Metformin

Pharmacological properties

metformin is a biguanide with an antihyperglycemic effect. reduces both the initial glucose level and the glucose level after a meal in plasma. does not stimulate insulin secretion and does not cause a hypoglycemic effect.

Metformin works in three ways:

• leads to a decrease in glucose production in the liver due to inhibition of gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles by improving the uptake and utilization of peripheral glucose;
• delays the absorption of glucose in the intestines.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. Increases transport capacity of all types of membrane glucose transporters (GLUT). Clinical studies have shown that the main effect of metformin is stabilization or a slight decrease in body weight.

Regardless of its effect on glycemia, immediate release metformin tablets reveal a beneficial effect on lipid metabolism. This effect has been proven with therapeutic dosages in controlled medium or long-term clinical trials: immediate release metformin tablets reduce total cholesterol, LDL and TG. A similar effect was not observed with the use of sustained-release tablets, probably in connection with the use of the drug in the evening. Therefore, an increase in TG content may also be observed.

Pharmacokinetics Suction. After oral administration of sustained release Diaformin SR tablets, the absorption of metformin is significantly slower compared to immediate release metformin tablets. Time to reach C_max (Tmax) is 7 hours (Tmax for fast release tablets is 2.5 hours).

At equilibrium, as with immediate release tablets, C_max and AUC are increasing disproportionately to the oral dose. AUC after a single oral administration of 2000 mg of metformin in the form of sustained release tablets is similar to AUC, which is observed after administration of 1000 mg of metformin in the form of tablets with immediate release 2 times a day.

Fluctuations C_max and AUC in individual subjects when taking sustained release metformin tablets are comparable to those observed with immediate release metformin tablets.

After taking fasting tablets, there was a 30% decrease in AUC (C_max and Tmax remained unchanged).

The absorption of metformin from sustained release tablets does not change depending on the composition of the food. No cumulation was observed with repeated administration of up to 2000 mg of metformin in the form of sustained release tablets.

Distribution. Plasma protein binding is negligible. Metformin penetrates red blood cells. C_max blood lower than C_max in blood plasma, and is reached after about the same time. Red blood cells most likely represent a second distribution chamber. The average volume of distribution (V_d) varies in the range of 63–276 liters.

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

The renal clearance of metformin is 400 ml / min, which indicates that metformin is excreted due to glomerular filtration and tubular secretion. After oral administration of a dose of T_½ is about 6.5 hours. In case of impaired renal function, renal clearance decreases in proportion to creatinine clearance, and therefore T_½ increases, which leads to an increase in the level of metformin in blood plasma.

Renal failure. Limited data are available on patients with moderate renal failure, so it is impossible to accurately assess the systemic exposure of metformin in this group of patients compared with patients with normal renal function. In this regard, dose adjustment is necessary according to clinical efficacy / tolerability (see APPLICATION).

Indications

Type II diabetes mellitus (non-insulin-dependent) in adults (especially in patients with overweight) with the ineffectiveness of diet therapy and physical activity, as monotherapy or in combination with other oral antidiabetic drugs or in combination with insulin.

Application

The tablets should be swallowed whole without chewing.

Monotherapy or combination therapy in combination with other oral hypoglycemic agents. The recommended starting dose is 500 mg / day.

After 10-15 days of treatment, the dose must be adjusted in accordance with the results of measurements of the level of glucose in the blood serum. Slow dose increase helps to reduce side effects from the digestive tract. The maximum recommended dose is 2000 mg / day.

The dose should be taken once a day during meals in the evening, increasing by 500 mg every 10-15 days to 2000 mg. If the required level of glycemia cannot be achieved with Diaformin SR at a maximum dose of 2000 mg, which the patient takes once a day, the dose can be divided into 2 doses per day (1 time in the morning and 1 time in the evening during meals). If the required glycemia level is not reached, Diaformin SR can be used at a maximum recommended dose of 3000 mg / day.

For patients who have already been treated with metformin, the initial dose of Diaformin SR, extended-release tablets, should be equivalent to a daily dose of immediate-release tablets. Patients receiving metformin therapy at a dose of 2000 mg / day are not recommended to switch to Diaformin SR therapy.

In case of switching to Diaformin SR, sustained release tablets, it is necessary to stop taking another antidiabetic drug for oral administration.

Combination therapy in combination with insulin. To achieve better control of blood glucose levels, metformin and insulin can be used as a combination therapy. Typically, the initial dose of Diaformin SR is 500 mg / day during meals in the evening, while the dose of insulin must be selected in accordance with the results of measuring blood glucose.

