Pharmacological properties

Pharmacodynamics. metformin — biguanide with anti-hyper glycemic effect. reduces glucose level in blood plasma as on an empty stomach, and after meal. does not stimulate secretion of insulin and does not cause the hypoglycemic effect mediated by this mechanism. metformin works in three ways:

leads

• to decrease in production of glucose in a liver at the expense of inhibition of a gluconeogenesis and a glycogenolysis;
• is improved by sensitivity to insulin in muscles that leads to improvement of peripheral capture and utilization of glucose;
• absorption of glucose in intestines detains.

Metformin stimulates with

intracellular synthesis of a glycogen, influencing a glikogensintetaza. Increases transport ability of all known types of membrane carriers of glucose (GLUT).

Irrespective of the action on glucose level in blood metformin shows positive effect on metabolism of lipids. This effect was proved at use of therapeutic doses in controlled average or long-term clinical trials: metformin reduces keeping of the general by XC, LDL and TG.

during clinical trials at metformin use the body weight of patients remained stable or moderately decreased.

Pharmacokinetics. Absorption. After intake of metformin time of achievement of the C _max is about 2.5 h. The bioavailability of tablets 500 or 800 of mg is about 50-60% at healthy volunteers. After intake not soaked up fraction is removed with a stake, it makes 20–30%.

After intake the absorption of metformin is saturable and incomplete. It is supposed that metformin absorption pharmacokinetics nonlinear. At use of metformin in the recommended doses and the modes of reception the stable concentration in blood plasma is reached during 24–48 h and makes 1 mkg/ml. In controlled clinical trials of the C _max metformin in blood plasma did not exceed 5 mkg/ml even at use in the maximum doses.

At a concomitant use of food the absorption of metformin decreases and slightly slows down. After intake in a dose of 850 mg noted decrease in the C _max in blood plasma for 40%, reduction of AUC — for 25% and increase on 35 min. time of achievement of the C _max in blood plasma. The clinical importance of these changes is unknown.

Distribution. Linking with proteins of blood plasma insignificant. Metformin gets into erythrocytes. The C _max in blood below, than that in blood plasma, is also reached through 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 metformin is 400 ml/min. It indicates that metformin is removed due to glomerular filtration and canalicular secretion. After oral administration of T _½ about 6.5 h make. In a renal failure the renal clearance decreases in proportion to clearance of creatinine and therefore the T _½ increases that leads to increase in level of metformin in blood plasma.

Indication

type ii Diabetes at inefficiency of a dietotherapy and mode of physical activities, especially at patients with excess body weight;

• as monotherapy or combination therapy in combination with other oral gipoglikemiziruyushchy means or it is combined with insulin for treatment of adults;
• as monotherapy or combination therapy with insulin for treatment of children 10 years and teenagers are aged more senior;
• reduction of expressiveness of complications of diabetes at adult patients with diabetes of the II type and excess body weight as medicament of the first line at inefficiency of a dietotherapy.

Use

Adult

Monoterapiya's

or combination therapy in combination with other oral gipoglikemiziruyushchy means. Usually initial dose makes 500 or 850 mg (Glyukofazh, tablets, film 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 a dose needs to be adjusted according to results of measurements of level of glucose in blood plasma.

Slow increase in a dose promotes reduction of severity of side effects from a GIT.

At use in high doses (2000–3000 mg/days) the substitution of each two tablets Glyukofazh, 500 mg on 1 tablet Glyukofazh, 1000 mg is possible

.

Maximum recommended dose makes 3000 mg/days, distributed on 3 receptions.

in case of transition from other antidiabetic means, it is necessary to stop reception of other antidiabetic means and to appoint metformin as it is stated above.

Combination therapy in 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 combination therapy. Usually initial dose makes 500 or 850 mg of the medicament Glyukofazh 2–3 times a day while the dose of insulin is selected according to results of measurement of level of glucose in blood.

