Metformin - instructions for use, dose, side effects, contraindications

Excipients: starch 1500 (corn starch partially pregelatinised) - 22.50 mg, povidone K-25 - 16.90 mg, croscarmellose sodium - 22.50 mg, magnesium stearate - 3.75 mg, microcrystalline cellulose - up to an average core weight of 750.00 mg, opadrai II (series 85 F) (21811, green) 38.00 mg;

dosage of 850 mg:

active substance: metformin hydrochloride in terms of 100% substance - 850.00 mg;

Excipients: starch 1500 (corn starch partially pregelatinized) 22.00 mg, povidone K-25 24.70 mg, croscarmellose sodium 22.00 mg, magnesium stearate 7.50 mg, microcrystalline cellulose up to an average core weight of 1100.00 mg, opadrai II (series 85 F) (21811, green) - 55.00 mg;

dosage of 1000 mg:

active substance: metformin hydrochloride in terms of 100% substance - 1000.00 mg;

Excipients: starch 1500 (corn starch partially pregelatinized) 26.00 mg, povidone K-25 29.30 mg, croscarmellose sodium 26.00 mg, magnesium stearate 8,80 mg, cellulose microcrystalline - up to the average mass of the nucleus 1300,00 mg, opadrai II (series 85 F) (21811, green) - 65.00 mg;

Composition of the Impudent II (series 85 F) (21811, green): alcohol polyvinyl, partially hydrolyzed - 40,000%, macrogol 3350 (polyethylene glycol) - 20,200%, talc - 14,800%, coloring pigment (titanium dioxide (E 171) - 24.170%, aluminum lacquer based on indigo carmine (E 132) - 0.590% Aluminum lacquer based on yellow quinoline (E 104) - 0.240% **) - 25,000%.

Dye content in aluminum varnish:

* 3 % - 5 %;

** 18%-24%.

Description:Round biconvex tablets, film-coated, green, tablets with a dosage of 500 mg and 1000 mg - with a risk, a dosage of 850 mg - without risks. Two layers are visible on the cross-section.

Pharmacotherapeutic group:Hypoglycemic agent for oral application of the biguanide group

ATX: & nbsp

A.10.B.A.02 Metformin

Pharmacodynamics:

Metformin reduces hyperglycemia, without leading to the development of hypoglycemia. Unlike derivatives of sulfonylurea, it does not stimulate insulin secretion and does not have a hypoglycemic effect in a healthy person.Increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. It inhibits gluconeogenesis in the liver. Delays the absorption of carbohydrates in the intestine. Stimulates the synthesis of glycogen, activating glycogen synthase. Increases the transport capacity of all types of membrane glucose transporters.

In addition, it has a beneficial effect on the metabolism of lipids: reduces the concentration of total cholesterol, low-density lipoproteins and triglycerides.

On the background of taking metformin, the patient's body weight either remains stable or moderately decreases.

Clinical studies have also shown the effectiveness of metformin for the prevention of diabetes mellitus in patients with prediabetes with additional risk factors for the development of overt diabetes mellitus type 2, in whom lifestyle changes did not allow adequate glycemic control.

Pharmacokinetics:

Absorption

Metformin is rapidly absorbed in the gastrointestinal tract (GIT). Absolute bioavailability is 50 - 60%. The maximum concentration (C_m_Oh) in the blood plasma is approximately 2 μg / ml or 15 μmol. Time of achievement in 2.5 hours.With simultaneous intake of food, absorption of metformin is reduced and delayed.

Distribution

Metformin is rapidly distributed into tissues, practically does not bind to blood plasma proteins.

Metabolism and excretion

Exposed to a very weak degree of metabolism and excreted by the kidneys. The clearance of metformin in healthy subjects is 400 ml / min (4 times more than the creatinine clearance), which indicates the presence of active canaliculia secretion. The half-life (T1 / 2) is approximately 6.5 hours. With renal insufficiency, it increases, there is a risk of cumulation of the drug.

Indications:

Diabetes mellitus type 2, especially in patients with obesity, with ineffectiveness of diet and exercise:

- in adults as a monotherapy or in combination with other oral hypoglycemic agents, or with insulin;

- in children from 10 years as a monotherapy or in combination with insulin.

Prevention of type 2 diabetes in patients with prediabetes with additional risk factors for developing type 2 diabetes mellitus, whose lifestyle changes did not allow adequate glycemic control.

