Pharmacological properties
Pharmacodynamics. Metformin is a biguanide with antihyperglycemic effect. It reduces both the initial glucose level and the glucose level after a meal in the blood plasma. It does not stimulate insulin secretion and does not exhibit a hypoglycemic effect mediated by this mechanism.
Metformin works in three ways:
helps reduce glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; improves insulin sensitivity in muscles, helping to improve peripheral glucose uptake and utilization; delays glucose absorption in the intestines.
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 metformin use, patients' body weight remained stable or decreased moderately.
Pharmacokinetics. Absorption. After oral administration of metformin, the time to reach C max (Tmax) is approximately 2.5 hours. Absolute bioavailability is approximately 50-60%. 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 assumed to be non-linear. When using the recommended doses of metformin and dosing regimens, steady-state plasma concentrations are achieved within 24-48 hours and are 1 μg/ml. In controlled clinical studies, C max of metformin in plasma did not exceed 5 μg/ml even at maximum doses.
When taken with food, the absorption of metformin is reduced and slowed down.
Distribution. Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes. C max in blood is lower than C max in plasma and is reached after approximately the same time. Erythrocytes most likely represent a second distribution chamber. The mean volume of distribution (V d ) 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, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, the half-life is approximately 6.5 hours. In cases of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore the half-life increases, leading to increased plasma metformin 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; as monotherapy or combination therapy with insulin for the treatment of children over 10 years of age.
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.
Application
adults
Monotherapy or combination therapy in combination with other oral hypoglycemic agents. Usually the initial dose is 500 mg or 850 mg 2-3 times a day during 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 gastrointestinal side effects.
When treating high doses, Diaformin film-coated tablets of 1000 mg are used.
The maximum recommended dose is 3000 mg/day, divided into 3 doses.
If switching from another antidiabetic drug, it is necessary to stop taking this drug and prescribe Diaformin as indicated above.
Combination therapy with insulin. To achieve better control of blood glucose levels, metformin and insulin can be used as combination therapy. The usual starting dose is 500 mg or 850 mg of Diaformin 2-3 times a day, while the insulin dose should be adjusted according to blood glucose measurements.
children
Monotherapy or combination therapy in combination with insulin. Diaformin is used in children over 10 years of age. Usually the initial dose is 500 mg or 850 mg of Diaformin once a day during 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 gastrointestinal side effects.
The maximum recommended dose is 2000 mg/day, divided into 2-3 doses.
Patients with renal insufficiency. Diaformin can be used in patients with moderate renal insufficiency, stage IIIa (creatinine clearance 45-59 ml/min or glomerular filtration rate (GFR) 45-59 ml/min/1.73 m2), only in the absence of other conditions that may increase the risk of lactic acidosis, with subsequent dose adjustment: the initial dose is 500 mg or 850 mg 1 time per day. The maximum dose is 1000 mg/day, divided into 2 doses. Careful monitoring of renal function should be carried out every 3-6 months.
If creatinine clearance or GFR decreases to 45 ml/min or 45-59 ml/min/1.73 m2, Diaformin should be discontinued immediately.
Contraindication
Hypersensitivity to metformin or any other component of the drug; diabetic ketoacidosis, diabetic precoma; moderate (stage IIIB) and severe renal failure or impaired renal function (creatinine clearance 45 ml/min or GFR 45 ml/min/1.73 m2); acute conditions with a risk of developing renal dysfunction, such as dehydration, severe infectious diseases, shock; diseases that can lead to the development of tissue hypoxia (especially acute diseases or exacerbation of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock; liver failure, acute alcohol poisoning, alcoholism.
Side effects
Metabolism: lactic acidosis.
With prolonged use of the drug, absorption of vitamin B12 may decrease, which is accompanied by a decrease in its level in the blood plasma. It is recommended to consider this possible cause of hypovitaminosis B12 if the patient has megaloblastic anemia.
From the nervous system: taste disturbance.
Gastrointestinal: gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain, loss 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 gastrointestinal tract, it is recommended to slowly increase the dose and use the drug in 2-3 doses during or after meals.
On the part of the hepatobiliary system: liver function tests or hepatitis, which completely disappear after metformin withdrawal.
Skin and subcutaneous tissue disorders: skin reactions including erythema, pruritus, urticaria.
Special instructions
Lactic acidosis is a very rare but serious metabolic complication (high mortality rate in the absence of urgent treatment) that may occur as a result of metformin accumulation. Cases of lactic acidosis have been reported in diabetic patients with renal failure or a sharp deterioration in renal function. Caution should be exercised in cases where renal function may be impaired, for example in case of dehydration (severe diarrhea or vomiting), or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with nonsteroidal anti-inflammatory drugs. In the event of these exacerbations, metformin should be temporarily discontinued.
Other risk factors for lactic acidosis should be considered: poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see Adverse Reactions).
Lactic acidosis may manifest as muscle cramps, indigestion, abdominal pain and severe asthenia. Patients should immediately inform their doctor about the occurrence of such reactions, especially if they have previously tolerated metformin well. In such cases, metformin should be temporarily discontinued until the situation is clarified. Metformin therapy should be resumed after assessing the benefit/risk ratio in individual cases and assessing renal function.
