Metformin

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

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet contains 1000 mg of metformin hydrochloride, calculated as 100 % dry substance;

Excipients: povidone, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate;

Film coating: hypromellose, macrogol 6000, titanium dioxide (E 171), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated white tablets, film-coated.

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

ATC code A10B A02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Metformin is a biguanide with antihyperglycemic effects that occur both in the fasting state and after meals. It does not stimulate insulin secretion and does not cause hypoglycemia.

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

The drug exerts its antihyperglycemic effect through several mechanisms:

• Metformin reduces glucose production in the liver and enhances peripheral glucose uptake and utilization, partly by improving insulin action;
• Metformin alters glucose metabolism in the intestine: systemic exposure increases, while absorption from food decreases. Among additional intestinal-related mechanisms are increased release of glucagon-like peptide-1 (GLP-1) and reduced reabsorption of bile acids. Metformin alters the gut microbiome;
• Metformin may improve lipid profile in patients with hyperlipidemia.

In clinical trials, patient body weight remained stable or decreased slightly 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 (GLUT).

Pharmacokinetics

Absorption. After oral administration of metformin, the time to reach maximum concentration (Cmax) is approximately 2.5 hours (Tmax). The absolute bioavailability of the 500 mg or 800 mg tablet formulation 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.

Non-linear pharmacokinetics of metformin absorption is expected. 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, 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 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 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 metformin plasma levels.

Special patient groups

Renal impairment. As data in patients with moderate renal impairment are limited, it is not possible to precisely assess systemic metformin exposure in this patient group compared to those with normal renal function. Therefore, dose adjustment should be based on clinical efficacy and tolerability (see section "Dosage and administration").

Pediatric population. Based on 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 type 2 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 dietary measures and physical exercise have failed, particularly in patients with excess body weight:

• the medicinal product is indicated as monotherapy or in combination with other oral hypoglycaemic agents or insulin for the treatment of adults;
• the medicinal product is indicated as monotherapy or in combination with insulin for the treatment of children from the age of 10 years and adolescents.

The medicinal product is indicated to reduce complications of type 2 diabetes in adult patients with type 2 diabetes and excess body weight as a first-line agent after failure of dietary management.

Contraindications

• Hypersensitivity to metformin or to any of the excipients;
• 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;
• 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, particularly during fasting, malnutrition or hepatic impairment.

Iodinated contrast media. Patients should discontinue metformin before or during radiological procedures with iodinated contrast agents and restart only no 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 precautions").

Combinations that should be used with caution

Some 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 adversely affect renal function, thereby increasing the risk of lactic acidosis. Renal function should be closely monitored at the start of treatment with these medicinal products or when used concomitantly with metformin.

Medicinal products with hyperglycaemic 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 (e.g. verapamil) may reduce the efficacy of metformin;
• OCT1 inducers (e.g. rifampicin) may increase gastrointestinal absorption and efficacy of metformin;

− OCT2 inhibitors (e.g. cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformin, leading to increased plasma metformin concentrations;

• inhibitors of both OCT1 and OCT2 (e.g. crizotinib, olaparib) may affect 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 metformin concentrations may increase. Dose adjustment of metformin may be 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 cases of acute deterioration of kidney function, metformin accumulates, increasing the risk of lactic acidosis.

In the event of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), metformin should be temporarily discontinued and medical advice sought.

Patients receiving metformin should initiate treatment cautiously with medicinal products that may abruptly 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, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause 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 should discontinue metformin immediately and seek 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 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 inherited diabetes and deafness (MIDD), due to the risk of exacerbating lactic acidosis and neurological complications, which may worsen the course of the disease.

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

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 affecting renal function (see section "Contraindications").

Cardiac function. Patients with heart failure have an increased risk of 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").

Iodinated contrast agents. Intravascular administration of iodinated contrast media may cause nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Patients should discontinue metformin before or during the procedure and resume treatment no 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 procedures performed under general, spinal, or epidural anesthesia and restarted no earlier than 48 hours after surgery or upon resumption of oral nutrition, and only after re-evaluation and confirmation of stable renal function.

Children. Prior to initiating metformin therapy, a confirmed diagnosis of type 2 diabetes mellitus must be established. One-year controlled clinical studies 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 have shown that the efficacy and safety of metformin in this patient group are comparable to those in older children and adolescents. The medicinal product should be prescribed with particular caution in children aged 10 to 12 years.

Other warnings. Patients must adhere to dietary recommendations, including 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 treatment duration, and in the presence of patient risk factors for vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and no contraindications arise, with appropriate corrective treatment for vitamin B12 deficiency 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, 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 from hyperglycemia 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 1000 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 periconceptional period and/or pregnancy.

There are limited, unconfirmed data on the long-term effects of metformin on weight in 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 adverse effects have not been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the medicinal product, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility. Metformin did not affect fertility in animal studies at doses of 600 mg/kg/day, which is nearly 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 hypoglycemia. However, caution is advised 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 hypoglycemic agents

The usual starting dose is 500 mg or 850 mg of metformin hydrochloride (use other medicinal products with corresponding dosage strengths) taken 2–3 times daily with meals or immediately after meals.

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

Gradual dose escalation helps reduce gastrointestinal side effects.

Metformin tablets, film-coated, 1000 mg, are intended for high-dose treatment (2000–3000 mg per day).

The maximum recommended daily dose is 3000 mg, 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

Metformin and insulin may be used together in a combined regimen to achieve better glycemic control. The usual starting dose is 500 mg or 850 mg of metformin hydrochloride (use other medicinal products with corresponding dosage strengths) 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 adjusted based on assessment of renal function, which should be performed regularly (see section "Special precautions").

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

Children

Monotherapy or combination therapy with insulin

Metformin may be used in children aged 10 years and older and in adolescents. The usual initial dose is 500 mg or 850 mg (use other medicinal products with corresponding dosage strengths) once daily, taken during or after a meal.

After 10–15 days, the dose should be adjusted according to blood plasma glucose measurements. A gradual dose increase helps reduce gastrointestinal side effects. 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, in this case, lactic acidosis developed. A significant overdose of metformin or concomitant risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency requiring hospital treatment. 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, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously. To prevent the occurrence of these adverse effects, a gradual increase in dosage is recommended, along with dividing the daily dose into 2–3 administrations.

Adverse effects are classified by frequency of occurrence as follows: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (< 1/10,000).

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

Disorders of metabolism

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 disappear spontaneously in most cases. To prevent gastrointestinal adverse effects, a gradual increase in dosage is recommended, along with administering the daily dose in 2–3 divided doses during or after meals.

From the liver and biliary system

Very rare: liver function test abnormalities 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 1 year, adverse effects in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is highly important. It enables ongoing 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 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 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 made of polyvinyl chloride film and aluminum foil.

3 or 6 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Limited liability company "FARMEKS GROUP".

Manufacturer's address and location of operations. 100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.