Amaryl - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 68.975 mg, sodium carboxymethyl starch (type A) - 4,000 mg, povidone 25,000 - 0.500 mg, cellulose microcrystalline - 10,000 mg, magnesium stearate - 0,500 mg, iron dye red oxide (E 172) - 0.025 mg.

In one tablet Amaryl® 2 mg

contains:

active substance - 2 mg of glimepiride;

Excipients: lactose monohydrate - 137,200 mg, sodium carboxymethyl starch (type A) - 8,000 mg, povidone 25,000 to 1,000 mg, cellulose microcrystalline - 20,000 mg, magnesium stearate - 1,000 mg, iron dye oxide yellow (E 172) - 0.400 mg, and idigicarbine (E 132) - 0.400 mg.

In one tablet, Amaryl® 3 mg

contains:

active substance - 3 mg of glimepiride;

Excipients: lactose monohydrate - 136,950 mg. sodium carboxymethyl starch (type A) - 8,000 mg, povidone 25,000 to 1,000 mg. cellulose microcrystalline - 20,000 mg, magnesium stearate - 1,000 mg, coloring agentThe iron oxide is yellow (E 172) 0.050 mg.

In one tablet Amaryl® 4 mg

contains:

active substance 4 mg of glimepiride;

Excipients: lactose monohydrate 135.850 mg, sodium carboxymethyl starch (type A) 8,000 mg, povidone 25,000 to 1,000 mg, microcrystalline cellulose 20,000 mg, magnesium stearate 1,000 mg, and idigicar- minine (E 132) -0.150 mg.

Description:

Amaryl® 1 mg: tablets are pink, oblong, flat with a separating risk on both sides. Engraving NMK and a stylized "d" on both sides.

Amaryl® 2 mg: tablets are green, oblong, flat with separating risk on both sides. Engraving NMM and a stylized "d" on both sides.

Amaryl® 3 mg: pale yellow tablets, oblong, flat with separating risk on both sides. Engraving NMN and stylized "A" on both sides.

Amaryl® 4 mg: blue tablets, oblong, flat with a separating risk on both sides. Engraving NMO and stylized "A" on both sides.

Pharmacotherapeutic group:hypoglycemic agent for oral use of the sulfonylurea group of the third generation

ATX: & nbsp

A.10.B.B.12 Glimepiride

Pharmacodynamics:

Glimepiride reduces the concentration of glucose in the blood, mainly by stimulating the release of insulin from the beta cells of the pancreas. Its effect is mainly associated with improving the ability of beta cells of the pancreas to respond to physiological stimulation with glucose. Compared to glibenclamide, taking low doses of glimepiride causes the release of less insulin when the blood glucose concentration is approximately the same.This fact is evidenced in use of glimepiride extrapancreatic hypoglycemic effects (increase of tissue sensitivity to insulin and insulinomimetic Effect).

Secretion of insulin

Like all other derivatives sulfonylureas, glimepiride regulates the secretion of insulin for account of interaction with ATP-sensitive potassium channels on the membranes of beta cells. AT difference from other derivatives sulfonylureas glimepiride selectively binds to a protein with molecular weight of 65 kilodaltons (kDa), located in membranes beta cells of the pancreas.

This interaction of glimepiride with binding protein regulates the opening or closing ATP-sensitive potassium channels.

Glimepiride closes potassium channels. This causes depolarization beta cells and leads to the discovery of voltage-sensitive calcium channels and calcium intake inside the cell. As a result, an increase in the intracellular calcium concentration activates the secretion of insulin by exocytosis. Glimepiride much faster and, accordingly, more often enters into a bond and is released from the bond with the protein that binds it, than glibenclamide. It is suggested that this property of a high rate of exchange of glimepiride with the protein binding to it causes its pronounced effect of sensitizing beta cells to glucose and their protection against desensitization and premature exhaustion.

The effect of increasing the sensitivity of tissues to insulin Glimepiride enhances insulin effects on glucose uptake by peripheral tissues.

Insulinomimetic effect

Glimepiride has effects similar to insulin effects on glucose uptake by peripheral tissues and glucose output from the liver.

