SR Metaminum

General characteristics. Structure:

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

Auxiliary veshchestva:tsellyuloza microcrystallic, ethyl cellulose, gipromelloza, magnesium stearate, silicon dioxide colloid anhydrous.

Pharmacological properties:

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

Pharmacokinetics. Absorption. After intake of drug in the form of a tablet with the prolonged release absorption of Metforminum is considerably slowed down in comparison with use of a tablet with bystry release. Time of achievement of the maximum concentration (Tmax) makes 7 hours whereas for a tablet with bystry release – 2,5 hours.
At an equilibrium state the maximum concentration in a blood plasma (Cmax) and the area under a curve "concentration time" (AUC) increase to the dose which is disproportionately entered inside. AUC after one-time intake of 2000 mg of Metforminum in the form of tablets with the prolonged release is similar to AUC which is observed after reception of 1000 mg of Metforminum in the form of Metforminum tablets with bystry release 2 times a day.
Fluctuation of Cmax and AUC at some persons at reception of Metforminum in the form of tablets with the prolonged release is comparable with those at reception of Metforminum in the form of tablets with bystry release.
Though AUC decreases by 30% at reception of a tablet of the prolonged action on an empty stomach, Cmax and Tmax are left without changes.
Meal does not influence absorption of Metforminum from tablets with the prolonged release. Accumulation at reusable reception in a dose over 2000 mg of Metforminum in the form of tablets with the prolonged release is not observed.
Distribution. Linkng with proteins of plasma insignificant. Metforminum gets into erythrocytes. Cmax in blood is lower, than Cmax in plasma, and is reached approximately for an identical period. To erythrocytes the second volume of distribution is most characteristic. 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 in a human body are not revealed.

Removal. The renal clearance of Metforminum makes> 400 ml/min. It indicates that means is removed by glomerular filtering and canalicular secretion. After reception of a dose inside the valid elimination half-life makes about 6,5 hours. At an impaired renal function the renal clearance decreases in proportion to clearance to creatinine owing to what the elimination half-life increases that leads to increase in level of Metforminum in plasma.

Indications to use:

Diabetes mellitus of the II type (insulinonezavisimy) at adults at inefficiency of a dietotherapy (especially at patients who suffer from obesity) as monotherapy or in a combination with other peroral antidiabetic means or together with insulin.

Route of administration and doses:

The dose of drug is established by the doctor individually depending on glucose level in blood.
Drug is used as monotherapy or in a combination with other peroral antidiabetic means, or together with insulin.
Monotherapy and combination therapy together with other peroral antidiabetic means.
Usual initial dose – 1 tablet of 1 times a day during 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 – 4 tablets a day.
It is necessary to increase a dose by 500 mg every week, as much as possible to 2000 mg. For patients who were already treated by Metforminum the initial dose of the drug Metamin® SR with the prolonged release has to be equivalent to a daily dose of tablets with bystry release.
If the necessary level of a glycemia cannot be reached at the maximum dose which is accepted 1 time a day, this dose can be divided into 2 receptions a day: 1 reception – in the morning and 1 reception – in the evening, during meal.
Upon transition to the drug Metamin® SR with the prolonged release it is necessary to stop reception of other antidiabetic means and to begin administration of drug of Metamin® of SR in the dose stated above.

Combination 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. The usual initial dose of the drug Metamin® SR with the prolonged release makes 1 tablet of 1 times a day while the dose of insulin is selected according to results of measurement of level of glucose in blood.
At patients of advanced age deterioration in function of kidneys therefore the dose of Metforminum needs to be selected according to assessment of function of kidneys which needs to be seen off regularly is possible (see the section "Features of Use").

Features of use:

The lactacidemia is the rare and heavy metabolic complication caused by Metforminum accumulation. Cases of emergence of a lactacidemia take place, generally, at patients with a diabetes mellitus, patients with a heavy renal failure who accepted Metforminum. Extent of manifestation of a lactacidemia it is possible and it is necessary to reduce, considering such risk factors as the uncontrollable diabetes, a ketonemiya, starvation, excessive alcohol intake, a liver failure and states connected with a hypoxia.
The lactacidemia is characterized by an atsidotichesky asthma with further decrease in body temperature and a coma. Over 5 mmol/l, increase in a ratio lactate/pyruvate belong to diagnostic indicators low value рН blood, lactate level in a blood plasma. At the first symptoms of lactic acidosis it is necessary to stop immediately reception of Metforminum and to see a doctor.
As metformin is removed by kidneys, it is necessary to determine blood serum creatinine level prior to treatment and to control it with regular intervals:
- it is not less than 1 time in a year to patients with normal function of kidneys;
- not less than 2-4 times a year to patients with the level of creatinine of blood serum are higher than norm, and also to patients of advanced age.
The most frequent depression of function of kidneys is observed at patients of advanced age.
Extra care is recommended at a possible renal failure (for example, at the beginning of therapy by anti-hypertensive means or diuretics, during therapy by non-steroidal anti-inflammatory drugs).
In 48 hours prior to and for 48 hours after carrying out radio isotope or X-ray inspections with administration of iodinated contrast medium it is necessary to stop Metforminum reception.
Use of Metforminum needs to be stopped in 48 hours prior to carrying out surgical intervention with the general anesthesia. It is possible to continue therapy not earlier than in 48 hours after operation.
It is incompatible with alcohol.
During treatment by Metforminum patients have to keep to a diet. Patients with excess body weight need to keep to a low-calorie diet.
To patients, a sick diabetes mellitus, it is regularly necessary to control sugar level in blood.
Metforminum does not lead to a hypoglycemia though in a combination with insulin or derivatives of sulphonylurea care is recommended.
The film covering of tablets contains lactose therefore drug should not be used to patients with rare hereditary forms of intolerance of a galactose, insufficiency of lactase or a syndrome of glyukozo-galaktozny malabsorption.