Children

Monoterapiya's

or combination therapy in combination with insulin. The medicament Glyukofazh is used at children aged 10 years and teenagers are more senior. Usually initial dose makes 500 or 850 mg of the medicament Glyukofazh of 1 times a day in time or after meal. In 10–15 days of the carried-out treatment the dose needs to be adjusted according to results of determination of level of glucose in blood plasma.

Slow increase in a dose promotes reduction of severity of side effects from a GIT.

Maximum recommended dose makes 2000 mg/days, distributed on 2–3 receptions.

At patients of advanced age the deterioration in function of kidneys is possible

therefore the dose of metformin needs to be selected on the basis of assessment of function of kidneys which should be seen off regularly (see. Special INSTRUCTIONS).

Patients with a renal failure. Metformin can be applied at patients with a moderate renal failure, IIIa stage (clearance of creatinine of 45-59 ml/min. or the glomerular filtration rate of 45-59 ml/min. / 1.73 m ² ) only in the absence of other conditions which can increase risk of developing lactoacidosis, with the subsequent dose adjustment: the initial dose makes 500 or 850 mg of metformin of a hydrochloride of 1 times a day. The maximum dose makes 1000 mg/days and has to be divided into 2 receptions. It is necessary to carry out careful monitoring of function of kidneys (each 3–6 months).

If the clearance of creatinine or glomerular filtration rate decreases to 45 ml/min. or 45 ml/min. / 1.73 m ² respectively, it is necessary to stop metformin use immediately.

Contraindication

Hypersensitivity to metformin or other components of drug;

• diabetic ketoacidosis, diabetic prekoma;
• a renal failure moderated (IIIb stage) and heavy degree or a renal failure (clearance of creatinine of 45 ml/min. or the glomerular filtration rate of 45 ml/min. / 1.73 m ² );
• acute conditions which course is connected with risk of developing renal failures, such as organism dehydration, serious infectious diseases, shock;
• a disease which can lead to development of a hypoxia of fabrics (especially acute diseases or exacerbations of a chronic disease): dekompensirovanny heart failure, respiratory insufficiency, recently postponed myocardial infarction, shock;
• liver failure, acute alcoholic poisoning, alcoholism.

Side effects

Most frequent undesirable reactions in an initiation of treatment are nausea, vomiting, diarrhea, an abdominal pain, lack of appetite. these symptoms in most cases pass independently. for prevention of emergence of the specified by-effects the slow increase in a dose and use of a daily dose of medicament in 2–3 receptions is recommended.

Undesirable effects on the frequency of emergence classify

by such categories: very often (≥1/10), it is frequent (≥1/100, 1/10), infrequently (≥1/1000, 1/100), is rare (≥1/10,000 and 1/1000), is very rare (1/10,000). In each class of a system of bodies the side reactions are specified as decrease in their clinical value.

Metabolism: very seldom — lactoacidosis (see. Special INSTRUCTIONS).

At prolonged use of medicament the absorption of _{12 vitamin B} which is followed by decrease in its level in blood plasma can decrease. It is recommended to consider such possible cause of hypovitaminosis In ₁₂ if at the patient the megaloblastny anemia is revealed.

from nervous system: often — disturbance of taste.

from digestive system: very often — disturbances from digestive system, such as nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often these by-effects arise in an initiation of treatment and, as a rule, spontaneously disappear. For prevention of emergence of by-effects from digestive system the slow increase in a dose and use of medicament 2–3 times a day in time or after meal is recommended.

from a liver and biliary tract: very seldom — disturbance of indicators of function of a liver or hepatitis which completely disappear after metformin cancellation.

from skin and hypodermic cellulose: very seldom — skin allergic reactions, including an erythema, an itching, a small tortoiseshell.

Special instructions

Laktoatsidoz — a rare, but heavy metabolic complication (high level of lethality in the absence of urgent treatment) which can arise as result of cumulation of metformin. cases of developing of lactoacidosis at patients with diabetes and a renal failure or sharp deterioration in function of kidneys are registered. it is necessary to be careful when function of kidneys, for example, in case of dehydration (profound diarrhea or vomiting) or in an initiation of treatment by antihypertensives, diuretics and npvp can be broken. in case of the specified aggravations it is necessary to stop metformin use temporarily.

