Амарил® M

General characteristics. Structure:

Tablets of 1 mg +250 mg
Contains in one tablet:
active ingredients: глимепирид micronized - 1 mg, Metforminum a hydrochloride - 250 mg;
excipients: lactoses monohydrate - 25 mg, sodium carboxymethylstarch - 7,5 mg, povidon-K30 - 12,5 mg, cellulose microcrystallic - 25 mg, кросповидон - 5 mg, magnesium stearate - 2,5 mg;
film cover: a gipromelloza - 4,7 mg, a macrogoal-6000 - 0,85 mg, titanium
dioxide (Е 171) - 0,85 mg, wax of karnaubsky 0,1 mg.
Tablets of 2 mg +500 mg
Contains in one tablet:
active ingredients: глимепирид micronized - 2 mg, Metforminum a hydrochloride - 500 mg;
excipients: lactoses monohydrate - 50 mg, sodium carboxymethylstarch - 15 mg, povidon-K30 - 25 mg, cellulose microcrystallic - 50 mg, кросповидон - 10 mg, magnesium stearate - 5 mg;
film cover: a gipromelloza - 9,4 mg, a macrogoal-6000 - 1,7 mg, titanium dioxide
(Е 171) - 1,7 mg, wax of karnaubskiya - 0,2 mg.
Description
Tablets of 1 mg +250 mg
Oval biconvex tablets, film coated white color, with rID125 engraving on one party.

Tablets of 2 mg +500 mg
Oval biconvex tablets, film coated white color, with rID25 engraving on one party and risky on other party.

Pharmacological properties:

Pharmacodynamics. Амарил® the M is the combined hypoglycemic drug which part are глимепирид and Metforminum.
Pharmacodynamics of a glimepirid
Glimepirid, one of active agents of the drug Amaril® M, represents peroral hypoglycemic drug - derivative sulphonylurea of the third generation.
Glimepirid stimulates secretion and release of insulin from pancreas beta cells (pancreatic action), improves sensitivity of peripheral fabrics (muscular and fatty) to effect of endogenous insulin (ekstrapankreatichesky action). Influence on insulin secretion
Derivatives of sulphonylurea increase secretion of insulin by closing of the ATP-dependent potassium channels located in a cytoplasmic membrane of beta cells of a pancreas. Closing potassium channels, they cause depolarization of beta cells that promotes opening of calcium channels and increase in intake of calcium in cells. Glimepirid with the high replacing speed connects and disconnected from protein of beta cells of a pancreas (a pier. weight of 65 cd/SURX), which is associated with ATP-dependent potassium channels, but differs from the place of binding of usual derivatives of sulphonylurea (protein about a pier. weighing 140 cd / SURl). The specified process leads to release of insulin by an exocytosis, at the same time the amount of the cosecreted insulin is much less, than at action of the usual (traditionally applied) sulphonylurea derivatives (for example, Glibenclamidum). The minimum stimulating influence of a glimepirid on secretion of insulin provides also smaller risk of development of a hypoglycemia. Ekstrapankreatichesky activity
As well as traditional derivatives of sulphonylurea, but in much bigger degree глимепирид has the expressed ekstrapankreatichesky effects (insulin resistance reduction, smaller impact on serdechnoksosudisty system, anti-atherogenous, antiagregantny and antioxidant action).
Utilization of glucose from blood peripheral fabrics (muscular and fatty) happens to the help of special transport proteins (GLUT1 and GLUT4) located in cellular membranes. Glucose transport in these fabrics at a diabetes mellitus 2 types is the glucose utilization stage limited on speed. Glimepirid very quickly increases quantity and activity of the molecules transporting glucose (GLUT1 and GLUT4) that leads to increase in digestion of glucose peripheral fabrics.
Glimepirid exerts weaker inhibiting impact on K+ ATP-dependent - channels of cardiomyocytes. At reception of a glimepirid ability of metabolic adaptation of a myocardium to ischemia remains.
Glimepirid increases activity of a phospholipase With with which in isolated muscular and lipoblasts the lipogenesis and a glycogenesis caused by drug can correlate.
Glimepirid inhibits products of glucose in a liver by increase in intracellular concentration fruktozo-2,6-bisfosfata which in turn inhibits a gluconeogenesis.
Glimepirid selectively inhibits cyclooxygenase and reduces transformation of arachidonic acid into A2 thromboxane which promotes aggregation of thrombocytes, thus having antitrombotichesky effect. Glimepirid promotes decrease in maintenance of lipids, considerably reduces peroxide oxidations of lipids, it promotes anti-atherogenous effect of drug.
Glimepirid increases contents endogenous and - tocopherol, activity of a catalase, glutathione peroxidases and superoxide dismutases that promotes decrease in expressiveness of an oxidizing stress in an organism of the patient which constantly is present at a diabetes mellitus 2 types. Metforminum pharmacodynamics
Metforminum is hypoglycemic drug from group of guanyl guanidines. Its hypoglycemic action is possible only on condition of insulin secretion preservation (though lowered). Metforminum does not make impact on beta cells of a pancreas and does not increase insulin secretion. Metforminum in therapeutic doses does not cause a hypoglycemia in the person. The mechanism of effect of metformin so far is up to the end not found out. It is supposed that Metforminum can exponentiate effects of insulin or that it can increase effects of insulin in zones of peripheral receptors. Metforminum increases sensitivity of fabrics to insulin due to increase in number of insulin receptors on superficial cellular membranes. In addition Metforminum brakes a gluconeogenesis in a liver, reduces formation of free fatty acids and oxidation of fats, reduces concentration of triglycerides (TG) and liproteid of the low density (LPNP) and lipoproteids of very low density (LNONP) in blood. Metforminum slightly reduces appetite and reduces absorption of carbohydrates in intestines. It improves fibrinolitic properties of blood due to suppression of inhibitor of a plasminogen activator of fabric type.