Contraindications:

- Hypersensitivity to metformin and / or any auxiliary substance of the drug;

- diabetic ketoacidosis, diabetic precoma, coma;

- renal failure or impaired renal function (creatinine clearance less than 45 mL / min);

- acute conditions that occur at a risk of developing renal dysfunction: dehydration (with diarrhea, vomiting), severe infectious diseases, shock;

- clinically pronounced manifestations of acute and chronic diseases that can lead to the development of tissue hypoxia (including acute heart failure, chronic heart failure with unstable hemodynamics, respiratory failure, acute myocardial infarction);

- extensive surgery and trauma, when insulin therapy is indicated (see section "Special instructions");

- hepatic failure, a violation of liver function;

- chronic alcoholism, acute alcohol poisoning;

- pregnancy;

- lactic acidosis (including and in the anamnesis);

- use for less than 48 hours before and within 48 hours after radioisotope or X-ray studies with the introduction of iodine-containing contrast media;

- compliance with a low-calorie diet (less than 1000 kcal / day);

- children under 10 years old.

Carefully:

Use the drug in people over 60 years of age who perform heavy physical work, which is associated with an increased risk of developing lactic acidosis; in patients with renal insufficiency (creatinine clearance 45 -59 ml / min); in the period of breastfeeding.

Pregnancy and lactation:

Decompensated diabetes mellitus during pregnancy is associated with an increased risk of congenital malformations and perinatal mortality.

A limited amount of evidence suggests that taking metformin in pregnant women does not increase the risk of congenital malformations in children.

When planning pregnancy, as well as in case of pregnancy on the background of taking metformin with pre-diabetes or type 2 diabetes, the drug should be canceled and insulin therapy prescribed. It is necessary to maintain the level of glucose in the blood plasma at the level closest to the norm in order to reduce the risk of fetal malformations.

Metformin penetrates into breast milk. Side effects in newborns with breastfeeding against metformin were not observed.However, due to the limited amount of data, the use of the drug during breastfeeding is not recommended. The decision to stop breastfeeding should be taken in consideration of the benefits of breastfeeding and the potential risk of side effects in the child.

Dosing and Administration:

A drug Metformin taken inside, during or after a meal, without chewing, squeezed with enough water.

Adults

Monotherapy and combination therapy in combination with other oral hypoglycemic agents in type 2 diabetes mellitus

- The usual initial dose is 500 mg or 850 mg 2 to 3 times a day after or during meals. A further gradual increase in the dose is possible depending on the concentration of glucose in the blood.

- Every 10-15 days it is recommended to adjust the dose based on the results of measuring the concentration of glucose in the blood plasma.

- The maintenance dose of the drug is usually 1500 - 2000 mg / day. To reduce side effects from the gastrointestinal tract, the daily dose should be divided into 2 - 3 doses. The maximum dose is 3000 mg / day, divided into 3 doses.

- Slow increase in dose can help reduce unwanted reactions from the gastrointestinal tract.

- Patients receiving metformin in doses of 2000 - 3000 mg / day, can be transferred to receive the drug 1000 mg. The maximum recommended dose is 3000 mg / day, divided into 3 doses.

In the case of planning a transition from another hypoglycemic drug, it is necessary to stop taking this medication and begin taking the drug Metformin in the dose indicated above.

Combination with insulin

To achieve better control of blood glucose metformin and insulin can be used as a combination therapy. The usual initial dose of the drug Metformin in doses of 500 mg or 850 mg is one tablet 2-3 times a day, while the dose of insulin is selected based on the concentration of glucose in the blood.

Children and teens

From the age of 10 the drug can be used both in monotherapy and in combination with insulin. The usual initial dose is 500 mg or 850 mg once a day after or during a meal. Across 10-15 days the dose should be adjusted based on the blood glucose concentration. The maximum daily dose is 2000 mg, divided into 2 to 3 doses.

Monotherapy for pre-diabetes:

The usual dose is 1000-1700 mg per day after meals, divided into 2 doses.

It is recommended to carry out regular glycemic control to assess the need for further use of the drug.

Elderly patients

Because of the possible decrease in renal function, the dose of the drug Metformin it is necessary to select under regular monitoring indicators of kidney function (determine the concentration of creatinine in serum at least 2-4 times a year).

Patients with impaired renal function

Metformin can be used in patients with moderate renal insufficiency (creatinine clearance 45 - 59 ml / min) only in the absence of conditions that may increase the risk of lactic acidosis.

Patients with creatinine clearance 45 - 59 ml / min: the initial dose is 500 mg or 850 mg once a day. The maximum dose is 1000 mg per day, divided into 2 doses.

