Амарил®

General characteristics. Structure:

Contains in one tablet Амарил® 1 of mg: active agent - 1 mg of a glimepirid;
excipients: lactoses monohydrate, sodium carboxymethylstarch (type A), povidone 25000, cellulose microcrystallic, magnesium stearate, dye ferrous oxide red (Е 172).
Contains in one tablet Амарил® 2 of mg:
active agent - 2 mg of a glimepirid;
excipients: lactoses monohydrate, sodium carboxymethylstarch (type A), povidone 25000, cellulose microcrystallic, magnesium stearate, dye ferrous oxide yellow (Е 172), indigo carmine (Е 132).
Contains in one tablet Амарил® 3 of mg:
active agent - 3 mg of a glimepirid;
excipients: lactoses monohydrate, sodium carboxymethylstarch (type A), povidone 25000, cellulose microcrystallic, magnesium stearate, dye ferrous oxide yellow (Е 172).
Contains in one tablet Амарил® 4 of mg:
active agent - 4 mg of a glimepirid;
excipients: lactoses monohydrate, sodium carboxymethylstarch (type A), povidone 25000, cellulose microcrystallic, magnesium stearate, indigo carmine (Е 132).
Description
Амарил® 1 mg: tablets of pink color, oblong, flat with dividing risky on both parties. An engraving of NMK and stylized "h" on two parties.
Амарил® 2 mg: tablets of green color, oblong, flat with dividing risky on both parties. An engraving of NMM and stylized "h" on two parties.
Амарил® 3 mg: tablets of pale yellow color, oblong, flat with dividing risky on both parties. An engraving of NMN and stylized "h" on two parties.
Амарил® 4 mg: tablets of blue color, oblong, flat with dividing risky on both parties. An engraving of NMO and stylized "h" on two parties.

Pharmacological properties:

