Glimepirid

General characteristics. Structure:

Active agent: глимепирид - 2 mg or 3 mg.

Excipients: lactose (sugar milk), cellulose microcrystallic, starch prezhelatinizirovanny, sodium lauryl sulfate, magnesium stearate, sunset dye yellow E110 *, dye quinolinic yellow water-soluble E104.

Pharmacological properties:

Pharmacodynamics. Glimepirid represents hypoglycemic drug for oral administration - derivative generation sulphonylurea III.

Glimepirid acts, mainly, stimulating secretion and release of insulin from pancreas beta cells (pancreatic action). As well as at other derivatives of sulphonylurea, this effect increase in reaction of beta cells of a pancreas at physiological stimulation by glucose is the cornerstone, at the same time the amount of the cosecreted insulin is much less, than at effect of traditional drugs - sulphonylurea derivatives. The smallest stimulating influence of a glimepirid on secretion of insulin provides also smaller risk of development of a hypoglycemia. In addition to it, глимепирид possesses extra pancreatic action - ability to improve sensitivity of peripheral fabrics (muscular, fatty) to effect of own insulin, to reduce insulin absorption by a liver; inhibits products of glucose in a liver. Glimepirid selectively inhibits cyclooxygenase and reduces transformation of arachidonic acid into A2 thromboxane which promotes aggregation of thrombocytes, thus having antitrombotichesky effect.

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, it promotes anti-atherogenous effect of drug.

Glimepirid increases the level of endogenous a-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 of type 2.

Pharmacokinetics. At multiple dose of a glimepirid in a daily dose of 4 mg the maximum concentration in blood serum (Cmax) is reached approximately in 2,5 hours and makes 309 ng/ml; there is a linear ratio between a dose and Cmax, and also between a dose and AUC (the area under a curve "concentration time"). At intake of a glimepirid its bioavailability makes 100%. 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 degree of protein-binding (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% and through intestines - 35%. Not changed substance in urine was not found. The elimination half-life at the plasma concentration of drug in serum corresponding to the repeated mode of dosing makes 5-8 hours. After reception of high doses the elimination half-life increases a little.

In urine and excrements two inactive metabolites most of which likely 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. Drug badly gets through a blood-brain barrier.

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 drug owing to its lower linkng with protein. Thus, this category of patients does not have an additional risk of cumulation of drug.

Indications to use:

Drug is shown for treatment of a diabetes mellitus 2 types at inefficiency of earlier appointed diet and exercise stress.
At inefficiency of monotherapy glimepiridy, its use in a combination therapy with Metforminum or with insulin is possible.

Route of administration and doses:

Drug is used inside. The initial and supporting doses of a glimepirid are established individually on the basis of results of regular control of concentration of glucose in blood.

Initial dose and selection of a dose
In an initiation of treatment appoint 1 mg of a glimepirid once a day. At achievement of optimum therapeutic effect it is recommended to accept this dose as supporting.
In case of lack of glycemic control, the daily dose has to be step by step increased under regular control of concentration of glucose in blood (bucketed in 1-2 weeks) to 2 mg, 3 mg or 4 mg a day. Doses over 4 mg a day are effective only in exceptional cases. The maximum recommended daily dose - 6 mg.

Time and frequency rate of reception of a daily dose is defined by the doctor with a way of life of the patient. The daily dose is appointed in one step just before or during a big breakfast, or the first main meal. A pill of a glimepirid is taken entirely, without chewing, with enough liquid (about 0,5 glasses). It is not recommended to miss meal after the use of a glimepirid.

Treatment duration
Treatment glimepiridy long, under control of content of glucose in blood and urine.

Use in a combination with Metforminum
In case of lack of glycemic control at the patients accepting Metforminum the accompanying therapy glimepiridy can be begun. At preservation of a dose of Metforminum at the previous level treatment glimepiridy begins with the minimum dose, and then the dose gradually increases depending on the desirable level of glycemic control, up to the maximum daily dose. The combination therapy has to be carried out under careful medical observation.