The function of the kidneys should be carefully monitored (every 3-6 months). If the creatinine clearance is below 45 ml / min, the drug should be discontinued immediately.

Duration of treatment

A drug Metformin should be taken daily, without interruption.In the event of discontinuation of treatment, the patient should inform the physician about this.

Side effects:

The frequency of side effects of the drug is assessed as follows: very often:> 1/10; often: 1/10 - 1/100; infrequently: 1/100 - 1/1000; rarely: 1/1000 - 1/10000; very rarely: <1/10000.

Disorders from the metabolism and nutrition

Very rarely: lactic acidosis (see section "Special instructions").

With prolonged use of metformin, a decrease in the absorption of vitamin B₁₂. When detecting megaloblastic anemia, it is necessary to consider the possibility of such etiology.

Disturbances from the nervous system

Often: a taste disorder

Disorders from the gastrointestinal tract

Very often: nausea, vomiting, diarrhea, lack of appetite, abdominal pain. These side effects often occur during the initial period of treatment and in most cases, with continued admission, they spontaneously pass. To reduce side effects, it is recommended to take the drug during or after a meal. Slow increase in dose may improve gastrointestinal tolerance.

Disturbances from the liver and bile ducts

Very rarely: a violation of liver function and hepatitis.

After the withdrawal of metformin, these undesirable phenomena completely disappear.

Disturbances from the skin and subcutaneous tissues

Very rarely: skin reactions, such as erythema, pruritus, rash.

Published post-marketing data, as well as controlled clinical trials in a limited child population in the age group 10-16 years show that the side effects of children in nature and severity are similar to those in adult patients.

Overdose:

Symptoms: when metformin was used at a dose of 85 g (42.5 times the maximum daily dose), hypoglycemia was not observed, but lactoacidosis was noted.

A significant overdose of metformin or associated risk factors may lead to the development of lactic acidosis (see section "Special instructions").

Treatment: in the case of the appearance of signs of lactic acidosis, the drug should be discontinued immediately, the patient must be hospitalized and, having determined the concentration of lactate, clarify the diagnosis. The most effective measure for excretion from the body of lactate and metformin is hemodialysis. Conduct also symptomatic treatment.

Interaction:

Contraindicated combinations

Iodine-containing radiopaque agents: on the background of functional renal failure in patients with diabetes mellitus, a radiological study using iodine-containing radiocontrast agents can cause the development of lactic acidosis. Treatment with metformin should be canceled depending on the function of the kidneys 48 hours before or during the X-ray examination using iodine-containing radiopaque means and not to resume earlier 48 hours after, provided that during the examination the kidney function was recognized normal.

Unrecommended combinations

Alcohol: acute alcohol intoxication increases the risk of lactic acidosis, especially in the following cases:

- malnutrition;

- adherence to a low-calorie diet;

- liver failure.

When taking the drug, avoid drinking alcohol and medications containing ethanol.

Combinations requiring use with caution

Danazol: It is not recommended simultaneous reception of danazolum in order to avoid hyperglycemic action of the latter. If necessary, treatment with danazol and after discontinuation of the latter requires a dose adjustment of the drug Metformin under the control of the concentration of glucose in the blood.

Chlorpromazine: when taken in high doses (100 mg per day) increases the concentration of glucose in the blood, reducing the release of insulin. When treating with neuroleptics and after stopping the intake of the latter, a dose adjustment is required Metformin under the control of the concentration of glucose in the blood.

Glucocorticosteroids (GCS) systemic and local effects reduce glucose tolerance, increase the concentration of glucose in the blood, sometimes causing ketosis. During treatment with GCS and after stopping the intake of the latter, a dose adjustment is required Metformin under the control of the concentration of glucose in the blood.

Diuretics: simultaneous administration of "loop" diuretics can lead to the development of lactic acidosis due to possible functional renal failure. Do not assign metformin, if the SC is below 60 ml / min.

Beta2-adrenomimetics, administered parenterally: increase the concentration of glucose in the blood due to stimulation of beta2-adrenoreceptors. In this case, it is necessary to monitor the concentration of glucose in the blood. If necessary, the appointment of insulin is recommended.

With the simultaneous use of the above medicines, more frequent monitoring of the glucose level in the blood may be required, especially at the beginning of the treatment. If necessary, the dose of metformin can be adjusted during treatment and after its termination.

Hypotensive drugs, except for angiotensin-converting enzyme inhibitors can reduce the concentration of glucose in the blood. If necessary, the dose of metformin should be adjusted.

