Metfogama® 850

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFOGAMMA® 850 (METFOGAMMA® 850)

Composition:

Active substance: metformin;

1 tablet contains 850 mg of metformin hydrochloride;

Excipients: povidone, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Oral hypoglycaemic 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 through this mechanism.

Unlike sulfonylureas, metformin does not stimulate insulin secretion and does not produce a hypoglycemic effect in healthy volunteers. It reduces both fasting glucose levels and postprandial glucose levels in blood plasma.

Metformin acts via three pathways:

• reduces glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
• enhances peripheral glucose uptake and utilization in muscles by increasing insulin sensitivity;
• delays glucose absorption in the intestine.

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 effect on glycemia, metformin exerts a beneficial effect on lipid metabolism: it reduces levels of total cholesterol, low-density lipoproteins, 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 maximum concentration (Tmax) is 2.5 hours. Absolute bioavailability is about 50–60%.

Concomitant food intake reduces and delays metformin absorption.

Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached after approximately the same time period. Erythrocytes 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.

Excretion. 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 consequently increased metformin levels in plasma.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus (non-insulin-dependent) when dietary therapy is ineffective, particularly in patients with excess body weight:

• as monotherapy or combination therapy, together with other oral hypoglycemic agents, or together with insulin for treatment of adults;
• as monotherapy or combination therapy with insulin for 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., lactoacidosis, 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 agents;
• 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 consumption increases the risk of developing lactoacidosis during acute alcohol intoxication, particularly in cases of fasting, undernutrition, or adherence to a low-calorie diet, as well as in the presence of hepatic impairment. Alcohol consumption and the use of medicinal products containing alcohol should be avoided during treatment with this medicinal product.

Iodinated contrast agents. Metformin should be discontinued before or during radiological procedures involving intravascular administration of iodinated contrast agents and should not be restarted 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 "Method of administration and dosage").

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 adversely affect renal function, thereby increasing the risk of lactoacidosis. 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). More frequent monitoring of blood glucose levels is required, especially at the beginning of treatment. Dose adjustment of metformin may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate for both transporters – OCT1 and OCT2.

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;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal elimination of metformin.

Therefore, particular caution is recommended when co-administering these medicinal products 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 the efficacy of metformin.

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.

Lactic acidosis is characterized by muscle cramps, acidotic dyspnea, abdominal pain, and hypothermia; coma may subsequently develop. In case of 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 impair 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, 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 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 must discontinue metformin and seek immediate medical attention.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate concentration in blood 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 "Method of administration and dosage"). 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 "Interaction with other medicinal products and other forms of interaction" and "Method of administration and dosage").

Surgical procedures. Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and not resumed earlier than 48 hours after surgery or restoration 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. Results from one-year controlled clinical studies showed 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 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 evenly distributed carbohydrate intake throughout the day. Obese 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., sulfonylureas 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 anomalies. Preclinical studies have not shown any adverse effects on pregnancy, embryonal or fetal development, parturition, or postnatal development. When planning pregnancy or upon its occurrence, insulin rather than metformin is recommended for diabetes management to maintain blood glucose levels as close to normal as possible, thereby reducing the risk of fetal malformations.

Breastfeeding period. Metformin is excreted in breast milk, but no adverse effects 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 on discontinuing breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse effects to the infant.

Fertility. Metformin had no effect on fertility in animals when administered at doses up to 600 mg/kg/day, approximately three times the maximum recommended daily human 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 (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.

Dosage and Administration.

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

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

Gradual dose escalation reduces gastrointestinal side effects.

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

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

When switching to Metfogam® therapy, concomitant antidiabetic agents must be discontinued.

Combination therapy with insulin.

For better control of blood glucose levels, metformin and insulin may be used together in combination therapy. The usual initial dose is 500 mg or 850 mg of metformin 2–3 times daily, while the insulin dose should be individually adjusted based on blood glucose monitoring.

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

Renal impairment. eGFR should be evaluated before initiating therapy with metformin-containing medicinal products and at least annually thereafter. Patients at increased risk of progressive renal impairment and elderly patients should have renal function carefully monitored as frequently as possible, 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 taken 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 can be used in children aged 10 years and older.

Overdose.

Hypoglycemia has not been observed following administration of metformin at a dose of 85 g. Lactic acidosis with fatal outcome may occur in case of overdose. Accumulation of the drug due to impaired renal function may also lead to lactic acidosis. Initial symptoms of lactic acidosis include nausea, vomiting, diarrhea, fever, abdominal and muscular pain; subsequently tachypnea, dizziness, confusion, and coma may develop. If signs of lactic acidosis occur, the drug must be discontinued immediately, the patient should be urgently hospitalized, and diagnosis confirmed by measuring lactate concentration. Hemodialysis is the most effective method for elimination of lactate and metformin from the body. Symptomatic treatment should also be administered.

Side effects.

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, it is recommended to gradually increase the dosage and administer 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, it is recommended to gradually increase the dosage and take 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 disturbances: lactic acidosis (requires discontinuation of treatment). With prolonged use, absorption of vitamin B\12 may decrease, leading to reduced serum levels of vitamin B\12. This effect is observed when metformin is administered to patients with megaloblastic anemia.

Blood system: megaloblastic anemia.

Other: taste disturbances.

Shelf life. 5 years.

Storage conditions. Store at a temperature 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.

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