Amaryl, pills 4mg, 30pcs

Composition

Active ingredients:

glimepiride 4 mg.

Auxiliary substances:

lactose monohydrate,

sodium carboxymethyl starch (type A),

povidone 25 000,

microcrystalline cellulose,

magnesium stearate,

indigo carmine (E 132).

Pharmacological action

Pharmacodynamics

Oral hypoglycemic drug – a derivative of sulfonylureas of the third generation.

Glimepiride reduces the concentration of glucose in the blood, mainly by stimulating the release of insulin from pancreatic beta cells. Its effect is mainly associated with an improvement in the ability of pancreatic beta cells to respond to physiological glucose stimulation. Compared to glibenclamide, glimepiride in low doses causes the release of less insulin while achieving approximately the same reduction in blood glucose concentration. This fact suggests that glimepiride has extrapancreatic hypoglycemic effects (increased tissue sensitivity to insulin and an insulinomimetic effect).

Insulin secretion. Like all other sulfonylureas, glimepiride regulates insulin secretion by interacting with ATP-sensitive potassium channels on beta-cell membranes. Unlike other sulfonylurea derivatives, glimepiride selectively binds to a protein with a molecular weight of 65 kilodaltons located in the membranes of pancreatic beta cells. This interaction of glimepiride with its binding protein regulates the opening or closing of ATP-sensitive potassium channels.

Glimepiride closes the potassium channels. This causes depolarization of beta cells and leads to the opening of voltage-sensitive calcium channels and the entry of calcium into the cell. As a result, an increase in intracellular calcium concentration activates insulin secretion by exocytosis.

Glimepiride binds to and is released from the binding protein much faster and correspondingly more frequently than glibenclamide. It is assumed that this property of the high exchange rate of glimepiride with its binding protein causes its pronounced effect of sensitization of beta-cells to glucose and their protection against desensitization and premature depletion.

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

Insulinomimetic effect. Glimepiride has effects similar to those of insulin on glucose uptake by peripheral tissues and glucose release from the liver.

Glucose uptake by peripheral tissues is carried out by its transport into muscle cells and adipocytes. Glimepiride directly increases the number of glucose-transporting molecules in the plasma membranes of muscle cells and adipocytes. Increased glucose ingestion leads to activation of glycosylphosphatidylinositol-specific phospholipase C. As a result, the intracellular calcium concentration decreases, causing a decrease in protein kinase A activity, which in turn leads to stimulation of glucose metabolism.

Glimepiride inhibits the release of glucose 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 effect appears to be related to selective inhibition of COX, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor. Antiatherogenic effect. Glimepiride helps to normalize the lipid content, reduces the level of malonaldehyde in the blood, which leads to a significant decrease in lipid peroxidation. In animals, glimepiride significantly reduces the formation of atherosclerotic plaques.

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

Cardiovascular effects. Through ATP-sensitive potassium channels, sulfonylurea derivatives also have an effect on the cardiovascular system. Compared to traditional sulfonylurea derivatives, glimepiride has a significantly lower effect on the cardiovascular system, which may be explained by the specific nature of its interaction with the protein of ATP-sensitive potassium channels that binds to it.

In healthy volunteers, the minimum effective dose of glimepiride is 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to exercise (decreased insulin secretion) when taking glimepiride is preserved.

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

Combination therapy with metformin. In patients with insufficient metabolic control when using the maximum dose of glimepiride, combination therapy with glimepiride and metformin may be initiated. Two studies in combination therapy have shown improved metabolic control compared to that in the treatment of each of these drugs separately.

Combination therapy with insulin. In patients with insufficient metabolic control, when taking glimepiride at maximum doses, simultaneous insulin therapy may be initiated. According to the results of two studies, when using this combination, the same improvement in metabolic control is achieved as with the use of insulin alone. However, combination therapy requires a lower dose of insulin.

Pharmacokinetics

When comparing the data obtained with single and multiple (1 time/day) glimepiride use, there were no significant differences in pharmacokinetic parameters, and their variability between different patients was very low. There is no significant accumulation of the drug.

Suction

With repeated oral use of the drug in a daily dose of 4 mg, Cmax in blood serum is reached in about 2.5 hours and is 309 ng / ml. There is a linear relationship between the dose and Cmax of glimepiride in blood plasma, as well as between the dose and AUC. When taken orally, the bioavailability of glimepiride is 100%. Food intake does not significantly affect absorption, except for a slight slowdown in its rate.

Distribution

Glimepiride is characterized by a very low Vd (about 8.8 l), approximately equal to the Vd of albumin, a high degree of binding to plasma proteins (more than 99%) and a low clearance (about 48 ml / min).

Glimepiride is excreted in breast milk and passes through the placental barrier.

Metabolism

Glimepiride is metabolized in the liver (mainly with the participation of the CYP2C9 isoenzyme) with the formation of 2 metabolites – hydroxylated and carboxylated derivatives, which are found in the urine and feces.

The elimination

of T1 / 2 at plasma concentrations of the drug in serum, corresponding to a multiple dosage regimen, is approximately 5-8 hours. After taking glimepiride in high doses, T1 / 2 slightly increases. After a single oral dose,58% of glimepiride is excreted by the kidneys and 35% by the intestines. The unchanged Active ingredient is not detected in the urine.

T1 / 2 of the hydroxylated and carboxylated metabolites of glimepiride were approximately 3-5 h and 5-6 h, respectively

. Pharmacokinetics in special clinical cases

, the pharmacokinetic parameters are similar in patients of different gender and age groups.