Pharmacokinetics. Pharmacokinetics of a glimepirid
At multiple dose of a glimepirid in a daily dose of 4 mg the maximum concentration in blood serum (Sshchakh) is reached approximately in 2,5 hours and makes 309 ng/ml; there is a linear ratio between a dose and Sshchakh, and also between a dose and AUC (the area under a curve "concentration - time"). At intake of a glimepirid its bioavailability is almost full. Meal has no significant effect on absorption, except for insignificant delay of speed of absorption. Very low volume of distribution (about 8,8 l) approximately equal to albumine distribution volume, high extent of linkng with proteins of plasma (more than 99%) and low clearance (about 48 ml/min.) is characteristic of a glimepirid.
After a single dose in a dose of a glimepirid kidneys remove 58% (only in the form of metabolites) through intestines of 35%. The elimination half-life at the plasma concentration of a glimepirid in serum corresponding to multiple dose makes 5-8 hours. After reception of high doses the elimination half-life increases a little.
In urine and excrements two inactive metabolites which are formed as a result of metabolism in a liver come to light, one of them is hydroxyderivative, and another - to carboxyderivatives. After intake of a glimepirid the terminal elimination half-life of these metabolites makes 3-5 hours and 5-6 hours, respectively.
Glimepirid is allocated with breast milk and gets through a placental barrier. Glimepirid badly gets through a blood-brain barrier. Comparison single and repeated (2 times a day) reception of a glimepirid did not reveal reliable distinctions in pharmacokinetic indicators, different patients had insignificant their variability. Significant accumulation of a glimepirid was absent.
At patients of a different floor and various age groups pharmacokinetic parameters are identical. At patients with renal failures (with low clearance of creatinine) the tendency to increase in clearance of a glimepirid and to decrease in its average concentration in blood serum was observed that most likely, is caused by more bystry removal of a glimepirid owing to its lower linkng with proteins of plasma. Thus, this category of patients does not have an additional risk of cumulation of a glimepirid.
Metforminum pharmacokinetics
After intake Metforminum is absorbed from digestive tract rather fully. Absolute bioavailability makes 50-60%. The maximum concentration (Cmax) (about 2 mkg/ml or 15 µmol) in plasma is reached in 2,5 h. At a concomitant use of food absorption of Metforminum decreases and late.
Metforminum is quickly distributed in fabric, practically does not contact proteins of plasma. Is exposed to metabolism in very weak degree and it is removed by kidneys. The clearance at healthy subjects makes 440 ml/min. (4 times more, than at creatinine) that demonstrates existence of active kanaltsiyevy secretion. The elimination half-life makes about 6,5 hours. At a renal failure it increases, the risk of cumulation of drug appears.

Indications to use:

Treatment of a diabetes mellitus 2 types:
- when glycemic control cannot be reached by means of a combination of a diet, exercise stresses, decrease in body weight and monotherapy glimepiridy or Metforminum;
- in case of replacement of a combination therapy glimepiridy and Metforminum on reception of one combined drug Amaril® M.

Route of administration and doses:

Use for adult patients.
Dosing of hypoglycemic medicines has to be carried out in an individual order taking into account concentration of glucose to the patient's blood. As a rule, it is recommended to begin treatment with the smallest effective dose and, depending on concentration of glucose in the patient's blood, to increase a dose. For this purpose it is necessary to carry out the corresponding monitoring of concentration of glucose to blood.
It is necessary to appoint drug 1 or 2 times a day, to or during meal. Use for patients of children's age.
Studying of safety and efficiency of drug at children with a diabetes mellitus 2 types was not carried out.
Use for patients of advanced age.
It is known that metformin is removed, mainly, by kidneys and as the risk of development of heavy undesirable reactions to drug in patients with a renal failure is higher, patients can only use drug with normal function of kidneys. Because with age function of kidneys decreases, with age Metforminum should be applied with care. It is necessary to pick up carefully a dose and to provide careful and regular monitoring of renal function of kidneys.