Pharmacodynamics. Glimepirid reduces concentration of glucose in blood, mainly due to stimulation of release of insulin from pancreas beta cells. Its effect is preferential connected with improvement of ability of beta cells of a pancreas to react to physiological stimulation by glucose. In comparison with Glibenclamidum reception of low doses of a glimepirid causes release of smaller amounts of insulin at achievement of approximately identical decrease in concentration of glucose in blood. This fact testifies in favor of existence at a glimepirid of ekstrapankreatichesky hypoglycemic effects (increase in sensitivity of fabrics to insulin and insulinomimetichesky effect).
Insulin secretion. As well as all other derivatives of sulphonylurea, глимепирид regulates secretion of insulin due to interaction with ATP-sensitive potassium channels on membranes of beta cells. Unlike other derivatives of sulphonylurea глимепирид selectively contacts protein with a molecular weight of 65 килодальтон (kDa), being in membranes of beta cells of a pancreas. This interaction of a glimepirid with the protein contacting it regulates opening or closing of ATP-sensitive potassium channels.
Glimepirid closes potassium channels. It causes depolarization of beta cells and leads to opening a voltage - sensitive calcium channels and to intake of calcium in a cell. As a result, increase in intracellular concentration of calcium activates secretion of insulin by an exocytosis.
Glimepirid much quicker and according to a thicket takes up and Glibenclamidum is released from communication with the protein contacting him, than. It is supposed that this property of high speed of exchange of a glimepirid with the protein contacting it causes its expressed effect of a sensitization of beta cells to glucose and their protection against desensitization and premature exhaustion.
Effect of increase in sensitivity of fabrics to insulin. Glimepirid strengthens effects of insulin on glucose absorption by peripheral fabrics.
Insulinomimetichesky effect. Glimepirid has effects, similar to effects of insulin on glucose absorption by peripheral fabrics and a glucose exit from a liver.
Glucose absorption by peripheral fabrics is carried out by its transport in muscle cells and adipocytes. Glimepirid directly increases quantity     of the molecules transporting glucose  in  plasma membranes of muscle cells and adipocytes. Increase in receipt in cells of glucose leads to activation of a glikozilfosfatidilinozitol-specific phospholipase of Page. As a result of it intracellular concentration of calcium decreases, causing reduction of activity of a protein kinase And that in turn leads to glucose metabolism stimulation.
Glimepirid inhibits a glucose exit from a liver due to increase in concentration fruktozo-2,6-bisfosfata which inhibits a gluconeogenesis.
Influence on aggregation of thrombocytes and formation of atherosclerotic plaques. Glimepirid reduces aggregation of thrombocytes of in vitro and in vivo. This effect apparently, is connected with the selection inhibition of cyclooxygenase which is responsible for formation of thromboxane A, an important internal cause of aggregation of thrombocytes.
Anti-atherogenous effect of drug. Glimepirid contributes to normalization of maintenance of lipids, reduces the level of low-new aldehyde in blood that leads to considerable decrease in peroxide oxidation of lipids.
Decrease in expressiveness of an oxidizing stress which constantly is present at patients with a diabetes mellitus 2 types. Glimepirid increases level endogenous and - tocopherol, activity of a catalase, glyutationperoksidaza and superoxide scavenger.
Cardiovascular effects. Through ATP-sensitive potassium channels (see above), sulphonylurea derivatives also make impact on cardiovascular system. In comparison with traditional derivatives of sulphonylurea, глимепирид renders authentically smaller effect on cardiovascular system. It reduces aggregation of thrombocytes and leads to significant reduction of formation of atherosclerotic plaques.
At healthy volunteers the minimal effective dose of a glimepirid makes 0,6 mg. The effect of a glimepirid is dozozavisimy and reproduced. Physiological reaction to an exercise stress (decrease in secretion of insulin) at reception of a glimepirid remains.
There are no reliable distinctions in effect depending on that, drug in 30 minutes prior to food or just before food was accepted. At patients with a diabetes mellitus it is possible to reach sufficient metabolic control within 24 hours at a single dose of drug. Moreover, in clinical trial at 12 of 16 patients with a renal failure (clearance of creatinine of 4-79 ml/min.) sufficient metabolic control was also reached.
Combination therapy with Metforminum. At patients at whom it is not reached sufficient metabolic control at use of the maximum dose of a glimepirid the combination therapy glimepiridy and Metforminum can be begun. In two researches when carrying out a combination therapy improvement of metabolic control in comparison with that at treatment was proved to each of these drugs separately.
Combination therapy with insulin. At patients with achievement of insufficient metabolic control at reception of the maximum doses of a glimepirid simultaneous therapy can be begun with insulin. By results of two researches at use of this combination the same improvement of metabolic control is reached, as well as at use only of one insulin; however, at a combination therapy lower dose of insulin is required.
Use for children
Data on long-term efficiency and safety at use of drug for children are absent.

Pharmacokinetics. At multiple dose of a glimepirid in a daily dose of 4 mg the maximum concentration in blood serum (Stakh) is reached approximately in 2,5 h and makes 309 ng/ml. There is a linear ratio between a dose and the maximum plasma concentration of a glimepirid (Stakh), and also between a dose and the area under a curve "concentration - time" (AUC). At intake of a glimepirid its absolute bioavailability is full. Meal has no significant effect on absorption, except for insignificant delay of its speed. 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. The average elimination half-life determined by serumal concentration in the conditions of multiple dose of drug makes about 5-8 hours. After reception of high doses, insignificant increase in elimination half-lives is noted.
After a single dose of a glimepirid in 58% of a dose also 35% of a dose - through intestines are removed by kidneys. Not changed глимепирид in urine it is not found.
In urine and Calais two metabolites which are formed as a result of metabolism in a liver were revealed (mainly by means of CYP2C9), one of them was hydroxyderivative, and another - to carboxyderivatives. After intake of a glimepirid the terminal elimination half-life of these metabolites made 3-5 hours and 5-6 hours, respectively.
Glimepirid is allocated with breast milk and gets through a placental barrier.
Comparison of reception of a glimepirid single and repeated (once a day) did not reveal reliable distinctions in pharmacokinetic indicators, and their very low variability between different patients is observed. Significant accumulation of drug is absent.
Pharmacokinetic parameters are similar at patients of a different floor and various age groups. 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 is observed that most likely, is caused by more bystry removal of drug owing to its lower linkng with protein. Thus, this category of patients has no additional risk of cumulation of drug.