Absorption of glucose peripheral tissues is carried out by transport inmuscle cells and adipocytes. Glimepiride directly increases number of transporting glucose molecules in plasma membranes of muscle cells and adipocytes. Increase in revenue inside the glucose cells leads to activation glycosylphosphatidylinositol-specific phospholipase C. The result of this intracellular the concentration of calcium is reduced, causing a decrease in activity protein kinase A, which in turn leads to stimulation of metabolism glucose. Glimepiride inhibits the yield of gLycoses from the liver by increasing The concentration of fructose-2,6-bisphosphate, which inhibits gluconeogenesis.

Effect on platelet aggregation

Glimepiride reduces platelet aggregation in vitro and in vivo. This The effect appears to be related to selective inhibition cyclooxygenase, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor.

Anti-atherogenic action preparation

Glimepiride promotes the normalization of lipid content, reduces the content of malonic aldehyde in the blood, which leads to a significant reduction in peroxide oxidation of lipids. In animals glimepiride leads to a significant decrease in the formation of atherosclerotic plaques.

Decrease in severity oxidative stress, which is constantly present in patients with type 2 diabetes mellitus. Glimepiride increases the content of endogenous alpha-tocopherol, catalase activity, glutathione peroxidase and superoxide dismutase.

Cardiovascular Effects

Through ATP-sensitive potassium channels (see above) sulfonylureas derivatives also have an effect on the cardiovascular system. Compared with traditional derivatives sulfonylureas, glimepiride significantly less effect on cardiovascular system, which can be explained specific nature of its interaction with the protein of ATP-sensitive potassium channels.

In healthy volunteers minimum effective dose glimepiride is 0.6 mg. The effect of glimepiride is dose-dependent and reproducible.

Physiological response to physical activity (decrease secretion of insulin) upon admission glimepiride is retained.

There are no significant differences in effect depending on whether taken the drug 30 minutes before a meal or just before eating. Have patients with diabetes mYou can achieve sufficient metabolic control during 24 hours with a single admission preparation. Moreover, in the clinical study in 12 out of 16 patients with renal insufficiency (clearance creatinine 4-79 ml / min) was also sufficient metabolic control.

Combined therapy with metformin

In patients with insufficient metabolic control application of the maximum dose glimepiride, can be started combination therapy glimepiride and metformin. AT two studies combination therapy was improved metabolic control in comparison with that at treatment of each of these drugs in isolation.

Combined therapy with insulin

In patients with insufficient metabolic control at maximum doses glimepiride can be started simultaneous therapy with insulin. Based on the results of two studies when using this combination the same improvement is achieved metabolic control, as in use of only one insulin; however, combined therapy requires a lower dose of insulin.

Use in children

There is insufficient data on long-term efficacy and safety of the drug in children.

Pharmacokinetics:

With repeated administration of glimepiride in a daily dose of 4 mg, the maximum concentration in the blood serum (Сmах) is reached after about 2.5 hours and is 309 ng / ml. There is a linear relationship between the dose and the maximum plasma concentration of glimepiride (Сmах), as well as between the dose and the area under the concentration-time curve (AUC). When ingested glimepiride, its absolute bioavailability is complete. Eating does not have a significant effect on absorption, except for a slight slowing of its speed. For glimepiride characterized by a very low volume of distribution (about 8.8 liters) approximately equal to the albumin distribution volume, a high degree of binding to plasma proteins (99%) and low clearance (about 48 ml / min). The average half-life, determined from serum concentrations under repeated administration, is approximately 5-8 hours. After taking high doses, there is a slight increase in half-life.

After a single glimepiride intake, 58% of the dose is excreted by the kidneys and 35% by the intestine. Unchanged glimepiride in the urine is not found.

In urine and feces, two metabolites, formed as a result of metabolism in the liver, were detected (mainly with the help of CYP2C9), one of them was a hydroxy derivative, and the other was a carboxy derivative. After ingestion of glimepiride, the terminal half-life of these metabolites was 3-5 hours and 5-6 hours, respectively.

Glimepiride is excreted in breast milk and penetrates the placental barrier.

