Metamin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METAMINÒ (METAMINÒ)

Composition:

Active substance: metformin hydrochloride;

One tablet contains 500 mg, 850 mg, or 1000 mg of metformin hydrochloride;

Excipients: lactose monohydrate, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

Tablets 500 mg, 850 mg: film-coated tablets, white or almost white, round, biconvex, smooth on both sides;

Tablets 1000 mg: film-coated tablets, white or almost white, oval-shaped, biconvex, smooth on both sides.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic activity. It reduces plasma glucose levels both in 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 muscle tissue, leading to enhanced peripheral glucose uptake and utilization;
• delays intestinal glucose absorption.

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

Independent of its effects on glycemia, metformine has a beneficial effect on lipid metabolism: it reduces levels of total cholesterol, low-density lipoproteins, and triglycerides.

In clinical studies, patients' body weight remained stable or moderately decreased during metformin treatment.

Pharmacokinetics.

Absorption.

After oral administration of metformin, the time to reach maximum plasma concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin in 500 mg or 850 mg tablet formulations is about 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces amounts to 20–30%.

After oral administration, metformin absorption is saturable and incomplete.

Non-linear absorption of metformin is assumed. At recommended doses and dosing regimens, steady-state plasma concentrations are achieved within 24–48 hours and remain below 1 µg/mL. In controlled clinical trials, maximum plasma levels of metformin (Cmax) did not exceed 5 µg/mL, even with maximum doses.

Concomitant food intake reduces and slightly delays metformin absorption.

After an 850 mg oral dose, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to reach maximum plasma concentration were observed. The clinical significance of these changes is unknown.

Distribution.

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration, while time to peak is approximately the same. Erythrocytes likely serve as a secondary distribution compartment for metformin. 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, 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 plasma metformin levels.

Special patient groups.

Renal impairment.

Limited data are available in patients with moderate renal impairment; therefore, systemic exposure to metformin in this group compared to patients with normal renal function cannot be precisely determined. Dose adjustment is required based on clinical efficacy/tolerability (see section "Dosage and administration").

Children.

In a single-dose study of 500 mg metformin hydrochloride, the pharmacokinetic profile in pediatric patients was similar to that in healthy adults.

Data on multiple-dose administration are limited to one study.

After repeated administration of 500 mg metformin twice daily for 7 days in pediatric patients, peak plasma concentration (Cmax) and systemic exposure (AUC0–t) were reduced by approximately 33% and 40%, respectively, compared to adult diabetic patients receiving repeated 500 mg doses twice daily for 14 days.

Since the dose is individually titrated based on glycemic control, the above information has limited clinical significance.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus when diet and exercise have failed, particularly in patients with excess body weight;

• as monotherapy or in combination with other oral hypoglycemic agents or insulin for the treatment of adults;
• as monotherapy or in combination with insulin for the treatment of children aged 10 years and older and adolescents.

For reducing complications of diabetes in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line agent following ineffective dietary therapy.

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 a 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.

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly during fasting, undernutrition, or hepatic impairment.

Contrast media containing iodine. Metformin should be discontinued before or during radiological procedures using iodinated contrast agents and should not be restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of stable renal function (see sections "Dosage and administration" and "Special warnings and precautions for use").

Combinations requiring caution.

Certain medicinal products, such as non-steroidal 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, 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 EFFECT (systemic and local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of Metamin® should be adjusted during and after discontinuation of such concomitant therapy.

ORGANIC CATION TRANSPORTERS (OCT).

Metformin is a substrate of both transporters – OCT1 and OCT2.

Concomitant use 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 elimination of metformin, leading to increased plasma concentration of metformin;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal elimination 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 the presence of acute worsening of renal function, cardiopulmonary disease, or sepsis. Acute worsening of renal function leads to metformin accumulation, increasing the risk of lactic acidosis.

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

Patients receiving metformin should initiate treatment with caution when using medicinal products that may acutely impair renal function (e.g., antihypertensive agents, diuretics, and NSAIDs).

Other risk factors for lactic acidosis include poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency, 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 dyspnoea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. If any symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin immediately and seek urgent medical attention.

Lactic acidosis is characterized by diagnostic laboratory findings: decreased blood pH (˂7.35), elevated serum lactate concentration in plasma (˃5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Patients with mitochondrial disorders 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 disease progression.

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

Renal function. eGFR should be assessed before starting treatment and regularly thereafter (see section "Dosage and 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 hypoxia and renal insufficiency. 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").

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, and only after re-evaluation and confirmation of stable renal function (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures. Metformin should be discontinued during surgical interventions performed under general, spinal, or epidural anaesthesia and not restarted earlier than 48 hours after surgery or resumption of oral nutrition, and only after re-evaluation and confirmation of stable renal function.