Indications to use:

Diabetes mellitus 2 types (in monotherapy or as a part of a combination therapy with metformin or insulin).

Route of administration and doses:

As a rule, the dose of the drug Amaril® is defined by target concentration of glucose in blood. The smallest dose sufficient for achievement of necessary metabolic control has to be applied.
During treatment it is regularly necessary to determine by the drug Amaril® concentration of glucose in blood. Besides regular control of the level of glikozilirovanny hemoglobin is recommended.
The wrong administration of drug, for example, the admission of reception of the next dose, never has to be filled by the subsequent reception of higher dose.
Actions of the patient at mistakes at administration of drug (in particular at the admission of reception of the next dose or at the admission of meal), or in situations, when there is no an opportunity to accept drug, have to be discussed by the patient and the doctor beforehand.
Administration of drug
The pill Amaril® is taken entirely, without chewing, washing down with enough liquid (about 0,5 glasses).
Initial dose and selection of a dose
The initial dose makes 1 mg of a glimepirid once a day.
If necessary the daily dose can be gradually (bucketed in 1-2 weeks) is increased. It is recommended to carry out increase in a dose under regular control of concentration of glucose to blood and according to the following step of increase in a dose: 1 mg - 2 mg - 3 mg - 4 mg-6 mg (-8 mg).
Range of doses at patients with well controlled diabetes mellitus
Usually daily dose at patients with well controlled diabetes mellitus makes 1-4 mg of a glimepirid. The daily dose more than 6 mg is more effective only at a small amount of patients.
Dosing mode
Time of administration of drug and distribution of doses during the day is determined by the doctor, depending on a way of life of the patient at present (meal time, quantity of exercise stresses).
Usually, rather single dose of drug within a day.
It is recommended that in this case all dose of drug was accepted just before a full-fledged breakfast or if it was not accepted at this time, - just before the first main meal.
Very important after reception of tablets not to miss meal.
As improvement of metabolic control is associated with increase in sensitivity to insulin, during treatment the need for a glimepirida can decrease. To avoid development of a hypoglycemia it is necessary to reduce timely doses or to stop administration of drug of Amaril®.
States at which dose adjustment of a glimepirid can be also required:
- decrease in body weight at the patient;
- changes of a way of life of the patient (change of a diet, time of meal, quantity of exercise stresses);
- emergence of other factors which result in predisposition to development of a hypoglycemia or hyperglycemia (see the section "Special Instructions").
Treatment duration
Treatment glimepiridy is usually carried out is long.
Transfer of the patient from other hypoglycemic means for intake on Amaril®
There is no exact ratio between doses of the drug Amaril® and other hypoglycemic means for intake. When other hypoglycemic means for intake is replaced with the drug Amaril®, it is recommended that the procedure of its appointment was same as at initial purpose of the drug Amaril®, that is treatment has to begin 1 mg with an initial dose (even if the patient is transferred to Amaril® from the maximum dose of other hypoglycemic drug for intake). Any increase in a dose should be carried out step by step taking into account reaction on глимепирид according to the stated above recommendations.
It is necessary to consider force and duration of effect of the previous hypoglycemic means for intake. Treatment interruption can be required to avoid any summation of effects which can increase risk of development of a hypoglycemia.
Use in a combination with Metforminum
At patients with insufficiently controlled diabetes mellitus at reception of the maximum daily doses or a glimepirid or Metforminum treatment can be begun with a combination of these two drugs. At the same time the treatment which was carried out earlier or glimepiridy or Metforminum continues at the same level of doses, and additional reception of Metforminum or glimepirid is begun with a low dose which then is titrated depending on the target objective of metabolic control up to the maximum daily dose. The combination therapy has to begin under strict medical observation.
Use in a combination with insulin
To patients with insufficiently controlled diabetes mellitus at reception of the maximum daily doses of a glimepirid administration of insulin can be at the same time appointed. In this case the last, the dose of a glimepirid appointed to the patient, remains invariable. At the same time treatment by insulin begins with low doses which gradually raise under control of concentration of glucose in blood. The combined treatment demands careful medical observation.
Use for patients with a renal failure
There is a limited amount of information on use of drug for patients with a renal failure. Patients with an impaired renal function can be more sensitive to hypoglycemic effect of a glimepirid (see the sections "Pharmacokinetics", "Contraindications").
Use for patients with a liver failure
There is a limited amount of information on use of drug at a liver failure (see the section "Contraindications").
Use for children
Data on use of drug for children are not enough.

