Instructions Metafora tablets 1000mg No. 60
Composition
active ingredient: metformin hydrochloride;
1 tablet contains metformin hydrochloride 500 mg, which corresponds to metformin 390 mg;
1 tablet contains metformin hydrochloride 850 mg, which corresponds to metformin 662.9 mg;
1 tablet contains metformin hydrochloride 1000 mg, which corresponds to metformin 780 mg;
excipients: povidone; magnesium stearate; shell: Opadry Clear film coating mixture: hypromellose; polyethylene glycol.
Dosage form
Film-coated tablets.
Main physicochemical properties:
500 mg and 850 mg tablets: round tablets with a biconvex surface, coated with a white or almost white film coating;
1000 mg tablets: oblong tablets with a biconvex surface, with a score on both sides, coated with a white or almost white film coating.
Pharmacotherapeutic group
Oral hypoglycemic agents, except insulins. Biguanides. ATC code A10B A02.
Pharmacological properties
Pharmacodynamics.
Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after eating. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.
Metformin works in three ways:
– leads to a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis;
–improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization;
–delays the absorption of glucose in the intestine.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).
Regardless of its effect on glycemia, metformin has a positive effect on lipid metabolism: it reduces total cholesterol, low-density lipoproteins, and triglycerides.
During the studies, patients' body weight remained stable or decreased moderately while taking metformin.
Pharmacokinetics.
Absorption. After oral administration of metformin, the time to maximum concentration (Tmax) is approximately 2.5 hours. The absolute bioavailability of 500 mg or 850 mg tablets is approximately 50-60% in healthy volunteers. After oral administration, the fraction that is not absorbed and is excreted in the feces is 20-30%.
After oral administration, the absorption of metformin is saturable and incomplete.
The pharmacokinetics of metformin absorption are expected to be non-linear. At recommended metformin doses and dosing regimens, steady-state plasma concentrations are achieved within 24-48 hours and are less than 1 μg/ml. In clinical studies, maximum metformin plasma levels (Cmax) did not exceed 5 μg/ml even at maximum doses.
With simultaneous use of food, the absorption of metformin is reduced and slightly slowed down.
Following oral administration of an 850 mg dose, there was a 40% decrease in peak plasma concentration, a 25% decrease in AUC, and a 35-minute increase in time to peak plasma concentration. The clinical significance of these changes is unknown.
Distribution. Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and are reached at approximately the same time. Erythrocytes are likely to represent a second 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.
Elimination. Renal clearance of metformin is > 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the elimination half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance, so the elimination half-life increases, leading to increased metformin plasma levels.
Indication
Type 2 diabetes mellitus with ineffective diet therapy and exercise regimen, especially in patients with excess body weight:
· as monotherapy or combination therapy in combination with other oral hypoglycemic agents, or in combination with insulin for the treatment of adults;
To reduce the complications of diabetes in adult patients with type 2 diabetes mellitus and overweight as a first-line drug after ineffective diet therapy.
Contraindication
· Hypersensitivity to metformin or to any other component of the drug;
· any type of acute metabolic acidosis (e.g. lactic acidosis, diabetic ketoacidosis);
· diabetic precoma;
· severe renal failure (glomerular filtration rate (GFR) < 30 ml/min);
· diseases that can lead to the development of tissue hypoxia (especially acute diseases or exacerbation of a chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
· liver failure, acute alcohol poisoning, alcoholism.
Interaction with other medicinal products and other types of interactions
Combinations that are not recommended for use
Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, especially in the presence of fasting, malnutrition, or liver failure.
Iodine-containing radiopaque substances.
Patients should discontinue metformin prior to or during the study and not resume it until 48 hours after the study, only after re-evaluation and stable renal function (see sections 4.4 and 4.2).
Combinations to be used with caution
Some medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) II inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics, may adversely affect renal function, which may increase the risk of lactic acidosis. At the beginning of treatment with the above medicinal products, when used in combination with metformin, careful monitoring of renal function is necessary.
