Metformin

INSTRUCTION for medical use of the medicinal product METFORMIN (METFORMIN)

Composition:

active substance: metformin;

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

excipients: povidone K 29/32, magnesium stearate;

film-coating composition for 500 mg, 850 mg dosage: hypromellose;

film-coating composition for 1000 mg dosage: hypromellose, macrogol 400, macrogol 8000.

Medicinal form. Film-coated tablets.

Main physicochemical properties:

• 500 mg, 850 mg tablets: round, biconvex tablets, white or almost white, film-coated;
• 1000 mg tablets: white, oval, biconvex tablets, film-coated, with a score line on both sides.

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10B A02.

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.

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

Metformin exerts its antihyperglycemic effect through several mechanisms:

• Metformin reduces glucose production in the liver, facilitates peripheral glucose uptake and utilization, partly by enhancing insulin action.
• Metformin alters glucose metabolism in the intestine: systemic absorption increases, while glucose 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 intestinal microbiome.
• Metformin may improve lipid profile in patients with hyperlipidemia.

In clinical trials, patients' body weight remained stable or slightly decreased during metformin treatment.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK) and enhances the transport capacity of all types of glucose membrane transporters.

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 850 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, metformin absorption is saturable and incomplete.

It is assumed that metformin absorption is nonlinear. When metformin is administered 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 studies, plasma Cmax of metformin did not exceed 5 µg/mL, even with maximum doses.

When administered with food, metformin absorption is reduced and slightly delayed.

After oral administration of 850 mg, a 40% reduction in maximum plasma concentration, a 25% decrease in AUC, and a 35-minute prolongation of Tmax in plasma 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 via 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 metformin levels in plasma.

Special Patient Groups

Renal Impairment. Data in patients with moderate renal impairment are limited; therefore, systemic exposure to metformin in this patient group compared to those with normal renal function cannot be precisely assessed. Dose adjustment is required based on clinical efficacy/tolerability (see section "Dosage and Administration").

Pediatric Population. 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, Cmax and systemic exposure (AUC0–t) were reduced by approximately 33% and 40%, respectively, compared to adult patients with type 2 diabetes receiving repeated 500 mg doses twice daily for 14 days.

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

Clinical Characteristics

Indications

Type 2 diabetes mellitus when dietary therapy and physical exercise have failed, particularly in patients with excess body weight:

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

To be used 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., lactate 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;
• conditions 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, especially during fasting, undernutrition, or hepatic impairment.

Iodinated contrast agents. Patients should discontinue metformin before or during the procedure and resume only no earlier than 48 hours after the procedure and only after re-evaluation and confirmation of stable renal function (see sections "Special precautions for use" and "Dosage and administration").

Combinations that should be used with caution

Certain medicinal products, such as nonsteroidal 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, increasing the risk of lactic acidosis. Careful monitoring of renal function is required at the start of treatment with these medicinal products or when used in combination with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of metformin should be adjusted 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 elimination of metformin, leading to increased plasma concentrations of metformin;
• OCT1 and OCT2 inhibitors (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 may be necessary, as 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. Acute worsening of renal function leads to metformin accumulation, 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 attention should be sought.

When a patient is receiving metformin, caution should be exercised when initiating medications that may acutely impair renal function (e.g., antihypertensive agents, 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 their 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, with possible progression to coma. If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

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

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) and mitochondrial hereditary diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the disease course.

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

Renal function. eGFR should be assessed before initiating 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 altering 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 media may cause contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Patients should discontinue metformin before or during the procedure and resume no earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of stable renal function (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Surgery. Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia, and should not be restarted earlier than 48 hours after surgery or until oral nutrition is resumed, and only after re-evaluation and confirmation of stable renal function.

Children. Prior to initiating metformin therapy, a diagnosis of type 2 diabetes must be confirmed. One-year controlled clinical studies have not shown any effect of metformin on growth and sexual maturation in children. However, there are no data on the effects of metformin on growth and sexual maturation with longer-term use; 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. The drug should be prescribed with particular caution to children aged 10 to 12 years.

Other precautions. Patients must adhere to a diet with balanced carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Regular monitoring of carbohydrate metabolism parameters is necessary.

Metformin may reduce serum vitamin B12 levels. The likelihood of decreased vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and in patients with 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 monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and no contraindications arise, with appropriate corrective treatment for vitamin B12 deficiency provided 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, pregnancy loss, 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 for both mother and child.

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

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

There are limited unconfirmed data on the long-term effect of metformin on the body weight of children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed in utero, although data on long-term outcomes are limited.

If clinically indicated, 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 reactions have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, 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 reactions 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 influence the speed of reaction while driving or operating machinery

Metformin monotherapy does not affect the speed of reaction while 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.

Administration and Dosage

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

Monotherapy or combination therapy with other oral hypoglycemic agents

The usual starting dose of metformin hydrochloride 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 daily, divided into 3 doses.

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

Combination therapy with insulin

To achieve better blood glucose control, metformin and insulin can be used in combination. 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.

Elderly patients

Renal function may be reduced in elderly patients; therefore, the metformin dose should be adjusted based on assessment of renal function, which should be performed regularly (see section "Special precautions").

Patients with renal impairment

eGFR should be evaluated before initiating treatment with metformin-containing medications and at least annually during treatment. In patients at increased risk of worsening renal function and in elderly patients, renal function should be carefully monitored more frequently, for example every 3–6 months.

Children

Monotherapy or combination therapy with insulin

The medicinal product Metformin may be used in children aged 10 years and older and in adolescents.

The usual initial dose of metformin hydrochloride is 500 mg or 850 mg once daily, taken during or after a meal. After 10–15 days, the dose should be adjusted according to blood serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal adverse reactions.

The maximum recommended dose is 2000 mg daily, administered in 2–3 divided doses.

Overdose

When metformin was administered at a dose of 85 g, hypoglycemia was not observed. However, lactic acidosis developed in this case. 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 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 reactions, a gradual increase in dosage is recommended, along with administration of the daily dose in 2–3 divided doses.

The frequency of adverse reactions is defined according to 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 system organ class, adverse reactions are listed in order of decreasing clinical significance.

Metabolism 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 reactions most often occur at the beginning of treatment and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse reactions, a gradual increase in dosage is recommended, along with administration of 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

According to published and post-marketing data, as well as results from controlled clinical trials in a limited pediatric population of patients aged 10–16 years who received metformin for one year, adverse reactions in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

Film-coated tablets, 500 mg: 10 tablets per blister, 6 blisters per pack.

Film-coated tablets, 850 mg: 10 tablets per blister, 6 blisters per pack.

Film-coated tablets, 1000 mg: 10 tablets per blister, 3, 5, or 6 blisters per pack.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of its business activity

139 Saksahanskoho Street, Kyiv, 01032, Ukraine.