Should consider other risk factors in order to avoid development of lactoacidosis: badly controlled diabetes, a ketosis, long starvation, excessive alcohol intake, a liver failure or any state connected with a hypoxia (dekompensirovanny heart failure, an acute myocardial infarction) (see CONTRAINDICATIONS). Lactoacidosis can be shown in the form of muscular spasms, disturbance of digestion, an abdominal pain and a heavy asthenia. Patients should report immediately to the doctor about emergence of such reactions, especially if earlier patients well transferred metformin use. In such cases it is necessary to stop temporarily use of metformin before clarification of a situation. Therapy by metformin it is necessary to renew after ratio assessment advantage/risk in individual cases and estimates of function of kidneys.

Diagnostics. Lactoacidosis is characterized by an atsidozny asthma, an abdominal pain and a hypothermia, development of a coma is possible further. Diagnostic indicators: laboratory decrease rn blood, increase in concentration in blood plasma of a lactate of 5 mmol/l, increase in an anion interval and ratio lactate/pyruvate. In case of development of lactoacidosis it is necessary to hospitalize immediately the patient (see OVERDOSE). The doctor has to warn patients about risk of development and symptoms of lactoacidosis.

Renal failure. As metformin is emitted with kidneys, before the beginning and regularly during treatment by metformin it is necessary to check clearance of creatinine (it is possible to estimate on creatinine level in blood plasma by means of a formula Kokrofta — Gault) or glomerular filtration rate:

• to patients with normal function of kidneys — not less than 1 time a year;
• to patients with clearance of creatinine on the lower bound of norm and to patients of advanced age — not less than 2-4 times a year.

At clearance of creatinine of 45 ml/min. (glomerular filtration rate of 45 ml/min. / 1.73 m ² ) it is contraindicated to li to apply metformin (see CONTRAINDICATIONS).

Depression of function of kidneys at patients of advanced age is noted often, its course asymptomatic. It is necessary to be careful in a renal failure, for example, in dehydration or in an initiation of treatment antihypertensives, diuretics and NPVP. In such cases it is also recommended to control function of kidneys before an initiation of treatment metformin.

Function of heart. Patients with heart failure have higher risk of developing a hypoxia and renal failure. At patients with stable chronic heart failure metformin can be applied at regular monitoring of warm and renal function. Metformin is contraindicated to patients with acute and unstable heart failure (see CONTRAINDICATIONS).

Yodosoderzhashchy X-ray contrast means. In/in use of X-ray contrast means for radiological researches can lead to a renal failure and, as a result — to cumulation of metformin and increase in risk of developing lactoacidosis. Patients with glomerular filtration rate have 60 ml/min. / 1.73 m ² use of metformin needs to be stopped to or during a research and not to renew earlier than in 48 h after the research, only after repeated assessment of function of kidneys and confirmation of lack of further aggravation of symptoms of kidneys (see INTERACTIONS).

At patients with a moderate renal failure (glomerular filtration rate of 45-60 ml/min. / 1.73 m ² ) use of metformin should be stopped for 48 h before administration of yodosoderzhashchy X-ray contrast substances and not to renew earlier than in 48 h after carrying out a research, only after repeated assessment of function of kidneys and confirmation of lack of further aggravation of symptoms of kidneys (see INTERACTIONS).

Surgical interventions. It is necessary to stop use of metformin for 48 h before planned surgical intervention which is carried out under the general, spinal or peridural anesthesia and not to renew earlier than in 48 h after carrying out operation or restoration of oral food and only if normal function of kidneys is established.

Children. Prior to treatment the diagnosis of diabetes of the II type has to be confirmed with metformin. By results of one-year controlled clinical trials, influence 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 more prolonged use of metformin therefore attentive observation of these parameters at the children accepting metformin, especially during puberty is recommended.

Children at the age of 10–12 years. By results of controlled clinical trials with participation of 15 children at the age of 10–12 years the efficiency and safety of use of metformin for this group of patients did not differ from that at children of advanced age and teenagers. Children should appoint medicament with care at the age of 10–12 years.