With the simultaneous use of metformin with derivatives of sulfonylurea, insulin, acarbose, salicylates possibly the development of hypoglycemia.

Nifedipine increases absorption and C_m_Oh metformin.

Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and Vancomycin) secreted in the renal tubules compete with metformin over the tubular transport systems and can lead to an increase in its C_m_Oh.

Special instructions:

Lactic acidosis

Lactic acidosis is a rare, but serious (high mortality in the absence of emergency treatment) complication, which can occur due to the cumulation of metformin.Cases of lactic acidosis with metformin were developed mainly in patients with diabetes mellitus with severe renal insufficiency.

Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia, should be considered. This can help reduce the incidence of lactic acidosis. The risk of developing lactic acidosis when nonspecific signs appear, such as muscle cramps accompanied by dyspeptic disorders, abdominal pain and severe asthenia, should be considered. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory indicators are a decrease in blood pH (less than 7.25), a lactate content in the blood plasma above 5 mmol / l, an increased anion gap and a lactate / pyruvate ratio. If you suspect a metabolic acidosis, stop taking the medication and consult a doctor immediately.

Surgical operations

The use of metformin should be discontinued 48 hours before scheduled surgical operations and can be continued no earlier than 48 hours after, provided that during the examination the renal function was found to be normal.

Kidney function

Because the metformin is excreted by the kidneys, before the beginning of treatment and regularly in the future, it is necessary to determine the QC:

- at least once a year in patients with normal renal function;

- at least 2-4 times a year in elderly patients, as well as in patients with QC at the lower limit of the norm.

In the case of CC less than 45 ml / min, the use of the drug is contraindicated. Care should be taken if there is a possible impairment of kidney function in elderly patients, while using antihypertensive drugs, diuretics or non-steroidal anti-inflammatory drugs.

Heart failure

Patients with heart failure have a higher risk of developing hypoxia and kidney failure. Patients with chronic heart failure should regularly monitor cardiac function and kidney function during taking metformin.The use of metformin in heart failure with unstable parameters of hemodynamics is contraindicated.

Children and teens

The diagnosis of Type 2 diabetes mellitus should be confirmed before the start of treatment with metformin. In clinical studies of 1 year, it was shown that metformin does not affect growth and puberty. However, in view of the lack of long-term data, careful monitoring of the subsequent influence of metformin on these parameters in children, especially during puberty, is recommended.

The most thorough control is needed in children aged 10-12 years.

Other Precautions

- Patients are encouraged to continue to follow a diet with an even intake of carbohydrates throughout the day. Patients with excessive body weight should continue to observe a hypocaloric diet (but not less than 1000 kcal / day).

- It is recommended that regular laboratory tests be performed on a regular basis to control diabetes mellitus.

- Metformin with monotherapy does not cause hypoglycemia, but it is advisable to use caution when used in combination with insulin or other hypoglycemic agents (for example, derivatives of sulfonylurea, repaglinide, etc.).

Application of the drug Metformin recommended for the prevention of type 2 diabetes mellitus to persons with pre-diabetes and additional risk factors for the development of overt diabetes mellitus type 2, such as:

- age less than 60 years;

- body mass index (BMI) ≥35 kg / m²;

- Gestational diabetes mellitus in history;

- Family history of diabetes mellitus in relatives of the first degree;

- increased concentration of triglycerides;

- reduced concentration of HDL cholesterol;

- arterial hypertension.

Effect on the ability to drive transp. cf. and fur:

Monotherapy with the drug does not cause hypoglycemia, therefore does not affect the ability to drive vehicles and mechanisms. Patients should be cautioned about the risk of hypoglycemia when using metformin in combination with other hypoglycemic agents (derivatives of sulfonylureas, repaglinide, insulin, etc.), in which the ability to drive vehicles and engage in other potentially dangerous activities that require increased attention and rapid psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 500 mg, 850 mg, 1000 mg.

Packaging:

10 tablets are placed in a contoured cell pack of a polyvinyl chloride film or a film of unplasticized PVC and flexible packaging based on aluminum foil, or aluminum foil, or a composite material based on foil.

3 contour squares, together with instructions for medical use, are placed in a cardboard pack.

Storage conditions:

In a place protected from light and moisture, at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004380

Date of registration:19.07.2017

Expiration Date:19.07.2022

The owner of the registration certificate:BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Manufacturer: & nbsp

BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Information update date: & nbsp03.10.2017

Illustrated instructions

Instructions

Metformin (Metformin)