Features of use:

Efficiency of any hypoglycemic therapy should be controlled by periodic control of concentration of glucose and glikozilirovanny hemoglobin in blood. The purpose of treatment is normalization of these indicators. Concentration of glikozilirovanny hemoglobin allows to carry out assessment of glycemic control.
On the first week of treatment careful monitoring because of risk of development of a hypoglycemia is necessary, especially at the increased risk of its development (patients, not persons interested or incapable to follow recommendations of the doctor, most often elderly patients; at bad food, irregular meals, at admissions of meals; at discrepancy between an exercise stress and consumption of carbohydrates; at changes in a diet, at alcohol consumption especially in a combination with the admission of meals; at a renal failure; at heavy abnormal liver functions; at overdose of the drug Amaril® M; at some noncompensated disturbances of endocrine system (for example, dysfunction of a thyroid gland and insufficiency of function of a front share of a hypophysis or adrenal glands; at co-administration of some other medicines influencing carbohydrate metabolism (see. "Interactions with other medicines").
In such cases careful monitoring of concentration of glucose in blood is necessary. The patient has to report to the doctor about these factors and about hypoglycemia symptoms if those take place. With risk factors of a hypoglycemia dose adjustment of this drug or all therapy can be required. Such approach is used any times when during therapy any disease develops, and at change of a way of life of the patient. The hypoglycemia symptoms reflecting adrenergic antihypoglycemic regulation (see. "Side effects"), can be less expressed or in general be absent if the hypoglycemia develops gradually, and also at patients of advanced age, at neuropathy of the autonomic nervous system or at at the same time carried out therapy by beta adrenoblockers, a clonidine, guanetidiny and other sympatholytics.
It is necessary to support a target glycemia by means of complex measures: by means of a diet and physical exercises and if it is necessary, then due to decrease in body weight and by means of regular reception of this drug. In blood the oliguria, thirst, patholologically strong thirst, dry skin and others belong to clinical symptoms of inadequately adjustable glycemia.
Patients should be informed on possible side effects of this drug. Patients should be informed also on importance of observance of dietary instructions and carrying out regular physical exercises. Almost always the hypoglycemia can be stopped quickly by means of immediate reception of carbohydrates (glucose or sugar, for example: piece of sugar, the fruit juice containing sugar, tea with sugar etc.). For this purpose the patient has to carry at himself, at least, not less than 20 g of sugar. The help of people around in order to avoid complications can be required by him. Substitutes of sugar are inefficient.
By experience of use of other drugs of sulphonylurea it is known that, despite initial effectiveness of the undertaken counter-measures, the hypoglycemia can repeat. Therefore, patients have to remain under careful observation. Development of a heavy hypoglycemia demands immediate treatment and medical observation, in certain cases - hospitalization.
If treatment to the patient is carried out not by the attending physician (for example, hospitalization, accident, need for a visit to the doctor to the day off, etc.), the patient has to let him know a disease of a diabetes mellitus and the carried-out treatment.
In stressful situations (for example, an injury, operation, an infectious disease with a temperature) glycemic control can be broken, and for ensuring necessary control over metabolism temporary transition to an insulin therapy can be required.
Monitoring of function of kidneys: it is known that metformin is removed, mainly, by kidneys. At a renal failure the risk of cumulation of Metforminum and development of lactoacidosis grows. Therefore, at concentration of creatinine in the serum exceeding an upper age limit of norm it is not recommended to accept this drug. Patients of advanced age require careful titration of a dose of this drug to pick up the dose, minimum for rendering the corresponding glycemic effect, as with age function of kidneys decreases. Function of kidneys at elderly patients should be controlled regularly, and, as a rule, this medicinal substance should not be titrated to the maximum dose.
The concomitant use of other medicines can influence function of kidneys or Metforminum removal. The concomitant use of other medicines can influence function of kidneys or cause considerable changes of a hemodynamics, or influence release of this drug. X-ray inspections with intravascular administration of iodinated contrast mediums [for example, intravenous urography, an intravenous holangiografiya, an angiography and the computer tomography (CT) using a contrast agent]: the contrast intravenous iodinated agents intended for carrying out researches can cause an acute disorder of function of kidneys, their use is associated with lactoacidosis at the patients accepting this medicine (see the section "Contraindications"). Therefore, if carrying out such research is planned, this drug needs to be cancelled in 48 hours prior to holding a procedure and not to resume its appointment in the subsequent after the procedure of 48 hours. It is possible to resume treatment by this drug only after control of renal function if the last is normal.
Conditions of a hypoxia: the collapse or shock of any origin, an acute heart failure, an acute myocardial infarction and other states which are characterized by an anoxemia are followed by lactoacidosis and can cause a prerenalny renal failure also. If the patients accepting this drug have such states, it is necessary to cancel drug immediately. Surgeries: at any surgical intervention it is necessary to stop temporarily therapy by this drug (except for the small procedures which are not demanding restrictions in meal and liquid), therapy cannot be resumed until oral administration of food is recovered and renal function will not be recognized as normal.
Alcohol intake: it is known that alcohol strengthens effect of metformin on metabolism of a lactate. Therefore, it is necessary to warn patients against consumption of alcohol during reception of this drug.
Abnormal liver function: as in certain cases the abnormal liver function was accompanied by lactoacidosis, as a rule, patients with clinical or laboratory signs of damage of a liver should avoid use of this drug.