Other measures. Patients need to keep to a diet, uniform intake of carbohydrates within a day. Patients with excess body weight should continue to adhere to a low-calorie diet. It is necessary to control indicators of carbohydrate metabolism of patients regularly.

Monoterapiya's

metformin does not cause a hypoglycemia, however it is necessary to be careful at simultaneous use of metformin with insulin or other oral hypoglycemic means (for example derivatives of sulphonylurea or a meglitinidama).

Use during pregnancy and feeding by a breast. Pregnancy. Uncontrollable diabetes during pregnancy (gestational or constant) increases risk of developing congenital anomalies and perinatal lethality. There are limited these uses of metformin for pregnant women which do not indicate the increased risk of congenital anomalies. Preclinical trials did not reveal negative impact on pregnancy, development of an embryo or a fruit, childbirth and postnatal development. In case of pregnancy planning and also at approach of pregnancy for treatment of diabetes it is recommended to apply not metformin, but insulin to maintenance of the level of glucose of blood as close as possible to normal, to reduction of risk of development of defects of a fruit.

Feeding by a breast. Metformin is removed in breast milk, but at the newborns/babies who were on breastfeeding, side effects were not noted. However, as there are not enough data on safety of use of drug, feeding by a breast is not recommended during therapy by metformin. The decision on the termination of breastfeeding needs to be made taking into account advantages of feeding by a breast and potential risk of side effects for the child.

Fertility. Metformin did not affect fertility of animals at use in doses of 600 mg/kg/days which almost by 3 times exceeded the maximum recommended daily dose for the person per body surface area.

Children. The medicament Glyukofazh is used for treatment of children aged 10 years are more senior.

Ability to influence speed of response at control of vehicles or other mechanisms. Monotherapy by metformin does not influence speed of response at control of vehicles or other mechanisms as medicament does not cause a hypoglycemia. However it is necessary to be careful at use of metformin in a combination with other hypoglycemic means (sulphonylurea derivatives, insulin or meglitinida) because of risk of development of a hypoglycemia.

Interaction

Combination which it is not recommended to apply

Alcohol. The acute drunkenness is associated with the increased risk of developing lactoacidosis, especially in cases of starvation or observance of a low-calorie diet and also in a liver failure. At the Glyukofazh medicament treatment it is necessary to avoid alcohol intake and intake of medicines which contain alcohol.

Yodosoderzhashchy X-ray contrast substances. In/in introduction of yodosoderzhashchy X-ray contrast means can lead to a renal failure and, as a result, accumulation of metformin and increase in risk of developing lactoacidosis.

At patients with the glomerular filtration rate of 60 ml/min. / 1.73 m ² use of metformin should be stopped to or during a research and not to renew earlier than in 48 h after the research, only after repeated assessment of function of kidneys and confirmation of lack of further aggravation of symptoms of kidneys (see. Special INSTRUCTIONS).

At patients with a moderate renal failure (glomerular filtration rate of 45-60 ml/min. / 1.73 m ² ) use of metformin should be stopped for 48 h before administration of yodosoderzhashchy X-ray contrast substances and not to renew earlier than in 48 h after carrying out a research, only after repeated assessment of function of kidneys and confirmation of lack of further aggravation of symptoms of kidneys.

Combination which should be applied with care. The medicines having hyperglucomized effect (GKS of systemic and local action, sympathomimetics). It is necessary to control to a thicket glucose level in blood, especially in an initiation of treatment. In time and after the termination of such combined therapy it is necessary to adjust a dose of Glyukofazha.

Diuretics, especially loopback, can increase risk of developing lactoacidosis owing to possible depression of function of kidneys.

Overdose

At use of medicament in a dose of 85 g of development of a hypoglycemia was not noted, but in this case there was lactoacidosis. considerable exceeding a dose of metformin or contributing factors of risk can lead to developing of lactoacidosis. lactoacidosis is medical emergency and he should be treated in a hospital. the most effective action for removal from an organism of a lactate and metformin is the hemodialysis.

Storage conditions

does not demand special storage conditions.

UA/CVM/1116/0116