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

Active substance: Metformin hydrochloride (in terms of 100% of the substance) Auxiliary substances of the core:	- 500 mg	-1000 mg
povidone (K 30)	- 36 mg	- 48.6 mg
crospovidone (collidine CT-M)	- 12 mg	-
silicon dioxide colloid (aerosil)	- 6 mg	- 10.7 mg
calcium stearate	- 6 mg	- 10.7 mg
microcrystalline cellulose Shell accessories:	- 40 mg	~
hypromellose	- 18 mg	- 32.1 mg
titanium dioxide	- 2.88 mg	- 5.14 mg
polysorbate-80 (twin 80)	- 3.6 mg	- 6.42 mg
magnesium hydrosilicate (talc)	- 1.44 mg	- 2.57 mg
lactose monohydrate (milk sugar)	- 4.022 mg	- 3.684 mg
dye azorubin (acidic red 2 C)	- 0.048 mg	- 0.086 mg

Description:Oblong biconvex form of the tablet, covered with a film membrane. pink color (dosage 500 mg).Oblong biconvex tablet form. covered with a film shell, pink color with a risk (dosage 1000 mg). On the cross-section, two layers are visible: the outer layer is pink, the inner one is white or almost white.

Pharmacotherapeutic group:The hypoglycemic agent of the biguanide group for oral administration

ATX: & nbsp

A.10.B.A.02 Metformin

Pharmacodynamics:

Metformin reduces hyperglycemia, without leading to the development of hypoglycemia. Unlike derivatives, sulfonylurea does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals. Increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. Reduces the production of glucose by the liver by inhibiting gluconeogenesis and glycogenolysis. Delays the absorption of glucose in the intestine.

Metformin stimulates the synthesis of glycogen, affecting glycogen synthase. Increases the transport capacity of all types of membrane glucose transporters.

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

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

Pharmacokinetics:

Absorption and distribution

After oral administration metformin absorbed from the gastrointestinal tract quite fully. Absolute bioavailability is 50 - 60%. The maximum concentration (approximately 2 μg / ml or 15 μmol) in plasma is achieved after 2.5 hours. With simultaneous intake of food, absorption of metformin is reduced and delayed.

Metformin is rapidly distributed into tissues, practically does not bind to 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 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 with 10 beds as a monotherapy or in combination with insulin.

Contraindications:

- Hypersensitivity to metformin or to any auxiliary substance;

- 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 or 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");

- liver failure, a violation of liver function;

- chronic alcoholism, acute alcohol poisoning;

- Pregnancy;

- children's age till 10 years;

- lactic acidosis (including in the anamnesis);

- use for less than 48 hours before and within 48 hours of radioisotope or radiographic studies withintroduction of iodine-containing contrast medium (see section "Interaction with other medicinal products");

- compliance with the hypocaloric diet (less than 1000 kcal / day).

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, 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.Undesirable reactions in newborns during breastfeeding with 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 made in consideration of the benefits of breastfeeding and the potential risk of adverse reactions in the child.

Dosing and Administration:

Apply inside.

Adults

Monotherapy and combination therapy in combination with other oral hypoglycemic agents:

- The usual initial dose is 500 mg or 850 mg 2 to 3 times a day after or during meals.

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

A slow increase in dosage can help improve gastrointestinal tolerance.

- 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 to 3 doses. The maximum dose is 3000 mg / day, divided into 3 doses.

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

In the case of planning a transition from taking another hypoglycemic agent: it is necessary to stop taking another medication and begin taking metformin at 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 is 500 mg or 850 mg 2 to 3 times a day, while the insulin dose is selected based on the concentration of glucose in the blood.

Children and teens

In children from 10 years of age metformin 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. After 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.

Patients with renal insufficiency

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

Patients with SC 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 SC is below 45 ml / min, the drug should be discontinued immediately.

Elderly patients

Because of the possible decrease in renal function, the dose of metformin should be selected under regular monitoring of renal function (to determine the concentration of serum creatinine at least 2-4 times per year).

Duration of treatment

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 frequent: ≥ 1/10,

- Frequent: ≥1 / 100, <1/10,

- Infrequent: ≥1 / 1000, <1/100,

- rare: ≥1 / 10,000, <1/1000,

- very rare: <1/10 000

Side effect is presented in order of decreasing importance.

