Metfogama® 500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFOGAMMA® 500 (METFOGAMMA® 500)

Composition:

Active substance: metformin;

1 tablet contains 500 mg of metformin hydrochloride;

Excipients: sodium starch glycolate, maize starch, povidone K30, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), propylene glycol, polyethylene glycol 6000, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, practically odorless.

Pharmacotherapeutic group. Oral hypoglycemic agents, excluding insulin. Biguanides. ATC code A10BA02.

Pharmacological Properties

Pharmacodynamics

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 through this mechanism.

In contrast to sulfonylureas, metformin does not stimulate insulin secretion and does not cause hypoglycemia in healthy individuals. It reduces both fasting plasma glucose levels and postprandial glucose levels.

Metformin acts through three main mechanisms:

• Reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• Enhances peripheral glucose uptake and utilization in muscles by increasing insulin sensitivity;
• Delays intestinal absorption of glucose.

Metformin stimulates intracellular glycogen synthesis by affecting glycogen synthase.

It increases the transport capacity of all types of glucose membrane transporters (GLUT).

Independent of its glucose-lowering effect, metformin exerts beneficial effects on lipid metabolism: it reduces levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Pharmacokinetics

Absorption. After oral administration, metformin is almost completely absorbed from the gastrointestinal tract; approximately 20–30% is excreted unchanged in feces. Time to reach maximum plasma concentration (T_max) is 2.5 hours. Absolute bioavailability is approximately 50–60%.

Concomitant food intake reduces and delays the absorption of metformin.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum concentration in whole blood is lower than maximum plasma concentration and is reached after approximately the same time. Erythrocytes represent a secondary compartment of distribution. The mean volume of distribution (V_d) ranges between 63 and 276 L.

Metabolism. Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

Elimination. Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated by both 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.

Clinical characteristics.

Indications. Type 2 diabetes mellitus (insulin-independent) when dietary therapy is ineffective, 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 older.

Reduction of complications of type 2 diabetes in adult patients with type 2 diabetes and excess body weight who have used metformin as a first-line agent after ineffective dietary therapy.

Contraindications.

• Hypersensitivity to metformin or to any of the other components 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 a risk of developing renal dysfunction, such as: dehydration, severe infections, shock;
• use during radioisotope or radiological examinations involving intravascular administration of iodinated contrast media;
• acute and chronic conditions that may lead to the development of hypoxia: cardiac or respiratory failure, acute or recent myocardial infarction, shock;
• major surgical procedures;
• hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended for use.

Alcohol intake increases the risk of lactic acidosis during acute alcohol intoxication, especially in cases of fasting, undernutrition, or adherence to a low-calorie diet, as well as in the presence of hepatic impairment. Alcohol consumption and medicinal products containing alcohol should be avoided during treatment with this medicinal product.

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

Combinations to 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, particularly 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 local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Metfogam® 500 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 reduce renal elimination of metformin, leading to increased plasma metformin concentrations;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both 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 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 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 development.

Lactic acidosis is characterized by muscle cramps, acidotic dyspnea, abdominal pain, and hypothermia; coma may subsequently develop. In suspected lactic acidosis, the drug must be discontinued immediately and the patient should be urgently hospitalized.

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.

In patients receiving metformin, caution is required when initiating treatment with agents that may acutely worsen 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, 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 lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop. If any symptom suggestive of lactic acidosis occurs, the patient should discontinue metformin and seek immediate medical attention.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate concentration in plasma (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

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 affecting 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 "Posology and method of 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 resumption of oral nutrition, 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. Controlled clinical studies of one year's duration 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 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 efficacy and safety of metformin in this patient group do not differ from 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 balanced carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Regular monitoring of carbohydrate metabolism parameters is required.

Metformin monotherapy does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylurea derivatives or meglitinides).

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital anomalies and perinatal mortality. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital malformations. Preclinical studies have not shown any adverse effects on pregnancy, embryonic or fetal development, delivery, or postnatal development. When planning pregnancy or upon becoming pregnant, insulin rather than metformin is recommended for diabetes management to maintain blood glucose levels as close to normal as possible, thereby minimizing the risk of fetal malformations.