Use in a combination with insulin
In cases when it is not possible to reach glycemic control by reception of the maximum dose of a glimepirid in monotherapy or in a combination with the maximum dose of Metforminum, the combination of a glimepirid with insulin is possible. 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 the minimum dose, with possible subsequent gradual increase in its dose under control of concentration of glucose in blood. The combined treatment demands obligatory medical control.

Transfer of the patient from other peroral hypoglycemic drug on глимепирид
At transfer of the patient from other peroral hypoglycemic drug on глимепирид the initial daily dose of the last has to make 1 mg (even if the patient is transferred on глимепирид from the maximum dose of other peroral hypoglycemic drug). Any increase in a dose of a glimepirid should be carried out step by step according to the stated above recommendations. It is necessary to take efficiency, a dose and duration of action of the used hypoglycemic means into account. In certain cases, especially at reception of hypoglycemic drugs with a big elimination half-life (for example, Chlorproramidum) there can be a need in temporary (within several days) the termination of treatment in order to avoid the additive effect increasing risk of development of a hypoglycemia.

Transfer of the patient from insulin on глимепирид
In exceptional cases, when performing insulin therapy at patients with a diabetes mellitus of type 2, at compensation of a disease and at safe secretory function of b-cells of a pancreas, insulin replacement glimepiridy is possible. Transfer has to be carried out under careful observation of the doctor. At the same time transfer of the patient on глимепирид is begun with the minimum dose in 1 mg.

Features of use:

Glimepirid it is necessary to accept in the recommended doses and in due time. Mistakes in drug use, for example, the admission of reception, it is never impossible to eliminate by means of the subsequent reception of higher dose. The doctor and the patient have to discuss in advance measures which should be accepted in case of such mistakes (for example, the admission of administration of drug or meal) or in situations when reception of the next dose of drug at the scheduled time is impossible. The patient has to inform immediately the doctor in case of reception of too high dose of drug.

Development of a hypoglycemia in the patient after reception of 1 mg of a glimepirid a day means a possibility of control of a glycemia only by means of a diet.
At achievement of compensation of a diabetes mellitus of type 2 sensitivity to insulin increases. In this regard in the course of treatment the need for a glimepirida can decrease. In order to avoid development of a hypoglycemia it is necessary to reduce temporarily a dose or to cancel глимепирид. Dose adjustment has to be carried out also at change of body weight of the patient, his way of life, or at emergence of other factors promoting increase in risk of development hypo - or a hyperglycemia.

The adequate diet, regular and sufficient physical exercises and, if necessary, decrease in body weight have the same importance for achievement of optimum control of level of glucose in blood, as well as regular reception of a glimepirid.

Clinical symptoms of a hyperglycemia are: increase in frequency of urinations, strong thirst, dryness in a mouth and dryness of integuments.

In the first weeks of treatment the risk of development of a hypoglycemia can increase that demands especially careful observation of the patient. Against the background of treatment glimepiridy at irregular meal or the admission of meal the hypoglycemia can develop. Its possible symptoms are: a headache, feeling of hunger, nausea, vomiting, feeling of fatigue, drowsiness, sleep disorders, concern, aggression, disturbances of concentration of attention and reaction, a depression, confusion of consciousness, speech and visual frustration, aphasia, a tremor, paresis, touch disturbances, dizziness, self-checking loss, a delirium, cerebral spasms, confusion or a loss of consciousness, including coma, shallow breathing, bradycardia. Besides, such symptoms as a cold, clammy sweat, concern, tachycardia, increase in arterial pressure, stenocardia and disturbances of a cordial rhythm can result from an adrenergic feedback mechanism.

Treat the factors promoting development of a hypoglycemia:
· unwillingness or (especially at advanced age) insufficient ability of the patient to cooperation with the doctor;
· defective, irregular food, admission of meals, starvation, change of a usual diet;
· an imbalance between an exercise stress and consumption of carbohydrates;
· alcohol intake, especially in combination with the admission of meal;
· renal failure;
· heavy abnormal liver function;
· overdose of a glimepirid;
· some noncompensated diseases of endocrine system exerting impact on carbohydrate metabolism (for example, dysfunctions of a thyroid gland, pituitary insufficiency or insufficiency of bark of adrenal glands);
· simultaneous use of some other medicines (see the section "Interaction with Other Medicines").
The doctor has to be informed on the factors stated above and on hypoglycemia episodes as they demand especially strict observation of the patient. In the presence of such factors increasing risk of development of a hypoglycemia it is necessary to correct a dose of a glimepirid or all scheme of treatment. It needs to be made also in case of an intercurrent disease or change of a way of life of the patient.