Comparison of single and multiple (once daily) glimepiride did not reveal significant differences in pharmacokinetic parameters, and their very low variability among different patients was observed. There is no significant accumulation of the drug.

Pharmacokinetic parameters are similar in patients of different sex and different age groups. In patients with impaired renal function (with low creatinine clearance), there is a tendency to increase the clearance of glimepiride and to reduce its average serum concentrations, which is most likely due to a faster release of the drug due to its lower binding to the protein. Thus, in this category of patients there is no additional risk of cumulation of the drug.

Indications:

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

Contraindications:

Diabetes mellitus type 1.
Diabetic ketoacidosis, diabetic precoma and coma.
Hypersensitivity to glimepiride or to any auxiliary substance of the drug,to other derivatives of sulfonylureas or to other sulfanilamide preparations (risk of developing hypersensitivity reactions).
Severe liver dysfunction (lack of clinical experience).
Severe violations of kidney function, including in patients on hemodialysis (lack of clinical experience).
Pregnancy and lactation.
Childhood (lack of clinical experience).
Rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

In the first weeks of treatment (increased risk of hypoglycemia).
If there are risk factors for developing hypoglycemiaandand (see "Special instructions", it may be necessary to adjust the dose of glimepiride or the whole therapy).
With intercurrent illnesses during treatment or when changing the lifestyle of patients (changing diet and eating time, increasing or decreasing physical activity).
With insufficiency of glucose-6-phosphate dehydrogenase.
In violation of absorption of food and drugs in the gastrointestinal tract (intestinalobstruction, intestinal paresis).

Pregnancy and lactation:

Glimepiride is contraindicated for use in pregnant women. In the case of a planned pregnancy or at the onset of pregnancy, a woman should be transferred to insulin therapy.

Glimepiride penetrates into breast milk, so it can not be taken during breastfeeding. In this case, you need to switch to insulin therapy or stop breastfeeding.

Dosing and Administration:

As a rule, the dose of Amaril is determined by the target concentration glucose in the blood. Must Apply the smallest dose, sufficient to achieve necessary metabolic control.

During treatment with the drug Amaryl is needed regularly determine the concentration of glucose in blood. In addition, it is recommended regular level control glycosylated hemoglobin.

Incorrect drug intake, for example, skipping a regular dose, should never make up reception of a higher dose.

The patient's actions in case of mistakes when taking Amarilk (in In particular, if you miss a reception the next dose or when you pass food intake) or in situations where there is no possibility to take the drug, should be discussed by the patient and doctor in advance.

Reception of the drug Amaryl

Tablets of the drug Amaryl are taken without chewing, drinking down sufficient amount of liquid (about 0.5 cup). When need Amaryl tablets can be divided along the risks in two equal parts.

Initial dose and dose selection

The initial dose is 1 mg glimepiride 1 time per day. If necessary, the daily dose can be gradual (with intervals of 1-2 weeks) is increased. Increased dose is recommended conduct under regular supervision concentration of glucose in the blood and in the next step dose increase: 1 mg - 2 mg - 3 mg - 4 mg - 6 mg (-8 mg).

The range of doses in patients with good controlled diabetes mellitus

Usually the daily dose in patients with a well-controlled sugar diabetes is 1-4 mg glimepiride. Daily dose is more 6 mg is more effective only a small amount patients.

Dosing regimen

The time of taking Amaril and dose distribution during the day established by a doctor, in depending on lifestyle the patient at a given time (time food intake, the number of physical loads).

Usually, a single dose of Amaril is sufficient for a day.

It is recommended that in this case the entire dose of Amaril was taken immediately before full breakfast or in case, if it was not accepted at this time, - just before the first the main meal.

It is very important after taking the Amaryl tablets not to miss food intake.

Since the improvement of metabolic control is associated with increased sensitivity to insulin, during treatment can reduce the need for glimepiride. In order to avoid the development of hypoglycemia it is necessary to reduce theor stop taking Amaril.

The states under which the dosage adjustment is required glimepiride:

- reduction in body weight in the patient;

- changes in the patient's lifestyle (changing diet, taking time food, the number of physical loads);

- the emergence of other factors, which lead to predisposition to development hypoglycemia or hyperglycemia (see section "Special instructions").