Change in a clinical condition of the patient with earlier controlled diabetes mellitus: the patient with a diabetes mellitus, earlier well kontroliruyeiy Metforminum reception, is subject to immediate inspection, especially at indistinctly and badly recognizable disease, for an exception of ketoacidosis and lactoacidosis. Has to join in a research: definition of electrolytes and ketonic bodies of serum, glucose of blood and if it is necessary, рН for blood, concentration of a lactate, pyruvate and Metforminum. In case of existence of any of acidosis forms this drug it is necessary to cancel and appoint immediately other means for maintenance of glycemic control. Information for patients: it is necessary to inform patients on possible risk and on advantages of this drug, and also on alternative ways of treatment. It is necessary to explain also well all importance of observance of instructions on a diet, a regular exercise stress and regular control of glucose in blood, glikozilirovanny hemoglobin, function of kidneys and hematologic indicators.
Usually, Metforminum in itself does not cause a hypoglycemia though the last is possible if Metforminum is applied together with sulphonylurea derivatives to intake. Starting a combination therapy, it is necessary to tell patients about risk of development of a hypoglycemia, about its symptoms and treatment, and also about the states contributing to its development. Concentration of B12 vitamin
Decrease in concentration of B12 vitamin in blood serum below norm in the absence of clinical manifestations was observed, approximately, at 7% of the patients accepting this drug during the controlled clinical trials lasting 29 weeks. Possibly, this decrease is caused by influence of a complex V12-vitamin an internal factor of Kasl on B12 vitamin absorption, nevertheless, it very seldom is followed by anemia and at cancellation of this drug or at purpose of B12 vitamin quickly reversibly. Some people (with insufficient consumption or digestion of B12 vitamin) are predisposed to decrease in concentration of B12 vitamin. For such patients definition in B12 vitamin serum can be useful regular, each 2-3 years.
It is necessary to control periodically hematologic indicators (hemoglobin or a hematocrit, quantity of erythrocytes) and indicators of function of kidneys (creatinine) not less once a year and the corresponding inspection and treatment of any, explicit pathological changes. In spite of the fact that at Metforminum reception development of megaloblastny anemia was observed seldom, at suspicion of it it is necessary to conduct examination for an exception of deficit of B12 vitamin.
Lactoacidosis
Lactoacidosis is a rare, but heavy metabolic complication which develops as a result of accumulation of Metforminum during treatment. Approximately in 50% of cases lactoacidosis has death. Lactoacidosis can arise also in connection with some pathophysiological states, including, at a diabetes mellitus, and also at considerable ischemia of fabrics and an anoxemia. Lactoacidosis is characterized by increase in concentration of a lactate in blood (> 5 mmol/l), decrease рН blood, disturbance of electrolytic balance with increase in deficit of anions and increase in a ratio between a lactate and pyruvate. In cases when Metforminum is the reason of lactoacidosis, plasma concentration of Metforminum, as a rule, makes> 5 mkg/ml. Frequency of the registered lactoacidosis cases at the patients accepting Metforminum, very low (about 0,03 cases / 1000 patsiyento-years with approximate quantity of deaths of 0,015 cases / 1000 patsiyento-years). The registered cases occurred, mainly, at patients with a diabetes mellitus with the expressed renal failure, including, with inborn diseases of kidneys and hypoperfusion of kidneys, is frequent in the presence of the numerous accompanying states demanding conservative or surgical treatment and the accompanying drug treatment. The risk of development of lactoacidosis increases in process of expressiveness of renal failures and with age. The probability of lactoacidosis at reception of Metforminum can be reduced considerably at regular control of renal function and use of minimal effective doses of Metforminum. For the same reason at the states interfaced to an anoxemia or dehydration it is necessary to avoid reception of this medicine.
As a rule, because the abnormal liver function can limit considerably removal of a lactate, it is necessary to avoid purpose of this drug the patient with clinical or laboratory signs of a disease of a liver. Besides, administration of drug should be stopped temporarily before carrying out X-ray analyses using intravascular contrast agents and before surgical interventions.
Often lactoacidosis develops gradually and breath disturbances, the increasing drowsiness and nonspecific disturbances from digestive tract is shown only by nonspecific symptoms, such as feeling sick, a mialgiya. At more expressed acidosis development of a hypothermia, a lowering of arterial pressure and a resistant bradyarrhythmia is possible. Both the sick, and attending physician have to know how important can be these symptoms. It is necessary to instruct the patient about that he in case of such symptoms immediately informed the doctor. For specification of the diagnosis of lactoacidosis it is necessary to carry out definition of concentration of electrolytes and ketones to blood, concentration of glucose in blood, рН blood, a lactate and Metforminum in blood. If the patient is already stabilized on any dose of this drug, then gastrointestinal symptoms which often arise at the beginning of therapy by Metforminum can be caused by development of lactoacidosis or other serious illness. But lower than 5 mmol/l the patients accepting this drug have a plasma concentration of a lactate in a venous blood on an empty stomach exceeding an upper limit of norm, not necessarily indicates lactoacidosis, it can be explained with other mechanisms, such as badly controlled diabetes mellitus or obesity, an intensive exercise stress or technical errors at blood sampling on the analysis.
It is necessary to assume existence of lactoacidosis at the patient with a diabetes mellitus with a metabolic acidosis in the absence of ketoacidosis (a ketonuria and a ketonemiya). Lactoacidosis is the critical state demanding hospitalization. In case of lactoacidosis it is necessary to cancel immediately reception of this drug and to start the general supporting measures. Because Metforminum is removed from blood by means of a hemodialysis with clearance to 170 ml/min. on condition of lack of hemodynamic disturbances, immediate carrying out a hemodialysis for correction of acidosis and removal of the collected Metforminum is recommended. Such measures often lead to bystry disappearance of symptoms and recovery.
Influence on ability to manage vehicles or other mechanisms
Speed of reactions of the patient treatments or after changes in treatment can worsen as a result of a hypoglycemia and a hyperglycemia, especially, in the beginning, or at irregular administration of drug. It can affect the abilities necessary for control of vehicles and other mechanisms. It is necessary to warn patients about need to be careful at control of vehicles, especially in case of tendency to development of a hypoglycemia and/or reduction of expressiveness of its harbingers.