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 consider the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin did not affect fertility in animal studies at doses of 600 mg/kg/day, approximately three times the maximum recommended human daily dose based on body surface area.

Ability to influence 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 required when metformin is used in combination with other hypoglycemic agents (sulfonylurea derivatives, insulin, or meglitinides) due to the risk of hypoglycemia.

Method of Administration and Dosage

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

The usual initial dose for adults is 500 or 850 mg (Metfogama® 500 or Metfogama® 850) 2–3 times daily, taken during or after meals, swallowed whole with sufficient fluid (a glass of water). After 10–15 days of treatment, the dose should be adjusted according to serum glucose measurements.

A gradual increase in dose reduces gastrointestinal side effects.

The maximum daily dose is 3000 mg, divided into 3 doses.

When treating with high doses, metformin 1000 mg tablets should be used.

When switching to Metfogama® therapy, concomitant antidiabetic medication must be discontinued.

Combination therapy with insulin.

To achieve better blood glucose control, metformin and insulin may be used together as combination therapy. The usual initial dose is metformin 500 mg or 850 mg 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 metformin dose should be selected based on assessment of renal function, which should be performed regularly (see section "Special Warnings and Precautions for Use").

Renal impairment. eGFR should be evaluated before initiating treatment with metformin-containing medicinal products and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should undergo more frequent monitoring of renal function, for example every 3–6 months.

Children aged 10 years and older.

Monotherapy and combination therapy with insulin:

• Initial dose: 1 tablet containing 500 mg or 850 mg of metformin, once daily during or after a meal;
• After 10–15 days the dosage should be adjusted based on blood glucose measurements. Gradual dose escalation may reduce gastrointestinal side effects. The maximum recommended daily dose is 2 g of metformin hydrochloride, divided into 2–3 doses.

Pediatric use. The drug may be used in children aged 10 years and older.

Overdose. No cases of hypoglycemia have been observed following administration of metformin at a dose of 85 g. However, metformin overdose may lead to lactic acidosis, which can be fatal. Accumulation of the drug due to impaired renal function may also cause lactic acidosis. Initial symptoms of lactic acidosis include nausea, vomiting, diarrhea, fever, abdominal and muscle pain. Later, tachypnea, dizziness, confusion, and progression to coma may occur. If signs of lactic acidosis occur, treatment with the drug must be immediately discontinued, and the patient should be urgently hospitalized. Diagnosis should be confirmed by measuring lactate concentration. Hemodialysis is the most effective method for removing both lactate and metformin from the body. Symptomatic treatment should also be administered.

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 the aforementioned adverse effects, a gradual increase in dosage is recommended, along with administration of the daily dose in 2–3 divided doses.

Gastrointestinal system: nausea, loss of appetite, metallic taste in the mouth, diarrhea, vomiting, abdominal pain, flatulence. These reactions usually do not require discontinuation of treatment and resolve spontaneously. To prevent gastrointestinal adverse effects, a gradual increase in dosage is recommended, along with administration of the drug 2–3 times daily during or after meals.

Hepatobiliary system: impaired liver function tests or hepatitis, which completely resolve after discontinuation of metformin.

Skin and subcutaneous tissue: allergic reactions, skin rashes, erythema, pruritus, urticaria.

Endocrine system: hypoglycemia (mainly when used in high doses).

Metabolic disorders: lactic acidosis (requires discontinuation of treatment). With prolonged use of the drug, vitamin B12 absorption may decrease, leading to reduced serum vitamin B12 levels. This is observed when metformin is prescribed to patients with megaloblastic anemia.

Blood system: megaloblastic anemia.

Other: taste disturbances.

Shelf life. 4 years.

Storage conditions. Store at temperatures not exceeding +25 °C in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister; 3 or 12 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Dragennopharm Apotheker Pueschl GmbH, Germany / Dragennopharm Apotheker Pueschl GmbH, Germany.

Manufacturer's address and place of business. Goellstrasse 1, 84529 Tittmoning, Germany / Goellstrasse 1, 84529 Tittmoning, Germany.