Metaminum

General characteristics. Structure:

Active ingredient: metformin hydrochloride; 1 tablet contains Metforminum of a hydrochloride 500 mg, 850 mg, 1000 mg.

Auxiliary вещества:повидон, magnesium stearate, silicon dioxide colloid anhydrous,
gidroksipropilmetiltsellyuloza.

Pharmacological properties:

Pharmacodynamics. Metforminum reduces a hyperglycemia, does not lead to development of a hypoglycemia. Unlike sulphonylurea does not stimulate secretion of insulin and does not cause hypoglycemic effect in healthy volunteers. Reduces both the initial level of glucose in a blood plasma, and glucose level after meal.
Metforminum works in 3 ways:
– causes decrease in production of glucose in a liver at the expense of inhibition of a gluconeogenesis and a glycogenolysis;
– improves capture and utilization of peripheral glucose in muscles due to increase in sensitivity to insulin;
– slows down absorption of glucose in intestines.
Metforminum stimulates intracellular synthesis of a glycogen, influencing glikogensintetaza.
Increases the transport capacity of all types of membrane carriers of glucose (GLUT).
Irrespective of the action on a glycemia Metforminum causes positive effect on metabolism of lipids: reduces the content of the general cholesterol, lipoproteins of low density and triglycerides.

Pharmacokinetics. Absorption. After oral administration Metforminum is almost completely absorbed from digestive tract, 20-30% are removed with excrements. Time of achievement of the maximum concentration (Tmax) makes 2,5 hours. Absolute bioavailability makes about 50-60%.
At a concomitant use of food absorption of Metforminum decreases and slowed down.

Distribution. Linkng with proteins of a blood plasma insignificant. Metforminum gets into erythrocytes. The maximum concentration in blood is lower, than the maximum concentration in a blood plasma, and is reached approximately for the same time. Erythrocytes most likely represent the second camera of distribution. The average volume of distribution (Vd) fluctuates in the range of 63-276 l.

Metabolism. Metformin is removed in not changed view with urine. Metabolites at the person are not revealed.

Removal. The renal clearance of Metforminum does not exceed 400 ml/min. It means that metformin is removed due to glomerular filtering and canalicular secretion. After oral administration of a dose the elimination half-life makes about 6,5 hours. At a renal failure the renal clearance decreases in proportion to clearance of creatinine and therefore the elimination half-life increases that leads to increase in level of Metforminum in a blood plasma.

Indications to use:

Diabetes mellitus 2 types (insulinonezavisimy) at inefficiency of a dietotherapy, especially at the patients having obesity;
– as monotherapy or a combination therapy together with other peroral hypoglycemic means or together with insulin for treatment of adults;
– as monotherapy or a combination therapy with insulin for treatment of children is more senior than 10 years.

Route of administration and doses:

Monotherapy or combination therapy together with other peroral hypoglycemic means.
Adults. Usually initial dose makes 500 mg or 850 mg (Metamin®, tablets, coated, on 500 mg or 850 mg) 2-3 times a day in time or after meal.
In 10-15 days of the carried-out treatment the dose needs to be modified according to results of measurements of level of glucose in blood serum.
Slow increase in a dose promotes decrease in side effects from a digestive tract.
The maximum recommended dose makes 3000 mg a day, distributed on 3 receptions.
At treatment by high doses apply Metamin®, tablets, coated, on 1000 mg. 
In case of transition to treatment by the drug Metamin® it is necessary to stop reception of antidiabetic means.

Combination therapy together with insulin.
In blood metformin and insulin can be applied to achievement of the best control of level of glucose in the form of a combination therapy. Usually initial dose makes 500 mg or 850 mg of the drug Метамин® 2-3 of time a day while the dose of insulin is selected according to results of measurement of level of glucose in blood.
Monotherapy or combination therapy together with insulin.
Children. The drug Metamin® is used to children 10 years are more senior. Usually initial dose makes 500 mg or 850 mg of the drug Метамин® 1 of times a day in time or after meal. In 10-15 days of the carried-out treatment the dose needs to be modified according to results of measurements of level of glucose in blood serum.
Slow increase in a dose promotes decrease in side effects from a digestive tract.
The maximum recommended dose makes 2000 mg a day, distributed on 2-3 receptions.
At patients of advanced age deterioration in function of kidneys therefore the dose of Metforminum needs to be selected on the basis of assessment of function of kidneys which needs to be seen off regularly is possible (see the section "Features of Use").