In elderly patients, impaired renal function is possible, therefore, the dose of metformin must be selected based on an assessment of renal function, which should be performed regularly (see SPECIAL INSTRUCTIONS).

Patients with renal failure. Metformin can be used in patients with moderate renal failure, stage IIIa (creatinine clearance 45–59 ml / min or 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 750 mg of metformin hydrochloride 1 time per day. The maximum dose is 1000 mg / day. Careful monitoring of renal function (every 3–6 months) should be carried out.

If creatinine clearance or GFR decreases to 5 ml / min or 45 ml / min / 1.73 m² accordingly, metformin should be discontinued immediately.

Contraindications

- Hypersensitivity to metformin or any other component of the drug;

• diabetic ketoacidosis, diabetic precoma;
• moderate renal failure (stage IIIb) and severe 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 a chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• liver failure, acute alcohol poisoning, alcoholism.

Side effects

The most common adverse reactions, especially at the beginning of treatment, are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. these symptoms usually resolve on their own.

Metabolic and nutritional disorders: lactic acidosis (see SPECIAL INSTRUCTIONS).

With prolonged use of the drug in patients with megaloblastic anemia, vitamin B absorption may decrease₁₂, which is accompanied by a decrease in its level in blood serum.

From the nervous system: taste disturbance.

From the gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and, as a rule, disappear spontaneously. To prevent the occurrence of side effects from the gastrointestinal tract, a slow increase in the dose of the drug is recommended.

From the hepatobiliary system: impaired liver function indicators or hepatitis, which completely disappear after the abolition of metformin.

On the part of the skin and subcutaneous tissue: skin allergic reactions, including erythema, pruritus, urticaria.

special instructions

Lactic acidosis is a rare but severe metabolic complication (high mortality rate in the absence of emergency treatment), which can occur as a result of cumulation of metformin. cases of lactic acidosis have been reported in patients with diabetes mellitus with renal failure or a sharp deterioration in renal function. caution must be exercised in cases where renal function may be impaired, for example, during dehydration (severe diarrhea or vomiting), or at the beginning of treatment with antihypertensive drugs, diuretics, and at the beginning of NSAID therapy. in case of occurrence of these exacerbations, it is necessary to temporarily stop the use of metformin.

Other risk factors to prevent the development of lactic acidosis should be considered: poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure, or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction) (see CONTRAINDICATIONS).

Lactic acidosis can occur in the form of nonspecific symptoms, such as muscle cramps, indigestion, abdominal pain, and severe asthenia. Patients should immediately inform the doctor about the occurrence of such reactions, especially if patients had previously tolerated the use of metformin. In such cases, it is necessary to temporarily stop taking metformin until the situation is clarified. Metformin therapy should be resumed after evaluating the benefit / risk ratio in individual cases and evaluating renal function.

Diagnostics. Lactic acidosis is characterized by acidic shortness of breath, abdominal pain and hypothermia, further development of coma is possible. Diagnostic indicators: laboratory decrease in blood pH, increase in serum lactate concentration of 5 mmol / l, increase in the anion gap and the ratio of lactate / pyruvate. In the case of lactic acidosis, it is necessary to hospitalize the patient immediately (see OVERDOSAGE). The physician should warn patients about the risk of developing symptoms of lactic acidosis.

Renal failure. Since metformin is excreted by the kidneys, before and regularly during treatment with Diaformin SR, it is necessary to check the level of creatinine (can be estimated by the level of creatinine in blood plasma using the Cockroft-Gault formula) or GFR:

• patients with normal renal function at least 1 time per year;
• patients with creatinine clearance at the lower limit of normal and elderly patients at least 2–4 times a year.

In the case where creatinine clearance is 45 ml / min (GFR 45 ml / min / 1.73 m²), metformin is contraindicated (see CONTRAINDICATIONS).

Reduced renal function in elderly patients is often observed and is asymptomatic. Caution should be exercised in cases where renal function may be impaired, for example, during dehydration, or at the beginning of treatment with antihypertensive drugs, diuretics, and at the beginning of NSAID therapy. In such cases, it is also recommended to check kidney function before starting treatment with metformin.

Cardiac function. Patients with heart failure have a higher risk of developing hypoxia and renal failure. In patients with stable chronic heart failure, metformin can be used with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see CONTRAINDICATIONS).

Iodine-containing radiopaque agents. The intravascular use of radiopaque agents for radiological studies can lead to renal failure and, as a result, cumulation of metformin and an increased risk of lactic acidosis. Patients with GFR 60 ml / min / 1.73 m² the use of metformin must be discontinued before or during the study and not restarted earlier than 48 hours after the study, only after re-evaluating kidney function and confirming the absence of further renal impairment (see INTERACTIONS).