Side effects:

On the basis of clinical experience of use of a glimepirid and the known data on other derivatives of sulphonylurea, development of the listed below adverse reactions is possible.
Disturbances from a metabolism and food
- Hypoglycemia: development of a hypoglycemia which - judging by other drugs of sulphonylurea - can have long character. The headache, acute sense of hunger, nausea, vomiting, block, slackness, a sleep disorder, concern, aggression, decrease in concentration of attention, decrease in vigilance and delay of psychomotor reactions, a depression, the confused consciousness, disturbances of the speech, aphasia, vision disorders, a tremor, paresis, sensitivity disturbance, dizziness, helplessness, self-checking loss, a delirium, spasms, drowsiness and a loss of consciousness belong to symptoms of the developing hypoglycemia up to a coma, shallow breathing and bradycardia. Besides, development of signs of adrenergic reaction to a hypoglycemia, such as the increased sweating, stickiness of skin, the increased uneasiness, tachycardia, increase in arterial pressure, feeling of the strengthened heartbeat, stenocardia and arrhythmias is possible. The clinical picture of an attack of a heavy hypoglycemia can remind an acute disorder of cerebral circulation. Symptoms are almost always resolved after elimination of a hypoglycemia.
Disturbances from an organ of sight
- Deterioration in sight, especially, in an initiation of treatment because of fluctuation of concentration of glucose in blood.
Disturbances from digestive tract
- Development of gastrointestinal symptoms, such as nausea, vomiting, feeling of overflow of a stomach, abdominal pain and diarrhea.
Disturbances from a liver and biliary tract
- Increase in activity of "hepatic" enzymes and an abnormal liver function (for example, a cholestasia and jaundice), and also hepatitis which can progress in a liver failure.
Disturbances from blood and lymphatic system
- Thrombocytopenia, in some cases - a leukopenia or hemolitic anemia, an erythrocytopenia, a granulocytopenia, an agranulocytosis or a pancytopenia. Because during treatment drugs of sulphonylurea registered aplastic anemia and a pancytopenia, it is necessary to carry out careful monitoring. At their development it is necessary to cancel medicine and to begin the corresponding treatment.
Disturbances from immune system (hypersensitivity reaction)
- Allergic or pseudo-allergic reactions (for example, itch, urticaria or rashes). These reactions almost always wear an easy uniform, however, can pass into a severe form with short wind or a lowering of arterial pressure, up to development of an acute anaphylaxis. In case of development of a small tortoiseshell it is necessary to report about it to the doctor immediately. The cross allergy with other derivatives of sulphonylurea, streptocides, or similar to them substances is possible.
- Allergic vasculitis. Other
- Photosensitization, hyponatremia. Metforminum
Disturbances from a metabolism and food
- lactoacidosis (see. "Special instructions").
- Hypoglycemia.
Disturbances from digestive tract
- Gastrointestinal symptoms (diarrhea, nausea, abdominal pains, vomiting, the increased gas generation, a meteorism and lack of appetite) - the most frequent reactions at monotherapy by Metforminum meet, approximately, for 30% more often than at placebo reception, especially, in an initial stage of therapy. These symptoms, preferential, temporary, at treatment continuation they are spontaneously resolved. In some cases there can be useful a temporary dose decline. In clinical trials because of gastrointestinal reactions this drug was cancelled, approximately, at 4% of patients. Because development of gastrointestinal symptoms in an initial stage of treatment is dozozavisimy, these symptoms can be reduced due to gradual building of a dose and administration of drug during food. As severe diarrhea and (or) vomiting can lead to dehydration and a prerenalny renal failure, at their emergence it is necessary to stop reception of this drug temporarily.
- In an initiation of treatment Metforminum approximately at 3% of patients are possible emergence of unpleasant or metal taste in a mouth which, usually, spontaneously disappears.
Disturbances from skin and hypodermic fabrics
Skin reactions: erythema, itch, rash. Disturbances from blood and lymphatic system
- Anemia, leykotsitopeniya or thrombocytopenia. Approximately, at 9% of patients at monotherapy with this drug and at 6% of the patients receiving metformin or Metforminum/drug from group of sulphonylurea asymptomatic decrease in concentration of B12 vitamin in serum takes place
(concentration of folic acid in serum significantly does not decrease).
Despite it, in communication reception of this drug registered only megaloblastny anemia, increase of cases of neuropathy was not observed. Therefore, it is necessary to carry out the corresponding control of concentration of B12 vitamin in serum, periodic parenteral completion of B12 vitamin can be required.
Disturbances from a liver and biliary tract:
-  Abnormal liver function.
At development of the above-stated or other undesirable reactions the patient should report about it to the attending physician immediately. As some undesirable reactions, including a hypoglycemia, hematologic disturbances, heavy allergic and pseudo-allergic reactions and a liver failure can threaten the patient's life, in case of development of such reactions the patient should report immediately about it to the attending physician and to stop further administration of drug before obtaining instructions from the doctor. Except for already known reactions on глимепирид and Metforminum, unexpected undesirable reactions to Amaril® of M during clinical trials of the I phase and in open researches III of a phase were not observed.