Features of use:

Lactic acidosis is a rare, but heavy metabolic complication which can arise as result of accumulation of Metforminum of a hydrochloride. Cases of developing of lactic acidosis at patients with a diabetes mellitus and a liver failure of heavy degree are registered. Risk factors of developing of lactic acidosis: badly adjustable diabetes mellitus, a ketosis, long starvation, an alcohol abuse, a liver failure or any state connected with a hypoxia. 
Lactic acidosis is characterized by muscular spasms, an atsidozny asthma, abdominal pain and hypothermia, development of a coma is possible further. At suspicion of lactic acidosis it is necessary to stop use of drug and to immediately hospitalize the patient.
The diagnosis is confirmed by such laboratory indicators as reduction рН blood, increase in level of a lactate in plasma is higher than 5 mmol/l, increase in a lack of anions and a ratio lactate/pyruvate. At suspicion of lactic acidosis use of Metforminum of a hydrochloride is stopped, and the patient is immediately hospitalized.

Renal failure. As metformin is removed by kidneys, before the beginning and during treatment by drug it is necessary to control creatinine level in blood serum, especially at patients with an impaired renal function and at patients of advanced age. It is necessary to show care when function of kidneys, for example in an initiation of treatment by antihypertensives, diuretics and at the beginning of therapy by non-steroidal anti-inflammatory drugs can be broken.

Iodinated X-ray contrast means. When carrying out radiological researches using X-ray contrast means it is necessary to stop use of drug in 48 hours prior to carrying out a research and not to renew earlier, than in 48 hours after X-ray inspection and assessment of function of kidneys.

Surgical interventions. It is necessary to stop use of drug in 48 hours prior to the planned surgical intervention which is carried out under the general, spinal or peridural anesthesia and not to renew earlier, than in 48 hours after carrying out operation and assessment of function of kidneys.

Children. By results of clinical trials effect of metformin on growth and puberty at children is not revealed. However there are no data on effect of metformin on growth and puberty at prolonged use of Metaminum therefore children should use with special care drug during puberty, especially to children aged from 10 up to 12 years.
Patients need to keep to a diet and to control laboratory indicators. At combined use of drug with insulin or derivatives of sulphonylurea strengthening of hypoglycemic action is possible.

Ability to influence speed of response at control of motor transport or work with other mechanisms.
Monotherapy by Metforminum does not lead to a hypoglycemia and does not influence ability to manage vehicles and to work with the mechanisms requiring concentration and special attention. But the patient needs to report that at Metforminum combination with other antidiabetic means (sulphonylurea drugs, insulin, репаглинид) there is a risk of development of a hypoglycemia.

Use during pregnancy or feeding by a breast.
When planning pregnancy, and also in case of approach of pregnancy at drug use its reception it is necessary to cancel and appoint an insulin therapy. At therapy by Metforminum the patient has to report to the doctor about pregnancy approach. Mother and the newborn are subject to observation as data on penetration of Metforminum into breast milk are absent. This drug is contraindicated for use during feeding by a breast.
In need of use of drug during feeding by a breast it should be stopped.

Children. Drug is used for treatment of children 10 years are more senior.

Side effects:

Side reactions are listed on frequency: very often (> 1/10), it is frequent (> 1/100, <1/10), sometimes (> 1/1000, <1/100), is rare (> 1/10 000, <1/1000), is very rare (<1/10 000), including separate messages.
- From a digestive tract: very often (especially in an initiation of treatment) – nausea, vomiting, "metal" smack in a mouth, lack of appetite, a meteorism, diarrhea, an abdominal pain. Slow increase in a dose promotes decrease in side effects from a digestive tract.
- Symptoms, as a rule, pass independently. Purpose of antacids, derivatives of atropine or spasmolysants weaken the specified symptoms. For prevention of development of these side reactions, it is recommended to appoint drug in time or at the end of meal 2-3 times a day.
- Metabolic disturbances: very seldom (at prolonged treatment) – lactic acidosis (treatment cancellation is required).
- Decrease in absorption of B12 vitamin is followed by decrease in its level in blood serum.
- From a nervous system: often – taste disturbance.
- From gepatobiliarny system: separate messages - decrease in indicators of function of a liver, medicamentous hepatitis which are leveled at Metforminum cancellation.
- From skin and hypodermic cellulose: very seldom - skin rashes, an itch, urticaria.
- At some states administration of drug increases probability of development of lactic acidosis. The probability of development of lactic acidosis can increase in an overdose case.