Symptoms of a hypoglycemia can be maleficiated or be absent absolutely at elderly, at the patients having vegetative neuropathy or receiving simultaneous treatment by b-adrenoblockers, a clonidine, Reserpinum, guanetidiny or other sympatholytics. The hypoglycemia can be almost always quickly stopped by immediate reception of carbohydrates (glucose or sugar, for example, in the form of 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.

From experience of use of other drugs of sulphonylurea it is known that despite initial success of stopping of a hypoglycemia, its recurrence is possible. In this regard, continuous and careful observation of the patient is necessary. The heavy hypoglycemia demands immediate treatment under observation of the doctor, and under certain circumstances and hospitalization of the patient.

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.

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).

In stressful situations (for example, at an injury, surgical intervention, infectious diseases which are followed by fever) there can be a need for temporary transfer of the patient on an insulin therapy.

There is no experience of use of a glimepirid for patients with heavy abnormal liver functions and kidneys or the patients who are on a hemodialysis. And a liver transfer into an insulin therapy is shown to patients with heavy renal failures.

During treatment glimepiridy regular control of concentration of glucose in blood, and also concentration of glikozilirovanny hemoglobin is necessary.

Influence on ability to manage motor transport and other mechanisms

In an initiation of treatment, upon transition from one medicine to another, or at irregular reception of a glimepirid can take place caused hypo - or a hyperglycemia, decrease in concentration of attention and speed of psychomotor reactions of the patient. It can have an adverse effect on ability to control of motor transport or to control of various cars and mechanisms.

Side effects:

From a metabolism: development of hypoglycemic reactions is in rare instances possible. These reactions, mainly, arise soon after administration of drug, can have a severe form and a current and they not always manage to be stopped easily. Approach of these symptoms depends on individual factors, such as feeding habits and dosing.

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.

From system of digestive organs: nausea, vomiting, heavy feeling or discomfort in the epigastriums, abdominal pains, diarrhea which are very seldom leading to the treatment termination can sometimes be noted; in rare instances - increase in activity of "liver enzymes", a cholestasia, jaundice, hepatitis (up to development of a liver failure).

From system of a hemopoiesis: thrombocytopenia (from moderated to heavy), a leukopenia, hemolitic or aplastic anemia, an erythrocytopenia, a granulocytopenia, an agranulocytosis and a pancytopenia is seldom possible.

Allergic reactions: emergence of a small tortoiseshell (an itch, skin rash) is sometimes possible. Such reactions happen, as a rule, moderately expressed, but can progress, being followed by falling of arterial pressure, диспноэ, up to development of an acute anaphylaxis. At emergence of a small tortoiseshell it is necessary to see a doctor immediately. The cross allergy with other derivatives of sulphonylurea, streptocides is possible, development of an allergic vasculitis is also possible.

Other side effects: development of headaches, an adynamy, a hyponatremia, a photosensitization, a late skin porphyria is in exceptional cases possible.

Separate side effects (heavy hypoglycemia, serious changes of a picture of blood, heavy allergic reactions, liver failure), can represent under certain circumstances threat for the patient's 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.

Interaction with other medicines:

Simultaneous use of a glimepirid with some medicines can cause both strengthening, and weakening of hypoglycemic effect of drug. Therefore other medicines can be accepted only after approval of the doctor.

Strengthening of hypoglycemic action and, the connected with it, possible development of a hypoglycemia can be observed at simultaneous use of a glimepirid with the insulin, metformin or other peroral hypoglycemic drugs, inhibitors of an angiotensin-converting enzyme (APF), Allopyrinolum, anabolic steroids and male sex hormones, chloramphenicol derivative of coumarin, cyclophosphamide, trofosfamidy and ifosfamidy, fenfluraminy, fibrata, fluoxetine, sympatholytics (guanetidiny), inhibitors of a monoaminooxidase (MAO), Miconazolum, pentoksifilliny (at parenteral administration in high doses), phenylbutazone, azapropazony, oksifenbutazony, probenetsidy, hinolonovy antibiotics, salicylates and aminosalicylic acid, Sulfinpyrazonum, some streptocides of the prolonged action, tetracyclines, tritokvaliny, flukonazoly.