Features of use:

In special clinical stressful states, such as an injury, the surgical interventions, infections proceeding with a febrile temperature deterioration in metabolic control at patients with sugar debit is possible, and temporary transfer on an insulin therapy for maintenance of adequate metabolic control can be required by them.
In the first weeks of treatment the risk of development of a hypoglycemia can increase and therefore at this time especially careful control of concentration of glucose in blood is required.
Treat the factors promoting risk of development of a hypoglycemia:
- unwillingness or inability of the patient (more often observed at patients of advanced age) to cooperation with the doctor;
- malnutrition, irregular meal or admissions of meal;
- an imbalance between exercise stresses and consumption of carbohydrates;
- change of a diet;
- alcohol intake, especially in combination with admissions of meal;
- heavy renal failures;
- heavy abnormal liver functions (at patients with heavy abnormal liver functions transfer into an insulin therapy, at least, before achievement of metabolic control is shown).
- overdose of a glimepirid;
- some dekompensirovanny endocrine frustration breaking carbohydrate metabolism or adrenergic counterregulation in response to a hypoglycemia (for example some dysfunctions of a thyroid gland and front department of a hypophysis, insufficiency of bark of adrenal glands);
- a concomitant use of some medicines (see the section "Interaction with other medicines);
- reception of a glimepirid in the absence of indications to its reception.
Treatment by sulphonylurea derivatives which treats and глимепирид, can lead to development of hemolitic anemia therefore at patients with insufficiency glyukozo-6-fosfatdegidrogenazy it is necessary to observe extra care at purpose of a glimipirid and is better to apply the hypoglycemic means which are not sulphonylurea derivatives.
In case of existence of above-mentioned risk factors for development of a hypoglycemia dose adjustment of a glimepirid or all therapy can be required. It also belongs to developing of intercurrent diseases during treatment or to change of a way of life of patients.
Those symptoms of a hypoglycemia which reflect adrenergic counterregulation of an organism in response to a hypoglycemia (see the section "Side effect") can be poorly expressed or be absent at gradual development of a hypoglycemia, at patients of advanced age, at patients with neuropathy of the autonomic nervous system or at the patients receiving beta adrenoblockers, a clonidine, Reserpinum, гуанетидин and other sympatholytics.
The hypoglycemia can be quickly eliminated at immediate reception of quickly acquired carbohydrates (glucose or sucrose).
As well as at reception of other derivatives of sulphonylurea, despite initial successful stopping of a hypoglycemia, the hypoglycemia can renew. Therefore patients have to remain under constant observation.
At a heavy hypoglycemia immediate treatment and observation of the doctor, and in certain cases - hospitalization of the patient in addition is required.
During treatment glimepiridy carrying out regular control of function of a liver and a picture of peripheral blood is required (especially quantities of leukocytes and thrombocytes).
As separate side effects, such, as: the heavy hypoglycemia, serious changes of a picture of blood, heavy allergic reactions, a liver failure, can represent under certain circumstances threat for life, in case of development of undesirable or heavy reactions the patient needs to inform at once on them the attending physician and not to continue administration of drug without its recommendation at all.
Influence on ability of control of vehicles and other mechanisms.
In case of development of a hypoglycemia or a hyperglycemia, especially in an initiation of treatment or after treatment change or when drug is not accepted regularly, decrease in attention and speed of psychomotor reactions is possible. It can break ability of the patient to manage vehicles or other mechanisms.