Interaction with other medicines:

The concomitant use of a danazol in order to avoid hyper glycemic action of the last is not recommended. In need of treatment danazoly and after the termination of reception of the last dose adjustment of the drug Metamin® under control of level of a glycemia is required.
Alcohol intake increases risk of development of lactic acidosis during an acute drunkenness, especially in cases of starvation or observance of a low-calorie diet, and also at a liver failure. During administration of drug it is necessary to avoid the alcohol intake and medicines containing alcohol.

Iodinated radiopaque substances. Radiological researches using X-ray contrast means can cause development of lactic acidosis in patients with a diabetes mellitus against the background of a functional renal failure. Use of the drug Metamin® should be stopped in 48 hours prior to and not to renew before 2 days after X-ray inspection with use of radiopaque substances.

The combinations demanding extra care.
- Chlorpromazinum. At reception in high doses (100 mg a day) raises a glycemia, reducing insulin release. At treatment by neuroleptics and after the termination of reception of the last dose adjustment of the drug Metamin® and control of level of a glycemia is required.
- Glucocorticosteroids (GKS) of systemic and local action reduce tolerance to glucose, raise a glycemia, sometimes causing a ketosis. At treatment of GKS and after the termination of reception of the last dose adjustment of Metaminum under control of level of a glycemia is required.
- Diuretics. The concomitant use of loopback diuretics can lead to development of lactic acidosis because of a possible renal failure. It is not necessary to appoint Metamin® if creatinine level in blood exceeds 135 µmol/l at men і 110 µmol/l at women.
- Appointment in the form of injections β2 sympathomimetics. Raise a glycemia owing to stimulation β2-рецепторов. In this case control of a glycemia is necessary. If necessary purpose of insulin is recommended.
At co-administration of the drug Metamin® with sulphonylurea derivatives, insulin, acarbose, salicylates strengthening of its hypoglycemic action is possible.
- Angiotensin-converting enzyme inhibitors (APF inhibitors). APF inhibitors can lead to decrease in level of glucose in blood therefore they should be applied with extra care. If necessary the dose of antidiabetic means should be modified for use and after cancellation of these drugs.

Contraindications:

Hypersensitivity to active ingredient or to any other component of drug;
– diabetic ketoacidosis, diabetic prekoma, diabetic coma;
– renal failure;
– the acute diseases proceeding with risk of development of renal failures: dehydration (at diarrhea, vomiting), fever, serious infectious diseases, conditions of a hypoxia (shock, sepsis, renal infections, bronchopulmonary diseases);
– considerable clinical displays of acute and chronic diseases which can lead to development of a fabric hypoxia (heart or respiratory failure, an acute myocardial infarction, etc.);
– serious surgeries and injuries (when performing insulin therapy is reasonable);
– abnormal liver function;
– alcoholism, acute alcoholic poisoning;
– lactic acidosis (including in the anamnesis);
– use not less than 2 days to and within 2 days after carrying out radio isotope or X-ray inspections with administration of iodinated contrast medium;
– observance of a hypocaloric diet (less than 1000 кал / days).
It is not recommended to use drug to persons 60 years, performing hard physical activity that is connected with the increased risk of development in them of lactic acidosis are more senior.

Overdose:

At use of drug in a dose of 85 g of development of a hypoglycemia it was not observed. But in this case development of lactic acidosis was observed. Early symptoms of lactic acidosis are nausea, vomiting, diarrhea, fervescence, an abdominal pain, muscle pain, breath holding, dizziness, disturbance of consciousness and development of a coma can be noted further.
Treatment: in case of symptoms of lactic acidosis treatment by drug needs to be stopped, urgently to hospitalize the patient and, having defined concentration of a lactate, to specify the diagnosis. The most effective measure of removal from an organism of a lactate and drug is the hemodialysis. Therapy is symptomatic.

Storage conditions:

To store at a temperature not above 25 °C in dry, protected from light and the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets on 500 mg, on 850 mg: on 10 tablets in the blister. On 3 or 10 blisters in cardboard packaging.
Tablets on 1000 mg: on 15 tablets in the blister. On 2 or 6 blisters in cardboard packaging.