Interaction with other medicines:

When to the patient accepting глимепирид at the same time appoint or cancel other medicines, both undesirable strengthening, and weakening of hypoglycemic action of a glimepirid is possible. Proceeding from clinical experience of use of a glimepirid and other drugs of sulphonylurea, it is necessary to consider the listed below medicinal interactions.
- With the drugs which are inductors and inhibitors of an isoenzyme SUR2S9
Glimepirid is metabolized by means of P450 2C9 cytochrome (SUR2S9 isoenzyme). It is known that simultaneous use of inductors of an isoenzyme of SUR2S9, for example, of rifampicin (risk of reduction of hypoglycemic effect of a glimepirid exerts impact on his metabolism at simultaneous use with inductors of an isoenzyme SUR2S9 and increase in risk of development of a hypoglycemia in case of their cancellation without dose adjustment of a glimepirid) and SUR2S9 isoenzyme inhibitors, for example, of a flukonazol (increases in risk of development of a hypoglycemia and side effects of a glimepirid at its concomitant use with inhibitors of an isoenzyme SUR2S9 and risk of reduction of its hypoglycemic effect at their cancellation without dose adjustment of a glimepirid).
- With the medicines strengthening hypoglycemic action of a glimepirid: insulin and peroral hypoglycemic means, inhibitors of an angiotensin-converting enzyme, Allopyrinolum, anabolic steroids,  male sex hormones, chloramphenicol, coumarinic anticoagulants, cyclophosphamide, Disopyramidum, фенфлурамин, фенирамидол, fibrata, fluoxetine, гуанетидин, ифосфамид, inhibitors of a monoaminooxidase (MAO), Miconazolum, флуконазол, aminosalicylic acid, пентоксифиллин (high doses parenterally), phenylbutazone, пробенецид, antimicrobic means - derivatives of a hinolon, salicylates, Sulfinpyrazonum, sulfonamide derivatives, tetracyclines, тритоквалин, трофосфамид, азапропазон, оксифенбутазон. Increase in risk of development of a hypoglycemia at their simultaneous use with glimepiridy and risk of deterioration in glycemic control at their cancellation without dose adjustment of a glimepirid.
- With the medicines weakening hypoglycemic action: acetazoleamide, barbiturates, glucocorticosteroids, diazoxide, diuretics, Epinephrinum (adrenaline) or sympathomimetics, glucagon, laxative (prolonged use), niacin (high doses), estrogen, progestogens, fenotiazina, Phenytoinum, rifampicin, hormones of a thyroid gland.
Risk of deterioration in glycemic control at combined use with these drugs and increase in risk of development of a hypoglycemia in case of their cancellation without dose adjustment of a glimepirid
- With the medicines both strengthening, and weakening hypoglycemic action of a glimepirid: blockers H2-gistaminoretseptorov, clonidine, Reserpinum.
Perhaps both strengthening, and reduction of hypoglycemic effect of a glimepirid. Careful monitoring of concentration of glucose in blood is necessary.
- With beta adrenoblockers
Beta adrenoblockers reduce tolerance to glucose that can break metabolic regulation. Besides, as a result of blocking of reactions of a sympathetic nervous system in response to a hypoglycemia they can do development of a hypoglycemia more imperceptible for the patient and the doctor and by that to increase risk of its emergence.
- With sympatholytics
They are capable to reduce or block reactions of a sympathetic nervous system in response to a hypoglycemia that can do development of a hypoglycemia more imperceptible for the patient and the doctor and by that to increase risk of its emergence.
- With alcohol
Consumption of alcohol can either weaken, or strengthen hypoglycemic effect of a glimepirid.
- With coumarin derivatives
Glimepirid can both strengthen, and to reduce effects of derivatives
coumarin.
Metforminum
- With the iodinated contrast agents, antibiotics having the expressed nephrotoxic effect (gentamycin)
Increase in risk of development of lactoacidosis. In case of simultaneous use of these drugs it is necessary careful observation of the patient (see. "Special instructions").