Side effects:

From a metabolism
As a result of hypoglycemic effect of the drug Amaril® the hypoglycemia which, as well as at use of other derivatives of sulphonylurea, can be long can develop.
Symptoms of a hypoglycemia are: a headache, feeling of hunger, nausea, vomiting, feeling of fatigue, drowsiness, sleep disorders, concern, aggression, disturbance of concentration of attention, vigilance and speed of reactions, a depression, confusion of consciousness, speech frustration, aphasia, visual frustration, a tremor, paresis, touch disturbances, dizziness, self-checking loss, a delirium, cerebral spasms, a somnolention or a loss of consciousness up to a coma, shallow breathing, bradycardia.
Besides there can be manifestations of adrenergic counterregulation in response to a hypoglycemia, such as emergence of a cold clammy sweat, concern, tachycardia, arterial hypertension, stenocardia, heartbeat and disturbances of a cordial rhythm.
The clinical picture of a heavy hypoglycemia can be similar to a stroke. Hypoglycemia symptoms almost always disappear after its elimination. From an organ of sight
During treatment (especially at its beginning) the tranzitorny vision disorders caused by change of concentration of glucose in blood can be observed. The temporary change of swelling capacity of crystalline lenses depending on concentration of glucose in blood and at the expense of it change of index of refraction of crystalline lenses is their reason.
From digestive tract
In rare instances: nausea, vomiting, heavy feeling or overflow in epigastriums, abdominal pains, diarrhea.
In some cases: hepatitis, increase in activity of "hepatic" enzymes and/or a cholestasia and jaundice which can progress to a life-threatening liver failure, but can undergo involution at drug withdrawal.
From system of a hemopoiesis and lymphatic system
Seldom: thrombocytopenia
In some cases: leukopenia, hemolitic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia.
General disturbances
Allergic and pseudo-allergic reactions, such as itch, urticaria, skin rash are in rare instances possible. Such reactions can turn into heavy reactions with short wind, a sharp lowering of arterial pressure which can sometimes progress up to an acute anaphylaxis. At emergence of symptoms of a small tortoiseshell it is necessary to see a doctor immediately.
In some cases there can be a decrease in serumal concentration of sodium, an allergic vasculitis, a photosensitization.

Interaction with other medicines:

Glimepirid is metabolized by P4502C9 (CYP2C9) cytochrome that has to be considered at its simultaneous use with inductors (for example, rifampicin) or inhibitors (for example, флуконазол) CYP2C9.
Potentiation of hypoglycemic action and in certain cases the possible development of a hypoglycemia connected with it can be observed at a combination to one of the listed below drugs: insulin and other hypoglycemic means for intake, the inhibitors of an angiotensin-converting enzyme (APF), anabolic steroids and male sex hormones, chloramphenicol derivative of coumarin, cyclophosphamide, Disopyramidum, фенфлурамин, фенирамидол, fibrata, fluoxetine, гуанетидин, ифосфамид, inhibitors of a monoaminooxidase (MAO), флуконазол, p-aminosalicylic acid, пентоксифиллин (high parenteral doses), phenylbutazone, азапропазон, оксифенбутазон, пробенецид, hinolona, salicylates, Sulfinpyrazonum, кларитромицин, streptocides, tetracyclines, тритоквалин, трофосфамид.
Weakening of hypoglycemic action and the increase in concentration of glucose connected with it in blood can be observed at a combination to one of the listed below drugs:
acetazoleamide, barbiturates, glucocorticosteroids, diazoxide, diuretics, Epinephrinum and other sympathomimetic means, glucagon, purgatives (at prolonged use), niacin (in high doses), estrogen and progestogens, fenotiazina, Phenytoinum, rifampicin, iodinated hormones of a thyroid gland.
Blockers of H2-histamine receptors, beta adrenoblockers, clonidine and Reserpinum are capable, both to strengthen, and to weaken hypoglycemic action of a glimepirid.
Under the influence of sympatholytics, such as beta adrenoblockers, a clonidine, гуанетидин and Reserpinum, signs of adrenergic counterregulation in response to a hypoglycemia can decrease or be absent.
Against the background of reception of a glimepirid strengthening or weakening of action of derivatives of coumarin can be observed.
Single or chronic alcohol intake can both strengthen, and to weaken hypoglycemic action of a glimepirid.