Duration of treatment

Treatment with glimepiride usually is carried out for a long time.

Transfer the patient from admission another hypoglycemic agent for ing in drug intake Amaryl

There is no exact relation between doses of Amaril and other hypoglycemic agents for oral administration. When another hypoglycemic agent for ingestion is replaced by the drug Amaryl, it is recommended that the procedure for its appointment was same as with the original administration of Amaril, then there is a cure should start with initial dose of 1 mg (even case, if the patient is transferred to Amaril with a maximum dose of another hypoglycemic preparation for oral administration). Any an increase in the dose should be step by step, taking into account the response to glimepiride, according to above recommendations.

It is necessary to consider the strength and duration of effect preceding hypoglycemic agent for reception inside. It may be required interruption of treatment in order to avoid any summation effects that can increase risk of developing hypoglycemia.

Application in combination with metformin

Patients with insufficient controlled diabetes mellitus when receiving the maximum daily allowance doses of either glimepiride or metformin can be started treatment combination of these two drugs.

At the same time, the earlier treatment with glimepiride, or metformin continues on same level of doses, and additional metformin or glimepiride begin with a low dose, which is then titrated in depending on the target level metabolic control up to of the maximum daily dose.

Combined therapy should start under strict medical observation.

Application in combination with insulin

Patients with insufficient controlled diabetes mellitus when receiving the maximum daily allowance doses of glimepiride may be At the same time, an administration insulin. In this case, the last prescribed dose glimepiride remains unchanged.

In this case, treatment with insulin begins with low doses that gradually increase control of glucose concentration in blood. Combined treatment requires a thorough medical observation.

Use in patients with renal disease insufficiency

There is a limited number of information on use Amarilk in patients with renal insufficiency.

Patients with impaired function kidneys can be more sensitive to hypoglycemic effect of glimepiride (see Sections "Pharmacokinetics", "Contraindications").

Use in patients with hepatic insufficiency

There is a limited number of information on use Amaril for hepatic insufficiency (see "Contraindications").

Use in children

Data on the use of Amaril in children is not enough.

Side effects:

Violations from the exchange substances

As a result of hypoglycemic action of the drug Amaryl may develop hypoglycemia, which, like and when other sulfonylurea derivatives, can be prolonged. Symptoms of hypoglycemia are: headache, hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, anxiety, aggressiveness, violation of concentration, vigilance and speed of reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, paresis, sensory disorders, dizziness, loss self-control, delirium, cerebral cramps, doubt or loss consciousness up to coma, shallow breathing, bradycardia. In addition, there may be manifestations of adrenergic counter-regulation in response to hypoglycemia, such as the appearance of cold sticky sweat, anxiety, tachycardia, enhancement arterial pressure, angina pectoris, heart palpitations and disorders heart rate. The clinical picture is severe hypoglycemia may be similar to stroke.

Symptoms of hypoglycemia are almost always disappear after its elimination.

Violations by the body view

During treatment (especially in his beginning) can be observed transient vision disorders, caused by change concentration of glucose in the blood. Their the reason is temporary Change in the swelling of the lens, dependent on the concentration of glucose in blood, and due to this change the refractive index of the lens.

Disorders from the gastro-intestinal tract

In rare cases: nausea, vomiting, feeling of heaviness or overflow in epigastrium, abdominal pain, diarrhea. In some cases: hepatitis, increased activity "hepatic" enzymes and / or cholestasis and jaundice that can progress to a menacing life of hepatic insufficiency, but may undergo the reverse development when the drug is withdrawn.

Violations from the blood and lymphatic system

Rarely: thrombocytopenia In some cases: leukopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia.

In post-marketing use of the drug, cases of severe thrombocytopenia with a platelet count of less than 10,000 / μl and thrombocytopenic purpura (frequency unknown) have been reported.