Diagnostics. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia, and coma may develop later. Diagnostic indicators: laboratory decrease in blood pH, increase in serum lactate concentration above 5 mmol / l, increase in anion gap and lactate / pyruvate ratio. In case of development of lactic acidosis, the patient must be hospitalized immediately (see Conditions and shelf life). The doctor should warn patients about the risk of developing symptoms of lactic acidosis.
Renal failure. Since metformin is excreted by the kidneys, before starting and regularly during treatment with Diaformin, it is necessary to check the creatinine level (can be estimated from the level of creatinine in the blood plasma using the Cockcroft-Golta formula) or GFR:
patients with normal renal function at least once a year; patients with creatinine clearance at the lower limit of normal and elderly patients at least 2-4 times a year.
In the case of creatinine clearance of 45 ml/min (GFR 45 ml/min/1.73 m2), the use of metformin is contraindicated (see Side effects).
Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see Adverse Reactions).
Iodinated radiocontrast agents. Intravenous use of radiocontrast agents for radiological examinations may cause renal failure and, as a result, lead to metformin accumulation and an increased risk of lactic acidosis. In patients with a GFR of 60 ml/min/1.73 m2, metformin should be discontinued before or during the examination and not resumed earlier than 48 hours after the examination and only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal function (see Interactions with other medicinal products).
In patients with moderate renal impairment (GFR 45-60 ml/min/1.73 m2), metformin should be discontinued 48 hours before the administration of iodinated radiocontrast agents and not resumed earlier than 48 hours after the examination and only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal function (see Interactions with other medicinal products).
Surgical interventions. Diaformin should be discontinued 48 hours before elective surgery performed under general, spinal, or epidural anesthesia and not resumed until 48 hours after surgery or resumption of oral nutrition and only if renal function has been restored to normal.
Other precautions. Patients should follow a diet with a uniform intake of carbohydrates 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, however, caution should be exercised when using Diaformin simultaneously with insulin or other oral hypoglycemic agents (e.g. sulfonylurea derivatives or meglitinides), as the hypoglycemic effect may be enhanced.
Use during pregnancy and breastfeeding. Pregnancy. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. There are limited data on 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 and fetal development, childbirth and postnatal development. When planning pregnancy, as well as in the event of pregnancy, it is recommended to use insulin, not metformin, to treat diabetes mellitus to maintain glucose levels as close to normal as possible, to reduce the risk of fetal malformations.
Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed infants/newborns. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during therapy with Diaformin. The decision to discontinue breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of adverse effects for the child.
Fertility: Metformin had no effect on animal fertility at doses of 600 mg/kg/day, which was almost 3 times the maximum recommended daily human dose based on body surface area.
Children. Before starting treatment with metformin, a diagnosis of type 2 diabetes mellitus should be confirmed. Clinical studies over 1 year have not shown any effect of metformin on growth and puberty in children. However, there are no data on the effect of metformin on growth and puberty with long-term use of Diaformin, therefore, 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 clinical studies, the efficacy and safety in this group of patients did not differ from that in older children. The drug should be prescribed with particular caution to children aged 10 to 12 years.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Diaformin does not affect the reaction rate when driving vehicles or working with other mechanisms, since monotherapy with the drug does not cause hypoglycemia.
However, caution should be exercised when metformin is used in combination with other hypoglycemic agents (sulfonylureas, insulin, or meglitinides) due to the risk of hypoglycemia.
Interactions
Combinations that are not recommended for use
Iodinated radiocontrast agents. Intravenous use of iodinated radiocontrast agents may lead to renal failure and, as a result, to metformin accumulation and an increased risk of lactic acidosis.
In patients with a GFR of 60 ml/min/1.73 m2, metformin should be discontinued prior to or at the time of the test and not resumed until 48 hours after the test, only after re-evaluation of renal function and confirmation of no further deterioration of renal function (see SPECIAL PRECAUTIONS).
In patients with moderate renal impairment (GFR 45-60 ml/min/1.73 m2), metformin should be discontinued 48 hours before the administration of iodinated radiocontrast agents and not resumed earlier than 48 hours after the examination, only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal condition.
Combinations that should be used with caution. Drugs that have a hyperglycemic effect (systemic and local corticosteroids, sympathomimetics). It is necessary to monitor blood glucose levels more often, especially at the beginning of treatment. During and after discontinuation of such combined therapy, it is necessary to adjust the dose of Diaformin under the control of glycemia.
Diuretics, especially loop diuretics, may increase the risk of lactic acidosis due to possible decreased renal function.
Overdose
When using the drug in a dose of 85 g, the development of hypoglycemia was not observed. However, in this case, the development of lactic acidosis was noted. A significant excess of the dose of metformin 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 method for removing lactate and metformin from the body is hemodialysis.
Storage conditions
In a dry, dark place at a temperature not exceeding 25 °C.
Translation of the instructions can be