Medicinal products with hyperglycaemic effects (systemic and local glucocorticosteroids, sympathomimetics). Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. The dose of the medicinal product should be adjusted during and after discontinuation of such concomitant therapy.
Organic cation transporters (OCT).
Metformin is a substrate of both transporters – OCT1 and OCT2.
Concomitant use of metformin with:
· OCT1 inhibitors (such as verapamil) may reduce the effectiveness of metformin;
· OCT1 inducers (such as rifampicin) may increase the gastrointestinal absorption and efficacy of metformin;
· OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce the renal excretion of metformin with a subsequent increase in metformin plasma concentrations;
· inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect the efficacy and renal excretion of metformin.
Therefore, special caution is recommended when these drugs are used concomitantly with metformin, especially in patients with renal impairment, as metformin plasma concentrations may increase. If necessary, metformin dose adjustment should be considered, as OCT inhibitors/inducers may affect the efficacy of metformin.
Application features
Lactic acidosis is a very rare but serious metabolic complication that most often occurs in the setting of acute renal failure, cardiopulmonary disease, or sepsis. In acute renal failure, metformin accumulates, increasing the risk of lactic acidosis.
In case of dehydration (severe diarrhea or vomiting, fever, or decreased fluid intake), it is recommended to temporarily discontinue metformin and seek medical attention.
Patients receiving metformin should be cautiously initiated on drugs that may acutely impair renal function (e.g., antihypertensives, 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 can lead to lactic acidosis (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
Patients and/or caregivers should be informed of the risk of lactic acidosis. Characteristic signs of lactic acidosis are acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia, which may progress to coma. If any symptom of lactic acidosis occurs, the patient should discontinue metformin and seek medical attention immediately.
Diagnostic laboratory findings include decreased blood pH (< 7.35), increased serum lactate concentration (> 5 mmol/L), and increased anion gap and lactate/pyruvate ratio.
Kidney function.
GFR should be assessed before treatment is initiated and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with a GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).
Iodinated radiopaque agents. Intravascular administration of iodinated contrast agents may cause contrast-induced nephropathy, leading to metformin accumulation and an increased risk of lactic acidosis. Metformin should be discontinued in patients prior to or at the time of the examination and not resumed until 48 hours after the examination, and only after re-evaluation and stable renal function (see sections 4.5 and 4.2).
Surgery: Metformin should be discontinued during surgery performed under general, spinal or epidural anesthesia and should not be restarted until 48 hours after surgery or after oral nutrition has been re-established and renal function has been re-evaluated and stable.
Children. Type 2 diabetes mellitus should be confirmed before starting metformin treatment. Studies have not shown an effect of metformin on growth and puberty in children. However, there is no data on the effect of metformin on growth and puberty with longer-term use of metformin, so careful monitoring of these parameters is recommended in children treated with metformin, especially during puberty.
Children aged 10 to 12 years. According to the results of studies in children aged 10 to 12 years, the efficacy and safety of metformin in this group of patients did not differ from that in older children and adolescents. The drug should be prescribed with particular caution to children aged 10 to 12 years.
Other precautions: Patients should follow a diet with a balanced carbohydrate intake throughout the day. Overweight patients should continue to follow a low-calorie diet. Patients' carbohydrate metabolism should be monitored regularly.
Metformin monotherapy does not cause hypoglycemia, but caution should be exercised 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 permanent) increases the risk of congenital anomalies and perinatal mortality. There are limited data from the use of metformin in pregnant women, which do not indicate an increased risk of congenital anomalies. Preclinical studies have not revealed any negative effects on pregnancy, embryonal or foetal development, labour and postnatal development. In case of planning pregnancy, as well as in case of pregnancy, it is recommended to use insulin, not metformin, for the treatment of diabetes to maintain blood glucose levels as close to normal as possible, in order to reduce the risk of foetal malformations.
