Metformin

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

Composition:

Active substance: metformin hydrochloride;

One tablet contains metformin hydrochloride equivalent to 100% substance: 500 mg, 850 mg, or 1000 mg;

Excipients:

tablets of 500 mg or 850 mg: sodium starch glycolate (type A), povidone, maize starch, magnesium stearate, colloidal anhydrous silicon dioxide;
film-coating composition: hypromellose, polyethylene glycol 6000, talc, titanium dioxide (E171), propylene glycol;

tablets of 1000 mg: povidone, magnesium stearate;
film-coating composition: hypromellose, polyethylene glycol 6000, polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Basic physicochemical properties:

tablets of 500 mg and 850 mg: film-coated tablets, round-shaped, white or almost white, with a biconvex surface and beveled edges;

tablets of 1000 mg: film-coated tablets, white or almost white, capsule-shaped, with a biconvex surface and a groove on both sides.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulins. Biguanides.

ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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, leading to enhanced peripheral glucose uptake and utilization;
• delays intestinal absorption of glucose.

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, metformin has a positive effect on lipid metabolism. This effect has been demonstrated during administration at therapeutic doses in controlled medium- or long-term clinical studies: metformin reduces levels of total cholesterol, low-density lipoproteins, and triglycerides.

During clinical studies, patients' body weight remained stable or moderately decreased when metformin was administered.

Pharmacokinetics.

Absorption.

After oral administration of metformin, the time to reach maximum concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of metformin in 500 mg or 800 mg tablet formulations is approximately 50–60% in healthy volunteers. After oral administration, the fraction not absorbed and excreted in feces is 20–30%.

After oral administration, absorption of metformin is saturable and incomplete.

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

Concomitant food intake reduces and slightly delays metformin absorption.

After oral administration of an 850 mg dose, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to 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 represent 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. This indicates 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, thus prolonging elimination half-life and leading to increased metformin levels in plasma.

Special patient groups.

Renal impairment.

Limited data are available in patients with moderate renal impairment; therefore, systemic exposure to metformin in this patient group compared to patients with normal renal function cannot be precisely assessed. Dose adjustment is required according to clinical efficacy/tolerability (see section "Posology and method of 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 patients with diabetes 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 therapy and physical exercise have failed, particularly in patients with excess body weight:

• as monotherapy or in combination therapy together with other oral hypoglycemic agents or in combination with insulin for the treatment of adults;
• as monotherapy or in combination therapy 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 after failed diet therapy.

Contraindications.

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

Combinations not recommended for use.

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 the examination and not restarted earlier than 48 hours after the procedure, only after re-evaluation and confirmation of stable renal function (see sections "Method of administration and dosage" and "Special precautions for use").

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 exerting hyperglycemic effects (systemic and local glucocorticosteroids, sympathomimetics). Glucose levels in blood should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of metformin may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (such as verapamil) may reduce the efficacy of metformin;
• 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 excretion 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 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 diseases, or sepsis. Acute deterioration of kidney function leads to metformin accumulation, increasing the risk of lactic acidosis.

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

Patients receiving metformin should be treated with caution when initiating therapies that may acutely impair 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, any conditions associated with hypoxia, and 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; coma may develop later. 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), increased plasma lactate concentration (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

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 a higher 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 and unstable heart failure (see section "Contraindications").

Iodinated contrast agents. Intravascular administration of iodinated contrast agents 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, 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 procedures performed under general, spinal, or epidural anesthesia and not restarted earlier than 48 hours after surgery or until oral nutrition is re-established, 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. One-year controlled clinical studies have shown no effect of metformin on growth and sexual maturation in children. However, there are no data on the long-term effects of metformin on growth and sexual maturation; therefore, careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.

Children aged 10 to 12 years. Controlled clinical studies involving 15 children aged 10 to 12 years demonstrated that efficacy and safety of metformin in this patient group were comparable to those in older children and adolescents. The drug 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 to follow a low-calorie diet. Carbohydrate metabolism parameters should be monitored regularly.

Metformin may decrease 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. Serum vitamin B12 levels should be monitored in case of suspected deficiency (e.g., anemia or neuropathy). Periodic monitoring of vitamin B12 levels may be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued as long as it is tolerated and not contraindicated, while appropriate corrective treatment for vitamin B12 deficiency is administered according to current clinical guidelines.

Metformin monotherapy 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).

Use during pregnancy or breastfeeding.

Pregnancy

Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, miscarriage, pregnancy-induced 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 related to hyperglycemia for both mother and child.

Metformin crosses the placenta and reaches concentrations similar to maternal levels.

A large amount of data from pregnant women (over 1000 exposure outcomes) from cohort studies based on registries and published data (meta-analyses, clinical studies, and registries) indicate no increased risk of congenital anomalies or fetal/neonatal toxicity following metformin exposure in the preconception period and/or during pregnancy.

There are limited and inconclusive data on the long-term effects of metformin on offspring body weight following intrauterine exposure. Metformin appears not to 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 considered during pregnancy and in the preconception period as an adjunct or 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 take into account the benefits of breastfeeding and the potential risk of adverse effects for 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 does not affect reaction speed when driving or operating machinery, as the drug does not cause hypoglycemia. However, caution is required when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Dosage and Administration.

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

Monotherapy or combination therapy with other oral antihyperglycemic agents.

The usual starting dose is 500 mg or 850 mg (Metformin, film-coated tablets, 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 treating with high doses (2000–3000 mg per day), each 2 tablets of Metformin 500 mg may be replaced by 1 tablet of Metformin 1000 mg.

The maximum recommended dose is 3000 mg per day, divided into 3 doses.

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

Combination therapy with insulin.

To achieve better blood glucose control, metformin and insulin may be used together. The usual starting 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.

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

Renal impairment. eGFR should be assessed before initiating treatment 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 monitored more frequently, for example every 3–6 months.

Children.

Monotherapy or combination therapy in combination with insulin.

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

Gradual dose escalation reduces gastrointestinal side effects.

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

Overdose.

When 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 the development of lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital setting. Hemodialysis is the most effective intervention for removal of lactate and metformin from the body.

Adverse reactions.

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. To prevent the occurrence of these adverse effects, a gradual increase in dose is recommended, along with administration of the daily dose in 2–3 divided doses.

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

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).

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

Metabolic disorders.

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

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

From the nervous system.

Common: taste disturbances.

From the gastrointestinal system.

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. To prevent gastrointestinal adverse effects, it is recommended to gradually increase the dose and administer the daily dose in 2–3 divided doses during or after meals.

From the liver and biliary system.

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

From the skin and subcutaneous tissues.

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

Children.

In published and post-marketing data and controlled clinical trials in a limited pediatric population aged 10–16 years receiving metformin for 1 year, reported adverse effects in children were similar in nature and severity 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, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 3, 5, 6, or 12 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's location and address of place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.