Metfogama® 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METFOGAMMA® 1000 (METFOGAMMA® 1000)

Composition:

Active substance: metformin;

1 tablet contains 1000 mg of metformin hydrochloride;

Excipients: hypromellose, povidone (K 25), magnesium stearate, macrogol 6000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: elongated white film-coated tablets with a break line on one side and snap-tab on the other.

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

Pharmacological Properties

Pharmacodynamics. Metfogama® 1000 is an oral hypoglycemic agent belonging to the biguanide class. It inhibits hepatic gluconeogenesis, reduces glucose absorption from the gastrointestinal tract, enhances peripheral glucose utilization, and increases tissue sensitivity to insulin. It does not affect insulin secretion by pancreatic beta-cells. It lowers blood levels of triglycerides and low-density lipoproteins. It is used in diabetes mellitus, including cases associated with lipid metabolism disorders and obesity. It stabilizes or reduces body weight. It exerts fibrinolytic effects by inhibiting tissue-type plasminogen activator inhibitor.

Pharmacokinetics. After oral administration, the drug is absorbed from the gastrointestinal tract. Its bioavailability is 50–60%. Maximum plasma concentration is reached within 2 hours after administration. The elimination half-life ranges from 1.5 to 4.5 hours. The drug is not metabolized in the body and exhibits negligible plasma protein binding. It accumulates in salivary glands, liver, and kidneys. It is excreted unchanged by the kidneys. It does not cause increased arterial pressure or tachycardia.

Distribution. Plasma protein binding is minimal. Metformin penetrates into erythrocytes. The maximum blood concentration is lower than the maximum plasma concentration and is reached approximately at 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 the urine. No metabolites have been identified in humans.

Excretion. Renal clearance of metformin exceeds 400 mL/min, indicating that metformin is eliminated via glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance of metformin decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased plasma metformin concentrations.

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 together with insulin for treatment of adults;
• as monotherapy or combination therapy with insulin for 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 following ineffective 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);
• 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 (particularly 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, especially in cases of fasting, malnutrition, or hepatic impairment.

Iodinated contrast agents. Intravenous administration of iodinated contrast agents may lead to renal impairment and, consequently, metformin accumulation and increased risk of lactic acidosis.

Metformin should be discontinued before or during the procedure 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 section "Special precautions for use").

In patients with moderate renal impairment (GFR 45–60 mL/min/1.73 m²), metformin should be discontinued 48 hours prior to administration of 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 no further deterioration in renal status.

Combinations that should be used with caution.

Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (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 at the start of treatment with these medicinal products or when they are used in combination with metformin.

Medicinal products with hyperglycemic effect (systemic and local glucocorticoids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of Metfogam® 1000 should be adjusted during and after discontinuation of such combination therapy.

Organic cation transporters (OCTs)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• inhibitors of OCT1 (such as verapamil) may reduce metformin efficacy;
• inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal excretion of metformin, leading to increased plasma metformin concentrations;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both 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 concentrations of metformin may increase. Dose adjustment of metformin should be considered if necessary. Since inhibitors/inducers of OCTs may affect metformin efficacy.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication occurring in the context of 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 attention should be sought.

Patients receiving metformin should initiate treatment cautiously with medicinal products that may 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, 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 development of lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia; coma may subsequently develop.

If any symptoms suggestive of lactic acidosis occur, the patient must discontinue metformin and seek immediate medical attention.

Diagnosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, with possible subsequent development of coma. 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 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 and unstable heart failure (see section "Contraindications").

Iodinated contrast agents. Intravenous administration of iodinated contrast agents may induce 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 should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and not restarted earlier than 48 hours after surgery or upon resumption of oral nutrition, and only after re-evaluation and confirmation of stable renal function.

Children. Before initiating metformin therapy, a diagnosis of type 2 diabetes mellitus must be confirmed. Results from 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 receiving metformin, especially during puberty.

Children aged 10 to 12 years. Based on controlled clinical studies involving 15 children aged 10 to 12 years, the efficacy and safety of metformin in this patient group were not different from those observed in older children and adolescents. Metformin should be prescribed with particular caution in children aged 10 to 12 years.

Other precautions. Patients should adhere to a diet with balanced carbohydrate intake throughout the day. Obese patients should continue to follow 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 the use of metformin in pregnant women do not indicate an increased risk of congenital anomalies. Preclinical studies have not shown any adverse effects on pregnancy, embryonic or fetal development, delivery, or postnatal development. When planning pregnancy or upon confirmation of pregnancy, insulin rather than metformin is recommended for managing diabetes to maintain blood glucose levels as close to normal as possible, thereby reducing 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, 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.

Method of Administration and Dosage.

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

Monotherapy or combination therapy with other oral antihyperglycemic agents.

The usual starting dose is 500 mg (1/2 tablet of Metfogama® 1000) 2–3 times daily, taken with or after meals.

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

Gradual dose escalation helps reduce gastrointestinal side effects.

The maximum recommended dose is 3000 mg daily, 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 (1/2 tablet of Metfogama® 1000) or 850 mg of metformin hydrochloride 2–3 times daily, while the insulin dose should be adjusted based on blood glucose monitoring results.

Children.

Monotherapy or combination therapy with insulin.

Metfogama® 1000 may be used in children aged 10 years and older and adolescents. The usual starting dose is 500 mg (1/2 tablet of Metfogama® 1000) or 850 mg of Metfogama® once daily, taken with or after meals. After 10–15 days, the dose should be adjusted according to serum glucose measurements.

Gradual dose escalation helps reduce gastrointestinal side effects.

The maximum recommended dose is 2000 mg (2 tablets of Metfogama® 1000) daily, divided into two doses.

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 Warnings and Precautions for Use").

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

Children. Metfogama® 1000 may be used for the treatment of children aged 10 years and older.

Overdose. When the drug 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 the development of lactic acid游戏副本

Adverse reactions.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhoea, 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, and the daily dose should be administered 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 organ system class, adverse reactions are listed in decreasing order of clinical significance.

Metabolism disorders.

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

With prolonged use of the drug, vitamin B₁₂ absorption may decrease, leading to reduced serum levels of vitamin B₁₂. This possible cause of vitamin B₁₂ deficiency should be considered if a patient develops megaloblastic anaemia.

From the nervous system.

Common: taste disturbances.

From the gastrointestinal system.

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite. These adverse effects most often occur at the beginning of treatment and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse effects, gradual dose escalation is recommended, and the daily dose should be administered in 2–3 divided doses, taken during or after meals.

From the liver and biliary system.

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

From the skin and subcutaneous tissues.

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

Shelf life. 4 years.

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

Packaging. 15 tablets in a blister; 2 or 8 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Dr. Falk Pharma Apotheker Püschl GmbH, Germany.

Address. Gölsstraße 1, 84529 Tittmoning, Germany.