- With the drugs strengthening hypoglycemic effect of metformin: insulin, sulfonamides, sulphonylurea drugs, anabolic steroids, гуанетидин, salicylates (acetylsalicylic acid, etc.), beta adrenoblockers (propranolol, etc.), MAO inhibitors
In case of simultaneous use of these drugs with Metforminum careful observation of the patient and control of concentration of glucose in blood as strengthening of hypoglycemic action of a glimepirid is possible are necessary.
- With the drugs weakening hypoglycemic effect of metformin: Epinephrinum, glucocorticosteroids, hormones of a thyroid gland, are oestrogenic, Pyrazinamidum, an isoniazid, niacin, fenotiazina, thiazide diuretics and diuretics of other groups, oral contraceptives, Phenytoinum, sympathomimetics, blockers of "slow" calcic tubules
In case of simultaneous use of these drugs with Metforminum careful observation of the patient and control of concentration of glucose in blood as weakening of hypoglycemic action of a glimepirid is possible are necessary.
- With Glibenclamidum
In clinical trial on interaction of Metforminum and Glibenclamidum at a single dose any changes neither in pharmacokinetics, nor in Metforminum pharmacodynamics at patients with a diabetes mellitus 2 types were not observed. However decrease in AUC and Sshchakh of Glibenclamidum and their considerable inconstancy was observed. Because it was a research on a single dose of drugs and due to the lack of correlation between concentration of Glibenclamidum in blood and pharmakodinamichesky effects clinical value of such interaction is not clear.
- With furosemide
In clinical trial on interaction of Metforminum and furosemide at their single dose on healthy volunteers it was shown that co-administration of these drugs influences their pharmacokinetic indicators. Furosemide was increased by Sshchakh of Metforminum in plasma and in blood by 22%, and blood ATsS for 15% without any essential changes of renal clearance of Metforminum. At use with Metforminum Sshchakh and ATsS of furosemide decreased by 31% and 12%, respectively, in comparison with monotherapy by furosemide, and the period of final semi-removal decreased by 32% without any essential changes of renal clearance of furosemide. Information on interaction of Metforminum and furosemide at prolonged use is absent.
- With nifedipine
In clinical trial of interactions of Metforminum and nifedipine at their single dose at healthy volunteers it was shown that simultaneous use of nifedipine is increased by Sshchakh and ATsS of Metforminum in a blood plasma for 20% and 9%, respectively, and also increases its quantity excreted by kidneys. Metforminum rendered the minimum effect on nifedipine pharmacokinetics.
- With cationic drugs (amiloride, дикогсин, morphine, procaineamide, quinidine, quinine, ranitidine, Triamterenum, Trimethoprimum and Vancomycinum)
 
The cationic drugs which are removed by means of canalicular secretion in kidneys are theoretically capable to interact with Metforminum as a result of the competition for the general canalicular transport system. Such interaction between Metforminum and peroral Cimetidinum was observed at healthy volunteers in clinical trials of interaction of Metforminum and Cimetidinum at single and repeated use where 60% increase in the maximum plasma concentration and general concentration of Metforminum in blood and 40% increase in plasma and general AIS of Metforminum was noted. At a single dose changes in an elimination half-life were not. Metforminum did not influence Cimetidinum pharmacokinetics. In spite of the fact that such interactions remain purely theoretical (except for Cimetidinum), it is necessary to provide careful monitoring of patients and to carry out dose adjustment of Metforminum and (or) the medicine interacting with it in case of reception of the kationovy drugs which are brought out of an organism secretory system of proximal tubules of kidneys. - With propranolol, an ibuprofen
At healthy volunteers in researches on a single dose of Metforminum and propranolol, and also Metforminum and an ibuprofen changes of their pharmacokinetic indicators were not observed.

