Metformin-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFORMIN-ASTRAPHARM (METFORMIN-ASTRAPHARM)

Composition:

Active substance: metformin;

1 tablet contains 500 mg or 850 mg or 1000 mg of metformin hydrochloride;

Excipients: povidone, magnesium stearate; coating: hypromellose 2910, 5 cPz; PEG 6000; titanium dioxide.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

500 mg tablets: white, round, biconvex, film-coated tablets;

850 mg tablets: white, oval, biconvex, film-coated tablets;

1000 mg tablets: white, oval, biconvex, film-coated tablets with a break line on one side.

Pharmacotherapeutic group.

Drugs affecting the digestive system and metabolism. Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Metformin is a biguanide with antihyperglycemic activity. 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 acts via three mechanisms:

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

During clinical studies, patients' body weight remained stable or moderately decreased.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK). It increases the transport capacity of all known 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 metformin from 500 mg or 800 mg tablets 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.

Nonlinear pharmacokinetics of metformin absorption is expected. With 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, the maximum plasma concentration (Cmax) of metformin 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 the area under the concentration-time curve (AUC), and a 35-minute prolongation of time to maximum concentration (Tmax) 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 and is reached at approximately 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 elimination via 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 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 and 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 dosing 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 approximately 33% and 40% lower, 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 relevance.

Clinical characteristics.

Indications.

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

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

For reducing diabetes complications in adult patients with type 2 diabetes mellitus and excess body weight, as a first-line agent after failed 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 risk of renal function impairment, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or acute 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. Acute 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. Alcohol consumption and use of medicinal products containing alcohol should be avoided during metformin therapy.

Iodinated contrast media.

Metformin should be discontinued before or during radiological procedures involving iodinated contrast agents and should not be restarted earlier than 48 hours after the procedure, only after re-evaluation of renal function and confirmation of stable renal function (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 topical glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dosage adjustment of Metformin-Astrafarm 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 metformin efficacy;
• OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may decrease renal elimination of metformin, leading to increased plasma concentrations of metformin;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect metformin efficacy and renal excretion.

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 metformin efficacy.

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 advice should be sought.

Patients receiving metformin should begin 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 excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, 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; coma may subsequently develop. If any symptom of lactic acidosis occurs, the patient must discontinue metformin and seek immediate 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 therapy should be discontinued immediately and a prompt diagnostic evaluation should be performed.

Renal function. eGFR should be assessed before initiating 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 altering 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").

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 reassessment and confirmation of stable renal function (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures. Metformin should be discontinued 48 hours prior to elective surgery performed under general, spinal, or epidural anesthesia, and should not be resumed earlier than 48 hours after surgery or restoration of oral nutrition, and only upon confirmation of restored normal 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 or sexual maturation in children. However, there are no data on the effects of long-term metformin use 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 showed that the efficacy and safety of metformin were comparable to those observed 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 evenly distributed carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Glycemic control 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 duration of treatment, and/or in patients with risk factors known to cause vitamin B12 deficiency. Serum vitamin B12 levels should be monitored if vitamin B12 deficiency is suspected (e.g., anemia or neuropathy). Periodic monitoring of vitamin B12 may be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued as long as it is tolerated, and appropriate corrective treatment for vitamin B12 deficiency should be provided 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).

Use during pregnancy or breastfeeding.

Pregnancy.

Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the 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 risks of adverse outcomes of hyperglycemia for both mother and child. Metformin crosses the placenta in amounts that may reach concentrations similar to those in the mother.

A large amount of data from pregnant women (over 1000 exposure 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 during pregnancy.

There are some unconfirmed data on the long-term effect 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 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; however, no adverse effects have been observed in breastfed newborns/infants. Nevertheless, 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 to the infant.

Fertility.

Metformin had no effect on 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 in combination with other oral antihyperglycemic agents.

The usual starting dose is 500 mg or 850 mg two or three times daily, taken during or after meals.

After 10–15 days, the dose should be adjusted according to serum glucose measurements.

Gradual dose escalation reduces gastrointestinal side effects.

When high doses are used (2000–3000 mg daily), each two 500 mg tablets may be replaced by one 1000 mg tablet.

The maximum recommended daily dose is 3000 mg, divided into three 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 metformin hydrochloride two or three times daily. The insulin dose should be adjusted based on blood glucose monitoring results (see section "Special Warnings and Precautions for Use").

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.

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

Children.

Monotherapy or combination therapy together with insulin.

Metformin-AstraPharm may be used in children aged 10 years and older and in adolescents. The usual initial 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 blood glucose measurements.

Gradual dose escalation reduces gastrointestinal side effects.

The maximum recommended dose is 2000 mg per day given in 2–3 divided doses.

Children.

Metformin-AstraPharm may be used in children aged 10 years and older and in adolescents.

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 requiring hospital treatment. Hemodialysis is the most effective measure 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 in most cases. To prevent the occurrence of these adverse effects, a gradual dose escalation 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 system-organ class, adverse reactions are listed in order of decreasing clinical significance.

Metabolic disorders

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

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

From the nervous system:

Common: taste disturbances.

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

From the hepatobiliary system:

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

From the skin:

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 who received metformin for up to 1 year, reported adverse effects in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

After marketing authorization, it is important to report suspected adverse reactions. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life

Film-coated tablets, 500 mg, 850 mg – 5 years.

Film-coated tablets, 1000 mg – 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 printed lacquered aluminum foil; 3, 6, or 9 blisters per cardboard box.

Prescription status
By prescription only.

Manufacturer

ASTRAFARM LLC.

Manufacturer's address and location of operation

6, Kyivska St., city of Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.