Immune system disorders

In rare cases, allergic and pseudo-allergic reactions, such as pruritus, urticaria, skin rash, are possible. Such reactions are almost always of an easy form, but can turn into severe reactions with shortness of breath, a sharp decrease in blood pressure, which sometimes progresses down to anaphylactic shock.When symptoms of urticaria appear, consult a doctor immediately. In some cases, there may be a decrease in serum sodium concentrations, allergic vasculitis, photosensitivity.

Overdose:

Overdose Symptoms

Acute overdose, as well as long-term treatment with too high doses of glimepiride, can lead to the development of severe life-threatening hypoglycemia.

Treatment of overdose

As soon as an overdose is detected, the doctor should be informed immediately. Hypoglycemia can almost always be quickly stopped by the immediate intake of carbohydrates (glucose or a piece of sugar, sweet fruit juice or tea). In this regard, the patient should always have at least 20 grams of glucose (4 pieces of sugar). Sugary substitutes are ineffective in the treatment of hypoglycemia.

Until the doctor decides that the patient is out of danger, the patient needs careful medical supervision. It should be remembered that hypoglycemia may resume after initial recovery of blood glucose.

If a patient suffering from diabetes mellitus is treated by different doctors (for example,during a hospital stay after an accident, with a disease on the weekend), he must necessarily inform them about his illness and about the previous treatment.

Sometimes the patient may need to be hospitalized, even if only as a precaution. Significant overdose and severe reactions with such manifestations as loss of consciousness or other serious neurological disorders are urgent medical conditions and require immediate treatment and hospitalization.

In the unconscious state of the patient, intravenous administration of a concentrated solution of dextrose (glucose) (for adults, starting with 40 ml of a 20% solution) is necessary. As an alternative to adults, intravenous, subcutaneous or intramuscular glucagon administration, for example at a dose of 0.5-1 mg, is possible.

In the treatment of hypoglycemia due to the accidental administration of Amaril® to infants or young children, the dose of dextrose administered should be carefully adjusted from the standpoint of the possibility of dangerous hyperglycemia and the administration of dextrose should be carried out under a constant control of the concentration of glucose in the blood.

In case of an overdose of Amaril®, it may be necessary to perform gastric lavage and receive activated charcoal.

After a rapid recovery of the blood glucose concentration, an intravenous infusion of dextrose solution at a lower concentration is necessary to prevent the resumption of hypoglycemia. The concentration of glucose in the blood in these patients should be constantly monitored within 24 hours. In severe cases with prolonged course of hypoglycemia, the risk of lowering blood glucose levels to the hypoglycemic level may persist for several days.

Interaction:

Glimepiride metabolized by cytochrome P4502S9 (CYP2C9), what should be taken into account in its simultaneous application with inducers (for example, rifampicin) or inhibitors (eg, fluconazole) CYP2C9. Potentiation of hypoglycemic actions and in some cases the possible development hypoglycemia can be observed with combination with one of the listed below preparations: Insulin and other hypoglycemic means for ingestion, inhibitors angiotensin-converting enzyme (ACE), anabolic steroids and male genital hormones, chloramphenicol, derivatives of coumarin, cyclophosphamide, disopyramide, fenfluramine, pheniramidol, fibrates, fluoxetine, guanethidine, ifosfamide, inhibitors monoamine oxidase (MAO), fluconazole, para-aminosalicylic acid, pentoxifylline (high parenteral doses), phenylbutazone, azapropazon, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, tritokvaline, trophosfamide. Weakening of hypoglycemic action and, associated with this increase in the concentration of glucose in the blood, can be observed when combined with one of the following drugs: acetazolamide, barbiturates, glucocorticosteroids, diazoxide, diuretics, epinephrine and other sympathomimetic facilities, glucagon, laxatives (with prolonged application), a nicotinic acid (in high doses), estrogens and progestogens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones.

Blockers of H2-histamine receptors, beta-blockers, clonidine and reserpine are capable of amplify hypoglycemic action glimepiride.

Under the influence of sympatholytic means, such as beta-adrenoblockers, clonidine, guanethidine and reserpine, signs adrenergic counterregulation in response to hypoglycemia may diminished or absent.

Against the background of glimepiride there is an increase or weakening of derivatives coumarin.

Single or chronic alcohol use can both amplify hypoglycemic action glimepiride.