Children. Prior to initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. Controlled clinical studies of one year's duration have shown no effect of metformin on growth and sexual maturation in children. However, data on the long-term effects of metformin on growth and sexual maturation are lacking; therefore, careful monitoring of these parameters is recommended in children receiving metformin, especially during puberty.

Children aged 10 to 12 years. Controlled clinical studies involving 15 children aged 10 to 12 years showed that the efficacy and safety of metformin in this patient group were comparable to those in older children and adolescents. Metformin should be prescribed with particular caution to children aged 10 to 12 years.

Other precautions. Patients should adhere to a diet with balanced carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Carbohydrate metabolism parameters should be monitored regularly.

Metformin may reduce serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and/or the presence of known risk factors for vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anaemia 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.

Metformin monotherapy does not cause hypoglycaemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycaemic agents (e.g., sulfonylureas or meglitinides).

If you have an intolerance to certain sugars, consult your doctor before taking this medicinal product, as the drug contains lactose.

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycaemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, pregnancy-induced hypertension, pre-eclampsia, 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 of hyperglycaemia for both mother and child.

Metformin crosses the placenta in amounts that may be as high as maternal concentrations.

Extensive data from pregnant women (over 1,000 pregnancy outcomes) from cohort studies based on registries, as well as 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 pregnancy.

There are limited, unconfirmed data on 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 indicated, metformin may be used during pregnancy and in the preconception period, either as an adjunct to 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 did not affect 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 speed when driving or operating machinery.

Metformin monotherapy does not affect reaction speed when driving or operating machinery, as the drug does not cause hypoglycaemia.

However, caution is required when metformin is used in combination with other hypoglycaemic agents (sulfonylurea derivatives, insulin, or meglitinides) due to the risk of hypoglycaemia.

Method of Administration and Dosage

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

Monotherapy or combination therapy with other oral hypoglycemic agents.

The usual initial dose is 500 mg or 850 mg (Metamin®, tablets, coated, 500 mg or 850 mg) 2–3 times daily, taken during or after meals.

After 10–15 days, the dose should be adjusted based on serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

When high doses are required (2000–3000 mg daily), every two 500 mg tablets of Metamin® may be replaced by one 1000 mg tablet of Metamin®.

The maximum recommended dose is 3000 mg daily, administered in three divided doses.

When switching from another antidiabetic agent, discontinue the previous agent and initiate metformin as described above.

Combination therapy with insulin.

To achieve better glycemic control, metformin and insulin may be used together. The usual starting dose is 500 mg or 850 mg of Metamin® 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring results.

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

In elderly patients, renal function may be reduced; therefore, the dose of metformin should be adjusted based on regular assessment of renal function (see section "Special Warnings and Precautions").

Children.

Monotherapy or combination therapy with insulin.

Metamin® may be used in children aged 10 years and older and in adolescents. The usual starting dose is 500 mg or 850 mg of Metamin® once daily, taken during or after a meal. After 10–15 days, the dose should be adjusted based on blood plasma glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

The maximum recommended dose is 2000 mg per day, divided into 2–3 doses.

Children.

Metamin® should be used for the treatment of children aged 10 years and older.

Overdose.

When the drug was administered at a dose of 85 g, hypoglycemia was not observed. However, in this case, lactic acidosis developed. Significant overdose of metformin or concomitant risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital setting. Hemodialysis is the most effective intervention for removing lactate and metformin from the body.

Adverse reactions.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously in most cases. To prevent the occurrence of these adverse effects, a gradual dose escalation and administration of the daily dose in 2–3 divided doses are recommended.

Adverse reactions observed during the use of the medicinal product are listed below by organ system and frequency of occurrence: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000), unknown (cannot be estimated based on available data).

Within each organ system class, adverse reactions are listed in order of decreasing clinical significance.

Metabolism and nutrition disorders.

Common: vitamin B12 deficiency/low levels (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 disturbance.

Gastrointestinal disorders.

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite. These adverse effects most commonly occur at the beginning of treatment and usually resolve spontaneously. To prevent gastrointestinal adverse effects, a gradual dose escalation and administration of the daily dose in 2–3 divided doses during or after meals are recommended.

Hepatobiliary disorders.

Very rare: liver function test abnormalities or hepatitis, which completely resolve after discontinuation of metformin.

Skin and subcutaneous tissue disorders.

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

Paediatric population.

In published and post-marketing data and controlled clinical trials in a limited paediatric population aged 10–16 years treated with metformin for 1 year, adverse events reported in children were similar in nature and severity to those observed in adults.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

500 mg and 850 mg tablets: 10 tablets in a blister. 3, 6, or 10 blisters in a cardboard pack.

1000 mg tablets: 15 tablets in a blister. 2, 4, or 6 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

KUSUM PHARM LLC.

Manufacturer's address and location of operations.

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

or

Manufacturer.

GLEDFARM LTD.

Manufacturer's address and location of operations.

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