Contraindications:

- Diabetes mellitus of 1 type.
- Diabetic ketoacidosis, diabetic prekoma and coma.
- Hypersensitivity to a glimepirid or to any excipient of drug, to other derivatives of sulphonylurea or to other sulfanamide drugs (risk of development of reactions of hypersensitivity).
- Heavy abnormal liver functions (lack of clinical experience of use).
- Heavy renal failures, including, at the patients who are on a hemodialysis (lack of clinical experience of use).
- Pregnancy and period of a lactation.
- Children's age (lack of clinical experience of use).
- Rare hereditary diseases, such as intolerance of a galactose, insufficiency of lactase or glyukozo-galaktozny malabsorption.
With care
- In the first weeks of treatment (increases risk of development of a hypoglycemia).
- With risk factors for development of a hypoglycemia (see the section "Special Instructions", dose adjustment of a glimepirid or all therapy can be required).
- At intercurrent diseases during treatment or at change of a way of life of patients (change of a diet and time of meal, increase or reduction of physical activity).
- At insufficiency glyukozo-6-fosfatdegidrogenazy.
- At disturbances of absorption of food and medicines in digestive tract (intestinal impassability, intestines paresis).
Use during pregnancy and a lactation
Glimepirid is contraindicated to use for pregnant women. In case of the planned pregnancy or at pregnancy approach the woman should be transferred to an insulin therapy.
Glimepirid gets into breast milk therefore it cannot be accepted during feeding by a breast. In this case it is necessary to pass to an insulin therapy or to stop feeding by a breast.

Overdose:

Overdose symptoms
The acute overdose, and also prolonged treatment by too high doses of a glimepirid can lead to development of a heavy life-threatening hypoglycemia.
Overdose treatment
As soon as the overdose is found, it is necessary to report about it to the doctor immediately. The hypoglycemia can be almost always quickly stopped by immediate reception of carbohydrates (glucose or a piece of sugar, sweet fruit juice or tea). In this regard the patient has to have always at himself not less than 20 g of glucose (4 pieces of sugar). Sweeteners are inefficient in treatment of a hypoglycemia.
Until, until the doctor decides that the patient is out of danger, the patient needs careful medical observation. It is necessary to remember that the hypoglycemia can renew after initial recovery of concentration of glucose in blood.

If the patient suffering from a diabetes mellitus is treated by different doctors (for example, during stay in hospital after accident, at a disease on the weekend), he has to report surely to them about the disease and about the previous treatment.
Hospitalization of the patient, at least even as a precautionary measure can sometimes be required. The considerable overdose and heavy reaction with such manifestations as a loss of consciousness or other serious neurologic violations are medical medical emergencies and demand immediate treatment and hospitalization.
In case of unconsciousness of the patient intravenous administration of strong solution of a dextrose (glucose) is necessary (for adults, since 40 ml of 20% of solution). As an alternative the adult perhaps intravenous, hypodermic or intramuscular administration of a glucagon, for example in a dose of 0,5-1 mg.
At treatment of a hypoglycemia owing to accidental administration of drug of Amaril® by babies or children of younger age the dose of the entered dextrose has to be adjusted carefully from the point of view of possibility of a dangerous hyperglycemia and introduction of a dextrose has to be carried out under constant control of concentration of glucose to blood.
At overdose of the drug Amaril® carrying out a gastric lavage and reception of absorbent carbon can be required.
After bystry recovery of concentration of glucose in blood it is necessary performing intravenous infusion of solution of a dextrose in lower concentration for prevention of resuming of a hypoglycemia. Concentration of glucose in blood at such patients has to be controlled constantly within 24 hours. In hard cases with a long current of a hypoglycemia danger of decrease in concentration of glucose in blood to hypoglycemic level can remain within several days.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children. List B. Period of validity 3 years.
Not to use after the period of validity specified on packaging. Issue conditions from drugstores On the recipe.

Issue conditions:

According to the recipe

Packaging:

Tablets 1 of mg, 2 mg, 3 mg, 4 mg.
On 15 tablets in the blister from PVC / aluminum foil. On 2, 4, 6 or 8 blisters together with the application instruction in a cardboard pack.