Sequestants of bile acids: kolesevelam binds with glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. In the case of using glimepiride, at least 4 hours before the administration of colevelam, no interaction is observed. therefore glimepiride must be taken at least 4 hours prior to the intake of Wheezevelum.

Special instructions:

In special clinical stress conditions such as trauma, surgery, infection with febrile temperature, metabolic control may worsen in patients with diabetes mellitus, and they may need a temporary transfer to insulin therapy to maintain adequate metabolic control.

In the first weeks of treatment, the risk of developing hypoglycemia may increase, and therefore at this time a particularly careful control of the concentration of glucose in the blood is required.

Factors that contribute to the risk of developing hypoglycemia include:

unwillingness or inability of the patient (more often observed in elderly patients) to cooperate with a doctor;
malnutrition, irregular eating or skipping meals;
an imbalance between exercise and carbohydrate intake;
changing diet;
alcohol consumption, especially when combined with meals;
severe renal dysfunction;
severe impairment of liver function (in patients with severe impairment of liver function, a transfer to insulin therapy is indicated, at least until metabolic control is achieved).
an overdose of glimepiride;
Some decompensated endocrine disorders that disrupt carbohydrate metabolism or adrenergic counterregulation in response to hypoglycemia (eg, some disorders of the thyroid gland and anterior pituitary gland, adrenocortical insufficiency);
concomitant use of certain medicines.section "Interaction with other drugs";
reception glimepirida in the absence of indications for its reception.

Treatment with derivatives of sulfonylurea, which includes glimepiride, can lead to the development of hemolytic anemia, therefore, in patients with glucose-6-phosphate dehydrogenase deficiency, special care should be taken when prescribing gliipyride and it is better to use hypoglycemic agents that are not derivatives of sulfonylurea.

In case of presence of the above-listed risk factors for the development of hypoglycemia, a dose adjustment of glimepiride or the whole therapy may be required. This also applies to the occurrence of intercurrent illnesses during treatment or a change in the lifestyle of patients.

Those symptoms of hypoglycemia that reflect adrenergic counter-regulation of the body in response to hypoglycemia (see the section "Side effect") may be mild or absent with gradual development of hypoglycemia, in elderly patients, in patients with neuropathy of the autonomic nervous system or in patients, receiving beta-blockers, clonidine, reserpine, guanethidine and other sympatholytic agents.

Hypoglycemia can be quickly eliminated by immediate intake of rapidly digesting carbohydrates (glucose or sucrose).

As with the administration of other sulfonylureas, despite initial successful reduction of hypoglycemia, hypoglycemia may resume. Therefore, patients should remain under constant supervision.

In severe hypoglycemia, immediate treatment and supervision of the physician, and in some cases, hospitalization of the patient, are required.

During treatment with glimepiride, regular monitoring of liver function and peripheral blood pattern (especially the number of leukocytes and platelets) is required.

Since some side effects, such as severe hypoglycemia, severe changes in the blood picture, severe allergic reactions, liver failure, can under certain circumstances pose a life threat, if the unwanted or severe reactions develop, the patient should immediately be notified of the treating doctor and do not continue taking the drug without his recommendation.

Effect on the ability to drive transp. cf. and fur:

In the case of hypoglycemia or hyperglycaemia, especially at the beginning of treatment or after treatment change, or when the drug is not taken regularly, the attention and speed of psychomotor reactions may decrease. This can disrupt the patient's ability to drive vehicles or other mechanisms.

Form release / dosage:

Tablets 1 mg, 2 mg, 3 mg, 4 mg.

Packaging:For 15 tablets in a blister of PVC / aluminum foil. By 2, 4, 6 or 8 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature not exceeding 30 ° C.

Keep out of the reach of children.

List B.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015530 / 01

Date of registration:23.03.2009

The owner of the registration certificate:Sanofi-Aventis Deutschland GmbHSanofi-Aventis Deutschland GmbH Germany

Manufacturer: & nbsp

SANOFI-AVENTIS, S.p.A. Italy

Information update date: & nbsp28.01.2016

Illustrated instructions

Instructions

Amaryl® (Amaryl®)