose tolerance; IFG: Impaired fasting glucose

• Treatment of type 2 diabetes mellitus in adults, particularly in patients with overweight, when diet and physical activity alone do not provide adequate glycemic control. Metamin®SR may be used as monotherapy or in combination with other oral antidiabetic agents, or in combination with insulin.

Contraindications.

• Hypersensitivity to metformin or to any other component of the medicinal product;
• any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis);
• diabetic precoma;
• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• acute conditions associated with risk of renal function impairment, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially 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.

Combinations not recommended for use.

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting or adherence to a low-calorie diet, as well as in hepatic impairment.

Iodinated contrast agents. Metformin should be discontinued before or during radiological procedures involving iodinated contrast agents and not restarted earlier than 48 hours after the procedure, provided normal renal function has been confirmed (see sections "Method of administration and dosage" and "Special instructions").

Combinations that should be used with caution.

Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when using them in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics).

More frequent monitoring of blood glucose levels is required, especially at the beginning of treatment. Dose adjustment of metformin hydrochloride may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCTs).

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant administration of metformin with:

• inhibitors of OCT1 (such as verapamil) may reduce the efficacy of metformin;
• 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 both the efficacy and renal excretion of metformin.

Therefore, particular 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 the efficacy of metformin.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in acute worsening of renal function, cardiopulmonary disease, or sepsis. In acute worsening of renal function, metformin accumulates, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended, and medical advice should be sought.

When a patient is receiving metformin, caution is advised when initiating treatment with agents that may acutely worsen renal function (e.g., antihypertensive drugs, diuretics, and NSAIDs). Other risk factors for lactic acidosis include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, potentially progressing to coma. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate concentration (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.

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

If signs or symptoms suggestive of MELAS or MIDD occur after taking metformin, treatment should be immediately discontinued and a rapid diagnostic evaluation performed.

Renal impairment. eGFR should be assessed before starting treatment and regularly thereafter (see section "Posology and method of administration"). Metformin is contraindicated in patients with eGFR < 30 mL/min and should be temporarily discontinued in the presence of conditions affecting renal function (see section "Contraindications").

Cardiac function. Patients with heart failure have an increased risk of developing hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Elderly patients.

Due to limited data on therapeutic efficacy of metformin in reducing the risk of developing type 2 diabetes or delaying its onset in patients aged 75 years and older, metformin is not recommended for this age group.

Iodinated contrast agents. Intravascular administration of iodinated contrast media may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, provided normal renal function is confirmed (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures. Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and restarted no earlier than 48 hours after surgery or upon resumption of oral nutrition, provided normal renal function is confirmed.

Other precautions. Patients should adhere to a diet with evenly distributed carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Regular monitoring of blood glucose levels is required.

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 presence of 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 tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency administered according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides).

The presence of tablet coating fragments in feces may occur. This is a normal phenomenon and has no clinical significance.

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse outcomes for both mother and child.

Metformin crosses the placenta in concentrations similar to those in the mother.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from registry-based cohort studies and published meta-analyses and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure during the periconception period and/or during pregnancy.

There are some unconfirmed data regarding the long-term effects of metformin on the weight of children exposed in utero. Available evidence suggests that metformin does not affect motor and social development in children up to 4 years of age who were exposed in utero, although long-term outcome data are limited.

If clinically necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an alternative to insulin.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should consider the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin had no effect on fertility in animal studies 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 rate when driving or operating machinery.

Metformin hydrochloride does not affect the speed of reactions when driving or operating machinery, as monotherapy with the drug does not cause hypoglycemia.

However, caution is advised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin, meglitinides) due to the risk of hypoglycemia.

Method of Administration and Dosage.

Adult patients with normal renal function (eGFR ≥ 90 mL/min).

Reduction of risk or delay in onset of type 2 diabetes mellitus.

Metformin should only be prescribed when lifestyle modifications over a period of 3–6 months have not provided adequate glycemic control.

Treatment should be initiated with one tablet of Metamin®SR 500 mg once daily with the evening meal.