Contraindications:

- Diabetes mellitus of 1 type.
- Diabetic ketoacidosis in the anamnesis, diabetic ketoacidosis, a diabetic coma and a prekomatozny state, an acute or chronic metabolic acidosis.
- Hypersensitivity to sulphonylurea derivatives, sulfonamides or guanyl guanidines, and also to any of drug excipients.
- Heavy abnormal liver function (lack of experience of use; ensuring adequate glycemic control requires treatment by insulin).
- A renal failure, including the patients who are on a hemodialysis. Concentration of creatinine in serum:> Men have 1,5 mg/dl and> 1,4 mg/dl at women or decrease in clearance of creatinine (the increased risk of development of lactoacidosis and other side effects of Metforminum).
- Tendency to development of lactoacidosis, lactoacidosis in the anamnesis.
- Stressful situations (severe injuries, burns, surgeries, heavy infections with a feverish state, a septicaemia.).
- Heart failure, collapse (shock), acute myocardial infarction.
- Exhaustion, starvation, dehydration, observance of a hypocaloric diet (less than 1000 кал / days).
- Disturbance of absorption of food and medicines in digestive tract (at intestinal impassability, intestines paresis; to diarrhea, vomiting).
- Pituitary or adrenal insufficiency.
- Heavy disturbance of pulmonary function, and other hypoxemic states, including a fabric hypoxia (heart or respiratory failure, an acute myocardial infarction, etc.).
- Alcoholism, acute alcoholic poisoning.
- Intravenous administration of yodokontrastny substances as they can cause an acute disorder of function of kidneys (drug is not appointed the 48th hour prior to and the 48th hour after the research).
- Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.
- Pregnancy, pregnancy planning.
- Feeding by a breast.
- Children's age up to 18 years (lack of clinical data).
If at you one of the listed diseases or states, before administration of drug surely consult with the doctor. With care:
- at states at which the risk of development of a hypoglycemia (the patients, not wishing increases or not capable to cooperate with the doctor, most often elderly patients; badly eating, irregularly eating food, the patients missing meals; at discrepancy between an exercise stress and consumption of carbohydrates; at change of a diet; at alcohol intake, especially, in a combination with the admission of meals; at abnormal liver functions and kidneys; at some noncompensated endocrine frustration, such as dysfunctions of a thyroid gland, insufficiency of anterior pituitary hormones and bark of the adrenal glands exerting impact on metabolism of carbohydrates or activation of the mechanisms directed to increase in concentration of glucose in blood at a hypoglycemia (at such patients more careful control of concentration of glucose in blood and hypoglycemia signs is necessary);
- at simultaneous use of some other medicines (see. "Interaction with other medicines");
- at depression of function of kidneys at such states as advanced age, a collapse, shock (the increased risk of development of lactoacidosis and other side effects of Metforminum);
- when performing hard physical activity (danger of development of lactoacidosis at Metforminum reception increases);
- at a smoothness or lack of the hypoglycemia symptoms connected with activation of a sympathetic nervous system (at patients of advanced age, at neuropathic damages of the autonomic nervous system or at at the same time carried out therapy by beta adrenoblockers, a clonidine, guanetidiny and other sympatholytics) (at such patients more careful monitoring of concentration of glucose in blood is necessary).
 
If at you one of the listed diseases or states, before administration of drug surely consult with the doctor. Pregnancy and lactation Pregnancy
This drug cannot be accepted during pregnancy because of a possible adverse effect on pre-natal development. The pregnant women and women planning pregnancy have to report about it to the attending physician. During pregnancy of the woman with the disturbances of carbohydrate metabolism which are not adjusted one diet and exercise stresses have to receive an insulin therapy. Lactation
In order to avoid hit of drug with breast milk in the child's organism
the women nursing cannot accept this drug. In a case
need, the patient it is necessary to transfer to insulin or to stop chest
feeding.

Overdose:

Symptoms
As this drug contains глимепирид, the overdose can cause a hypoglycemia.
Because of the content in this drug of Metforminum development of lactoacidosis is possible. At hit of Metforminum in a stomach in quantity to 85 g of a hypoglycemia it was not observed.

Treatment
Easily expressed hypoglycemia without loss of consciousness and neurologic changes it is necessary to treat by means of peroral introduction of a dextrose (glucose) and a correcting of a dose of drug and (or) the patient's diet. Intensive monitoring should be continued until the doctor is not convinced that the patient is out of danger. Heavy hypoglycemic reactions meet a coma, spasms and other neurologic symptoms often and are the critical state demanding immediate hospitalization of the patient. In case of diagnosis of a hypoglycemic coma or at suspicion on it, the patient needs to enter concentrated (40%) dextrose solution intravenously struyno after which constant infusional introduction of 10% of solution of a dextrose with a speed providing maintenance of concentration of glucose in blood is necessary it is higher than 100 mg/dl. The patient is carefully observed within not less than 24-48 hours as after visible clinical recovery the hypoglycemia can repeat.
At a good hemodynamics metformin is capable to be removed by means of dialysis with clearance to 170 ml/min. Therefore, at suspicion on Metforminum overdose the hemodialysis can be useful to removal of the drug which collected in an organism.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 1 mg +250 mg and 2 mg +500 mg. On 10 tablets in PVC / the Aluminium blister.
On 3 blisters together with the application instruction in a cardboard pack.