Breastfeeding. Metformin is excreted in human 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. A decision on whether to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of adverse effects to the child.
Fertility: Metformin had no effect on animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area.
Ability to influence reaction speed when driving vehicles or other mechanisms
Metformin monotherapy does not affect the reaction rate when driving or operating other mechanisms, since the drug does not cause hypoglycemia. However, caution should be exercised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin or meglitinides) due to the risk of hypoglycemia.
Method of administration and doses
Adult patients with normal renal function (GFR ≥ 90 mL/min)
Monotherapy or combination therapy compatible with other oral hypoglycemic agents.
The usual starting dose is 500 mg or 850 mg (Metaphora®, film-coated tablets, 500 mg or 850 mg) 2-3 times daily with or after meals.
After 10-15 days, the dose should be adjusted according to the results of serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
When treating with high doses (2000-3000 mg per day), it is possible to replace every 2 tablets of the drug Metafora®, 500 mg, with 1 tablet of the drug Metafora®, 1000 mg.
The maximum recommended dose is 3000 mg per day, divided into 3 doses.
In case of switching from another antidiabetic agent, it is necessary to discontinue this agent and prescribe metformin as described above.
To achieve better blood glucose control, metformin and insulin can be used as combination therapy. The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2-3 times daily, while the insulin dose should be adjusted according to blood glucose measurements.
Elderly patients may have decreased renal function, therefore the dose of metformin should be selected based on assessment of renal function, which should be performed regularly (see section "Special instructions").
Renal impairment. GFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in elderly patients, renal function should be monitored closely as frequently as possible, e.g. every 3-6 months.
GCF (ml/min) | Total maximum daily dose (should be divided into 2-3 doses) | Additional information |
| 60-89 | 3000 mg | In case of decreased renal function, it is recommended to consider a dose reduction. |
| 45-59 | 2000 mg | Before starting metformin, factors that may increase the risk of lactic acidosis should be considered (see section "Special warnings and precautions for use"). The initial dose is no more than half the maximum dose. |
| 30-44 | 1000 mg | |
| < 30 | - | The use of metformin is contraindicated. |
Children.
Monotherapy or combination therapy compatible with insulin.
Metafora® is intended for use in children aged 10 years and older and adolescents. The usual starting dose is 500 mg or 850 mg of the drug once daily with or after meals. After 10-15 days, the dose should be adjusted based on serum glucose measurements.
Slowly increasing the dose helps reduce side effects from the digestive tract.
The maximum recommended dose is 2000 mg per day, divided into 2-3 doses.
Children
The drug Metafora® should be used to treat children aged 10 years and older.
Overdose
When using the drug in a dose of 85 g, hypoglycemia was not observed. However, in this case, the development of lactic acidosis was observed. A significant excess of the metformin dose or concomitant risk factors can cause the occurrence of lactic acidosis. Lactic acidosis is an emergency and should be treated in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.
Adverse reactions
The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms in most cases disappear on their own. To prevent the occurrence of these side effects, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses.
Metabolic disorders: lactic acidosis (see section "Special warnings and precautions for use").
With prolonged use of the drug, absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood serum. It is recommended to consider this possible cause of hypovitaminosis B12 if the patient has megaloblastic anemia.
From the nervous system: taste disturbance.
On the part of the digestive system: digestive disorders such as nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and in most cases disappear spontaneously. To prevent the occurrence of side effects from the digestive system, it is recommended to slowly increase the dosage and use the daily dose of the drug in 2-3 doses during or after meals.
Hepatobiliary disorders: abnormal liver function tests or hepatitis, which completely disappear after metformin withdrawal.
Skin and subcutaneous tissue disorders: skin reactions including erythema, pruritus, urticaria.
Expiration date
2 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a pack.
10 tablets in a blister; 6 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Location of the manufacturer and address of its place of business
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