Weakening of hypoglycemic action, and the increase in concentration of glucose connected with it in blood, can be observed at simultaneous use of a glimepirid with acetazoleamide, barbiturates, glucocorticosteroids, diazoxide, saluretics, thiazide diuretics, Epinephrinum and other sympathomimetic means, a glucagon, purgatives (at prolonged use), niacin (in high doses) and niacin derivatives, estrogen and progestogens, fenotiazina, Chlorpromazinum, Phenytoinum, rifampicin, hormones of a thyroid gland, lithium salts.

Blockers of H2-histamine receptors, clonidine and Reserpinum are capable both to potentsiirovat, and to weaken hypoglycemic action of a glimepirid.

Under the influence of such sympatholytics as b-adrenoblockers, a clonidine, гуанетидин and Reserpinum, easing or lack of clinical signs of a hypoglycemia is possible.

Against the background of reception of a glimepirid strengthening or weakening of action of derivatives of coumarin can be observed.

At simultaneous use with the medicines oppressing a marrowy hemopoiesis the risk of a miyelosupressiya increases.

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;
• the states which are followed by disturbance of absorption of food and development of a hypoglycemia (infectious diseases);
• leukopenia;
• heavy abnormal liver functions;
• heavy renal failures (including the patients who are on a hemodialysis);
• hypersensitivity to a glimepirid or to any inactive component of drug, to other derivatives of an ulfonilmochevina or to sulfanamide drugs (risk of development of reactions of hypersensitivity);
• lactose intolerance, lactose intolerance, glyukozo-galaktozny malabsorption;
• pregnancy and lactation;
• children's age up to 18 years.

With care
The states demanding transfer of the patient into an insulin therapy: extensive burns, severe multiple injuries, big surgical interventions, and also disturbances of absorption of food and medicines in digestive tract - intestinal impassability, stomach paresis etc.

Use at pregnancy and during feeding by a breast
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.
As глимепирид, apparently, gets into breast milk, women should not appoint it in the period of a lactation. In that case, it is necessary to pass to an insulin therapy or to stop feeding by a breast.

Overdose:

After intake of a high dose of a glimepirid development of a hypoglycemia, lasting from 12 till 72 o'clock which can repeat after initial recovery of concentration of glucose in blood is possible. Observation in the conditions of a hospital is in most cases recommended. There can be sweating strengthening, feeling of alarm, tachycardia, increase in arterial pressure, a heart consciousness, pains in heart, arrhythmia, a headache, dizziness, sharp increase in appetite, nausea, vomiting, apathy, drowsiness, concern, aggression, disturbance of concentration of attention, a depression, confusion of consciousness, a tremor, paresis, disturbance of sensitivity, a spasm of the central genesis. The clinical picture of a hypoglycemia can sometimes remind a stroke. Development of a coma is possible.

Treatment includes induction of vomiting, plentiful drink with absorbent carbon (adsorbent) and sodium pikosulfaty (laxative). At reception of a large amount of drug the gastric lavage, with the subsequent administration of sodium of a pikosulfat and absorbent carbon is shown. As soon as possible begin introduction of a dextrose, in need of a type of intravenous jet administration of 50 ml of 40% of solution, with the subsequent infusional introduction of 10% of solution, with careful monitoring of concentration of glucose in blood. Further treatment has to be symptomatic.

At treatment of the hypoglycemia which developed owing to accidental reception of a glimepirid by chest or small children to avoid a hyperglycemia, it is necessary to control a dextrose dose (50 ml of 40% of solution) and to continuously monitorirovat concentration of glucose in blood.

Storage conditions:

List B. At a temperature not above 25 °C.
To store in the place, unavailable to children!

Issue conditions:

According to the recipe

Packaging:

Tablets of 2 mg and 3 mg.
On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
3, 6 or 10 planimetric packagings together with the application instruction in a pack from a cardboard.