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 mechanisms which require concentration and special attention. But the patient needs to be notified 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.
Drug is not used during pregnancy and during feeding by a breast.
During treatment by Metforminum feeding by a breast should be stopped.

Children. It is not necessary to apply Metamin® of SR to children as are absent given concerning its use of this age category of patients.

Side effects:

Frequency of side reactions: very widespread (≥ 1/10), extended (≥ 1/100, <1/10), not widespread (≥ 1/1000, <1/100), seldom widespread (≥ 1/10 000, <1/1000), very seldom widespread (<1/10 000), including special cases.
- From a digestive tract: very widespread – nausea, vomiting, lack of appetite, a meteorism, diarrhea, an abdominal pain; widespread – metal smack in a mouth. These symptoms arise especially often in an initiation of treatment and, as a rule, disappear independently. These symptoms decrease at purpose of antacids, derivatives of atropine or spasmolysants. In order to avoid development of these side effects, it is recommended to appoint drug in time or at the end of meal 2–3 times a day. If dispepsichesky symptoms constant, treatment by Metforminum it is necessary to stop.
- From a metabolism: seldom widespread – at long treatment – B12 hypovitaminosis (absorption disturbance) that should be considered to patients with megaloblastny anemia; very seldom widespread – a lactacidemia (demands drug withdrawal).
- Gepatobiliarny disturbances: in some cases – an abnormal liver function or hepatitis which pass after Metforminum cancellation.
- From system of a krovoobrazovaniye: in some cases – megaloblastny anemia.
- From skin: very seldom widespread – an erythema, an itch, urticaria, rashes.
- Others: taste disturbance.

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 Metforminum under control of level of a glycemia is necessary.
Alcohol intake increases risk of development of a lactacidemia 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 alcohol intake and reception of medicines which contain alcohol.

Combinations which demand 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 Metforminum under control of level of a glycemia is necessary;
antagonists beta 2 - adrenoceptors, the APF inhibitors, MAO inhibitors, non-steroidal anti-inflammatory drugs derivative of Clofibratum, Oxytetracyclinum, cyclophosphamide and its derivatives can strengthen hypoglycemic effect of metformin; 
the drugs combined estrogen-gestagennye, adrenaline and other sympathomimetics, glucagon, hormones of a thyroid gland, fenotiazina, thiazide diuretics, derivatives of niacin reduce hypoglycemic effect of metformin;
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 Metforminum under control of level of a glycemia is necessary;
Cimetidinum slows down removal of Metforminum and increases risk of development of a lactacidemia;
diuretics: the concomitant use of loopback diuretics can lead to development of a lactacidemia because of a possible renal failure. It is not necessary to appoint Metforminum if creatinine level in blood exceeds 135 µmol/l at husband's and 110 µmol/l at women;
- iodinated radiopaque substances: radiological researches using radiopaque substances can cause development of lactic acidosis in patients with a diabetes mellitus against the background of a functional renal failure (see the section "Features of Use").
- Appointment in the form of injections beta 2 - sympathomimetics: raise a glycemia owing to stimulation beta 2 - receptors. In this case control of a glycemia is necessary. If necessary purpose of insulin is recommended.
At co-administration of Metforminum with sulphonylurea derivatives, insulin, acarbose, salicylates strengthening of its hypoglycemic action is possible.

Contraindications:

Hypersensitivity to active ingredient or to any other component of drug. Diabetic ketoacidosis, diabetic prekoma, coma, renal failure (clearance of creatinine <60 ml/min.), acute diseases which proceed 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.), heavy surgeries and injuries (when performing insulin therapy), an abnormal liver function, an alcoholism, an acute alcoholic poisoning, a lactacidemia (including in the anamnesis is reasonable), use is not less than 2 days to and for 2 days after carrying out radio isotope or X-ray inspections with administration of iodinated contrast medium, observance of a hypocaloric diet (it is less than 1000 кал / days).
It is not recommended to use drug to persons 60 years which perform hard physical activity that is connected with the increased risk of development of a lactacidemia are more senior.

Overdose:

At use of Metforminum in a dose of 85 g development of a hypoglycemia was not observed even if in these conditions the lactacidemia developed. Early symptoms of a lactacidemia is nausea, vomiting, diarrhea, fervescence, an abdominal pain, muscle pain, breath increase, dizziness, disturbance of consciousness and development of a coma can be noted further.
Treatment. At the first signs of a lactacidemia treatment by Metforminum needs to be stopped, urgently to hospitalize the patient and, having defined concentration of a lactate, to specify the diagnosis. The most effective method of removal from an organism of a lactate and Metforminum is the hemodialysis. Therapy is symptomatic.

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

On 7 tablets in the blister; on 4 blisters in cardboard packaging.
On 15 tablets in the blister, on 2 or 6 blisters in a cardboard box.