Disorders from the metabolism and nutrition:

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

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

Impaired nervous system:

Often: a violation of taste.

Disorders from the gastrointestinal tract:

Very often: nausea, vomiting, diarrhea, abdominal pain and lack of appetite.

Most often they occur during the initial period of treatment and in most cases spontaneously pass. To prevent symptoms, it is recommended to take metformin 2 or 3 times a day during or after a meal. Slow increase in dose may improve gastrointestinal tolerance.

Disturbances from the skin and subcutaneous tissues:

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

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.

Published data, postmarketing 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:

When metformin was used at a dose of 85 g (42.5 times the maximum daily dose), no development of hypoglycemia was observed. However, lactoacidosis was observed in this case. Significant overdose 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 should be hospitalized immediately and, after determining the concentration of lactate, clarify the diagnosis. The most effective measure but removal 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 nights 48 hours before or during the X-ray examination using iodine-containing radiopaque means and not to resume earlier 48hours after, provided that during the examination the renal function was found to be normal.

Unrecommended combinations

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

- malnutrition, compliance with a low-calorie diet;

- hepatic insufficiency.

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

Combinations that require caution

Danazol: It is not recommended simultaneous reception of danazolum in order to avoid hyperglycemic action of the latter. If it is necessary to treat danazol and after stopping the latter, a dose adjustment of metformin is required under the control of the glucose concentration 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. In the treatment of neuroleptics and after discontinuation of the latter, correction of the dose of metformin is required under the control of the concentration of glucose in the blood.

Glucocorticosteroids systemic and local effects reduce glucose tolerance, increase the concentration of glucose in the blood, sometimes causing ketosis.In the treatment of glucocorticosteroids and after discontinuation of the latter, correction of the dose of metformin is required 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 creatinine clearance is less than 60 ml / min.

Assigned in the form of injections beta₂ -adrenomimetics: increase the concentration of glucose in the blood due to stimulation of beta₂adrenoreceptors. 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 sulfonylureas, insulin, acarbose, salicylates possibly the development of hypoglycemia.

Nifedipine increases absorption and maximum concentration of 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 maximum concentration.

Special instructions:

Lactic acidosis

Lactic acidosis is a rare, but serious (high mortality in the absence of emergency treatment) complication, which may occur due to the cumulation of metformin. The cases of lactic acidosis with metformin were developed mainly in diabetic patients 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), lactate 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 daytime function was found to be normal.

Kidney function

Because the metformin it is necessary to determine the clearance of creatinine before the beginning of treatment and regularly in the future, at least once a year in patients with normal renal function and 2 to 4 times a year in elderly patients, as well as in patients with creatinine clearance at the lower limit of the norm .

Caution should be exercised when possible impairment of renal 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 acute heart failure and chronic heart failure with unstable 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 careful control is necessary for children aged 10-12 bed.

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

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

Monotherapy with metformin does not cause hypoglycemia, therefore does not affect the ability to drive vehicles and mechanisms.

Nevertheless, patients should be cautioned about the risk of hypoglycemia when using metformin in combination with other hypoglycemic drugs (sulfonylureas, insulin, repaglinide and others).

Form release / dosage:Film coated tablets, 500 mg and 1000 mg.

Packaging:

For 10, 30, 60 tablets in polymer cans made of polyethylene or polypropylene.

For 5, 10, 20 tablets in a contoured cell pack of a polyvinylchloride film and aluminum foil printed lacquered.

1 container or 2, 6, 12, 20, 24 contour cell packs of 5 tablets, or 1, 3, 6, 10. 12 contour cell packs of 10 tablets, or 3, 5, 6 outline packs of 20 tablets together with instructions for use are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003848

Date of registration:20.09.2016 / 10.10.2017

Expiration Date:20.09.2021

The owner of the registration certificate:BIOSINTEZ, PAO BIOSINTEZ, PAO Russia

Manufacturer: & nbsp

BIOSINTEZ, PAO Russia

Information update date: & nbsp11.05.2018

Illustrated instructions

Instructions

Metformin (Metforminum)