Megliport 850

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Meglifort 500 (Maglifort 500) Meglifort 850 (Maglifort 850) Meglifort 1000 (Maglifort 1000)

Composition:

Active substance: metformin hydrochloride;

One film-coated tablet contains metformin hydrochloride 500 mg, 850 mg, or 1000 mg;

Excipients:

Tablets of 500 mg or 850 mg: sodium starch glycolate (type A), povidone, corn starch, magnesium stearate, colloidal anhydrous silicon dioxide;
film coating: hypromellose, polyethylene glycol 6000, talc, titanium dioxide (E 171), propylene glycol;

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

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties:

Meglifort 500 or Meglifort 850: round, biconvex film-coated tablets, white to almost white in color;

Meglifort 1000: capsule-shaped, biconvex film-coated tablets with a score line on both sides, white to almost white in color.

Pharmacotherapeutic group.

Antidiabetic agents. Oral hypoglycemic agents, excluding insulin. Metformin. ATC code A10BA02.

Pharmacological Properties.

Pharmacodynamics.

Metformin is a biguanide with antihyperglycemic effects both on fasting and postprandial hyperglycemia. 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;
• Metformin enhances peripheral glucose uptake and utilization, partly by increasing insulin action;
• Metformin alters glucose metabolism in the intestine: uptake into the bloodstream increases, while 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 lipid profile in patients with hyperlipidemia.

In clinical trials, patients' body weight remained stable or moderately 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 (GLUT).

Pharmacokinetics.

Absorption.

After oral administration, the time to reach maximum concentration (Cmax) of metformin 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 amounts to 20–30%.

After oral administration, metformin absorption 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 levels of metformin (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 (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 approximately at the same time. Erythrocytes likely represent a secondary compartment of distribution. 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 (t1/2) is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, thus t1/2 increases, leading to elevated metformin plasma levels.

Special patient groups.

Renal impairment.

Limited data are available for patients with moderate renal impairment; therefore, systemic exposure to metformin in this group compared to patients with normal renal function cannot be precisely assessed. Dose adjustment is required according to 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 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 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 dietary therapy and physical exercise are ineffective, 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 type 2 diabetes in adult patients with type 2 diabetes and excess body weight, as a first-line agent following ineffective dietary therapy.

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 (particularly acute conditions or exacerbations of chronic diseases): 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 in cases of fasting, undernutrition, or hepatic impairment.

Iodinated contrast agents.

Metformin should be discontinued before or during contrast imaging procedures and should not be restarted earlier than 48 hours after the procedure, and only after reassessment and confirmation of stable renal function (see sections "Dosage and administration" and "Special precautions").

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, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these agents or when using them concomitantly with metformin.

MEDICINAL PRODUCTS CAUSING HYPERGLYCEMIC EFFECTS (systemic and local glucocorticoids, sympathomimetics).

More frequent monitoring of blood glucose levels is required, especially at the beginning of treatment. Dose adjustment of Megliphort 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 administration of metformin with:

• OCT1 inhibitors (e.g. verapamil) may reduce metformin efficacy;
• 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 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 metformin concentrations 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. In acute worsening of renal function, metformin accumulates, 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 initiate treatment cautiously with drugs that may acutely worsen 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. In the event of any symptom suggestive of lactic acidosis, the patient must discontinue metformin and seek immediate medical attention.

Lactic acidosis is characterized by diagnostic laboratory findings: decreased blood pH (< 7.35), elevated plasma lactate concentration in serum (> 5 mmol/L), increased anion gap, and increased 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 maternally 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 or 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 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 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 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 (Meglyfort) should be discontinued during surgical interventions performed under general, spinal, or epidural anesthesia, and should not be resumed 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 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, 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 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 should maintain a regular intake of carbohydrates throughout the day. Overweight patients should continue to follow a low-calorie diet. Glycemic parameters should be monitored regularly.

Metformin may reduce serum vitamin B12 levels. The risk of vitamin B12 deficiency increases with higher metformin doses, longer treatment duration, and/or in patients with known risk factors for vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Periodic monitoring of vitamin B12 levels may be required in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued as long as it is tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be 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 of 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 registry-based cohort studies, published meta-analyses, and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure in the periconceptional period and/or during pregnancy.

There are limited unconfirmed data on the long-term effect of metformin on the 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 necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an alternative to insulin.

Breastfeeding period. 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 animals 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.

Meglyfort does not affect reaction speed when driving or operating machinery, as monotherapy with the drug does not cause hypoglycemia. However, metformin should be used with caution in combination with other hypoglycemic agents (sulfonylureas, insulin, repaglinide) due to the risk of hypoglycemia.

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 starting dose is 500 mg or 850 mg (Megligfort 500 or Megligfort 850) 2–3 times daily, taken with meals or immediately after meals.

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

Gradual dose escalation helps reduce gastrointestinal side effects.

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

For high-dose treatment (2000–3000 mg per day), Megligfort 1000 should be used.

When switching from another antidiabetic agent, the previous therapy should be discontinued and metformin initiated as described above.

Combination therapy with insulin.

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

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

Patients with renal impairment.

Renal function (eGFR) should be evaluated before initiating therapy with metformin-containing medicinal products and at least annually during treatment. Patients at increased risk of progressive renal impairment, including elderly patients, should have renal function monitored more frequently, e.g., every 3–6 months.

eGFR (mL/min)	Total maximum daily dose (should be divided into 2−3 doses)	Additional information
60−89	3000 mg	In case of reduced kidney function, dose reduction should be considered.
45−59	2000 mg	Before initiating metformin, consider factors that may increase the risk of lactic acidosis (see section "Special precautions"). The initial dose should not exceed half of the maximum recommended dose.
30−44	1000 mg
< 30	-	Metformin is contraindicated.

Children.

Monotherapy or combination therapy with insulin.

The drug Meglifort is used in children aged 10 years and older and in adolescents. The usual initial dose is 500 mg or 850 mg of Meglifort once daily, taken during or after a meal. After 10–15 days of treatment, the dose should be adjusted according to blood plasma glucose measurements. Slow dose escalation helps reduce gastrointestinal side effects. The maximum recommended dose is 2000 mg per day, divided into 2–3 doses.

Overdose.

Administration of Meglifort at a dose of 85 g did not result in hypoglycemia. However, in this case, lactic acidosis developed. A 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 procedure for removing lactate and metformin hydrochloride 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 system-organ class, adverse reactions are listed in order of decreasing clinical significance.

Of the nervous system.

Common: taste disturbances.

Of 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, a gradual increase in dosage is recommended, along with administration of the daily dose in 2–3 divided doses during or after meals.

Of the skin and subcutaneous tissues.

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

Metabolic disorders.

Common: vitamin B12 deficiency/low levels (see section "Special precautions for use").

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

Of the liver and biliary system.

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

Children.

In published and post-marketing data and controlled clinical trials in a limited pediatric population aged 10–16 years who received metformin for 1 year, reports of adverse effects in children were similar in nature and severity to those observed in adults.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all 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 in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister.

1 or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Indoco Remedies Limited.

Indoco Remedies Limited.

Manufacturer's address.

L-14, Verna Industrial Area, Verna, IN-403722, India.

L-14, Verna Industrial Area, Verna, IN-403722, India.

Marketing Authorization Holder.

M. Biotech Ltd.

M. Biotech Ltd.

Address of the Marketing Authorization Holder.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom.

Gladstone House, 77–79 High Street, Egham TW20 9HY, Surrey, United Kingdom.