After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements (OGTT (oral glucose tolerance test) values and/or fasting plasma glucose and/or HbA1c should be within normal range). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose is 4 tablets (2000 mg) once daily with the evening meal.

Regular monitoring (every 3–6 months) of glycemic status (OGTT values and/or fasting plasma glucose and/or HbA1c), as well as risk factors, is recommended to guide decisions regarding the need for continuation, modification, or discontinuation of treatment.

Re-evaluation of therapy is also necessary if the patient subsequently improves diet and/or physical activity, or if changes in the patient's health status allow for lifestyle modifications.

Monotherapy or combination therapy with other oral hypoglycemic agents.

The recommended initial dose is 500 mg (1 tablet) once daily.

After 10–15 days of treatment, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg (4 tablets) once daily.

The dose should be taken once daily with the evening meal, increasing by 500 mg every 10–15 days up to 2000 mg.

If the desired glycemic control cannot be achieved with Metamin®SR 2000 mg once daily, the patient should switch to Metamin®SR 1000 mg twice daily with meals.

If adequate glycemic control is not achieved, tablets of metformin hydrochloride with immediate release may be used at the maximum recommended dose of 3000 mg daily.

For patients previously treated with metformin, the initial dose of Metamin®SR extended-release tablets should be equivalent to the daily dose of immediate-release tablets. Patients receiving metformin doses exceeding 2000 mg daily are not recommended to switch to Metamin®SR therapy.

When switching to Metamin®SR 500 mg extended-release tablets, concomitant oral antidiabetic drugs should be discontinued.

Combination therapy with insulin.

Metformin and insulin may be used together as combination therapy to achieve better glycemic control. The usual initial dose of Metamin®SR is 500 mg (1 tablet) once daily with the evening meal, while the insulin dose should be adjusted based on blood glucose monitoring.

In elderly patients, renal function may be impaired; therefore, the metformin dose should be adjusted based on assessment of renal function, which should be performed regularly (see section "Special Warnings and Precautions for Use").

The benefit of reducing the risk or delaying the onset of type 2 diabetes has not been established in patients aged 75 years and older (see section **"**Pharmacodynamics"), and therefore metformin is not recommended for use in these patients (see section "Special Warnings and Precautions for Use").

Renal impairment. eGFR should be assessed before initiating therapy with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of progressive renal impairment and in elderly patients, renal function should be carefully monitored more frequently, e.g., every 3–6 months.

Children.

The drug should not be administered to children, as there are no clinical data available for this age group of patients.

Overdose.

Hypoglycemia was not observed following administration of the drug at a dose of 85 g. However, in this case, lactic acidosis developed. Significant overdose of metformin or concomitant risk factors may lead to the development of lactic acidosis. Lactic acidosis is a medical emergency. If lactic acidosis occurs, treatment with Metamin®SR must be discontinued and the patient should be urgently hospitalized. Hemodialysis is the most effective procedure for removing lactate and metformin from the body.

Adverse reactions.

Adverse reactions in patients taking prolonged-release metformin hydrochloride were similar in nature and severity to those observed in patients taking immediate-release metformin hydrochloride.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously in most cases.

Adverse effects are classified by frequency of occurrence into the following categories:

very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000).

Metabolic disorders.

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

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

From the nervous system.

Common: taste disturbances.

Gastrointestinal tract.

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse effects most often occur at the beginning of treatment and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse effects, a gradual increase in the dose of the drug is recommended.

Hepatobiliary system.

Very rare: isolated reports of abnormal liver function tests or hepatitis, which completely resolve after discontinuation of metformin.

Skin and subcutaneous tissue.

Very rare: skin allergic reactions, including rash, erythema, pruritus, urticaria.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

7 tablets in a blister; 4 blisters in a cardboard pack.

15 tablets in a blister; 2 or 6 blisters in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

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

40020, Ukraine, Sumy region, Sumy, Skriabina St., 54.

or

Manufacturer.

LLC "GLEDFARM LTD".

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

40020, Ukraine, Sumy region, Sumy, Davydovskoho Hryhorii St., 54.