Patients with moderate renal failure (GFR 45-60 ml / min / 1.73 m²) the use of metformin should be discontinued 48 hours before the administration of iodine-containing radiopaque substances and should not be resumed earlier than 48 hours after the study, only after a repeated assessment of renal function and confirmation of the absence of further renal impairment (see INTERACTIONS).

Surgical interventions. It is necessary to stop the use of Diaformin SR 48 hours before the planned surgical intervention, which is carried out under general, spinal or epidural anesthesia, and not resume earlier than 48 hours after the operation or restoration of oral nutrition and only if normal renal function is established.

Other preventative measures. Patients need to follow a diet, uniform intake of carbohydrates throughout the day. Overweight patients should continue to follow a low-calorie diet. It is necessary to regularly monitor laboratory indicators of blood glucose levels.

Metformin monotherapy does not cause hypoglycemia. With the simultaneous use of Diaformin SR with insulin or other oral hypoglycemic agents (for example, sulfonylurea derivatives or meglitinide), an increase in hypoglycemic effect is possible.

Perhaps the presence of fragments of the shell of tablets in feces. This is normal and has no clinical significance.

Use during pregnancy and lactation. Pregnancy. Uncontrolled diabetes during pregnancy (gestational or persistent) increases the risk of congenital malformations 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 a negative effect on pregnancy, development of the embryo or fetus, childbirth and development after birth. In case of pregnancy planning, as well as its onset, metformin therapy should be canceled, the doctor should be informed and insulin therapy should be prescribed to maintain the blood glucose level as close to normal as possible to reduce the risk of fetal malformations.

Lactation. Metformin is excreted in breast milk, but no side effects were observed in newborns / infants who were breastfed.However, since there is insufficient data on the safety of the drug, breast-feeding is not recommended during the course of therapy with Diaformin SR. The decision to stop breastfeeding should be made taking into account the benefits of breastfeeding and the potential risk of side effects for the baby.

Fertility. Metformin did not affect animal fertility when used in doses of 600 mg / kg / day, which is almost three times the maximum recommended daily dose for humans and is calculated based on body surface area.

Children. The drug should not be used in children, since there is no clinical data regarding this age group of patients.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Diaformin SR does not affect the reaction rate when driving vehicles or working with other mechanisms, since monotherapy with the drug does not cause hypoglycemia.

However, metformin should be used with caution in combination with other hypoglycemic agents (sulfonylureas, insulin, meglinitides) due to the risk of hypoglycemia.

Interactions

Combinations not recommended

Alcohol. Acute alcohol intoxication is associated with an increased risk of lactic acidosis, especially in cases of fasting or following a low-calorie diet, as well as with liver failure. When treated with Diaformin SR, ethanol and drugs containing ethanol should be avoided.

Iodine-containing radiopaque substances. Intravascular use of iodine-containing contrast agents can lead to functional renal failure and the accumulation of metformin and increase the risk of lactic acidosis.

Patients with GFR 60 ml / min / 1.73 m² Metformin should be discontinued before or during the study and should not be resumed earlier than 48 hours after the study, only after re-evaluating renal function and confirming the absence of further renal impairment (see SPECIAL INSTRUCTIONS).

Patients with moderate renal failure (GFR 45-60 ml / min / 1.73 m²) Metformin should be discontinued 48 hours before the administration of iodine-containing radiopaque substances and should not be resumed earlier than 48 hours after the study, only after re-evaluating kidney function and confirming the absence of further renal impairment.

Combinations to be used with caution

Medicines that have a hyperglycemic effect (GCS of systemic and local action, sympathomimetics, chlorpromazine). It is necessary to control the level of glucose in the blood more often, especially at the beginning of treatment. During and after the termination of such combined therapy, it is necessary to adjust the dose of Diaformin SR under the control of glycemia level.

ACE inhibitors can lower blood glucose. If necessary, adjust the dose of the drug during combination therapy.

Diuretics, especially loop diuretics, can increase the risk of lactic acidosis due to a possible decrease in kidney function.

Overdose

When using the drug at a dose of 85 g, the development of hypoglycemia was not observed, however, the occurrence of lactic acidosis was noted. Significant excess doses of metformin or concomitant risk factors can lead to lactic acidosis. lactic acidosis is an emergency. in the case of lactic acidosis, treatment with diaformin sr must be stopped and the patient urgently hospitalized.

The most effective measure for removing lactate and metformin from the body is hemodialysis.

Storage conditions

At a temperature not exceeding 30 ° c.