In patients with impaired renal function (with low creatinine clearance), there is a tendency to increase the clearance of glimepiride and to decrease its average serum concentrations, which, in all likelihood, is due to faster elimination of the drug due to its lower binding to proteins. Thus, this category of patients does not have an additional risk of accumulation of glimepiride.

Indications

Type 2 diabetes mellitus (as monotherapy or as part of combination therapy with metformin or insulin).

Contraindications

• Diabetes mellitus type 1;
• diabetic ketoacidosis, diabetic precoma and coma;
• severe disturbances of liver function (no clinical experience);
• severe impairment of renal function, including patients on hemodialysis (no clinical experience);
• pregnancy;
• lactation (breastfeeding);
• children’s age (no clinical experience);
• rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• hypersensitivity to the components of the drug;
• hypersensitivity to other derivatives of sulfonylurea and sulfa drugs (risk of hypersensitivity reactions).

With caution: the drug should be used in the first weeks of treatment (increased risk of hypoglycemia); in the presence of risk factors for hypoglycemia (it may be necessary to adjust the dose of glimepiride or the entire therapy); in case of intercurrent diseases during treatment or when changing the lifestyle of patients (changing diet and meal times, increasing or decreasing physical activity) ; in case of glucose-6-phosphate dehydrogenase insufficiency; in case of impaired absorption of food and medicines from the gastrointestinal tract (intestinal obstruction, intestinal paresis).

Side effects

From the side of metabolism: hypoglycemia is possible, which, as with other sulfonylurea derivatives, can be prolonged. Symptoms of hypoglycemia include headache, hunger, nausea, vomiting, fatigue, drowsiness, sleep disorders, restlessness, aggressiveness, impaired concentration, alertness and speed of reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, paresis, sensory disturbances, dizziness, loss of self-control, delirium, cerebral convulsions, drowsiness or loss of 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, arterial hypertension, angina pectoris, palpitations and cardiac arrhythmias. The clinical picture of severe hypoglycemia may resemble a stroke. Symptoms of hypoglycemia almost always disappear after it is eliminated.

From the side of the visual organ: possible (especially at the beginning of treatment) transient visual disturbances due to changes in the concentration of glucose in the blood. Their cause is a temporary change in the swelling of the lenses, depending on the concentration of glucose in the blood, and due to this change in the refractive index of the lenses.

From the digestive system: rarely – nausea, vomiting, a feeling of heaviness or fullness in the epigastrium, abdominal pain, diarrhea; in some cases-hepatitis, increased activity of liver enzymes and/or cholestasis and jaundice, which may progress to life-threatening liver failure, but may reverse if the drug is discontinued.

From the hematopoietic system: rarely-thrombocytopenia; in some cases-leukopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia. Cases of severe thrombocytopenia with platelet counts have been reported with post-marketing use of the drug

Allergic reactions: rarely-allergic and pseudoallergic reactions, such as pruritus, urticaria, skin rash. Such reactions are almost always mild, but they can turn into severe reactions with shortness of breath, a sharp decrease in blood pressure, which sometimes progress to anaphylactic shock; in some cases, allergic vasculitis.

Other services: in some cases – hyponatremia, photosensitization.

If you experience symptoms of urticaria, you should immediately consult a doctor.

Interaction

Glimepiride is metabolized with the participation of the CYP2C9 isoenzyme, which should be taken into account when the drug is co-administered with inducers (for example, rifampicin) or inhibitors (for example, fluconazole) of CYP2C9.

Potentiation of the hypoglycemic effect and in some cases the associated possible development of hypoglycemia may occur when Amaryl® is combined with one of the following drugs: insulin, other oral hypoglycemic agents, ACE inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, phenyramidol, fibrates, fluoxetine, guanethidine, ifosfamide, MAO inhibitors, fluconazole, PASC, pentoxifylline (high parenteral doses), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, tritoqualin, trophosphamide.

Reducing the hypoglycemic effect and the associated increase in blood glucose concentration is possible when combined with one of the following drugs: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, sympathomimetic agents (including epinephrine), glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens and progestogens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones glands.

Histamine H2-receptor blockers, beta-blockers, clonidine and reserpine can both enhance and reduce the hypoglycemic effect of glimepiride.

Under the influence of sympatholytic agents, such as beta-blockers, clonidine, guanethidine and reserpine, signs of adrenergic counterregulation in response to hypoglycemia may decrease or be absent.

While taking glimepiride, the effect of coumarin derivatives may increase or decrease.

Single or chronic alcohol use may either increase or decrease the hypoglycemic effect of glimepiride.

Bile acid sequestrants: colesevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. In the case of glimepiride, at least 4 hours before taking colesevelam, no interaction is observed. Therefore, glimepiride should be taken at least 4 hours before taking colesevelam.

How to take, course of use and dosage

As a rule, the dose of Amaryl® is determined by the target concentration of glucose in the blood. The drug should be used at a minimum dose sufficient to achieve the necessary metabolic control.

During treatment with Amaryl®, it is necessary to regularly determine the level of glucose in the blood. In addition, regular monitoring of the level of glycosylated hemoglobin is recommended.

A violation of the drug intake, for example, skipping the next dose, should not be compensated by taking a higher dose of the drug later.

The doctor should instruct the patient in advance about actions that should be taken in case of mistakes in taking Amaryl® (in particular, when skipping the next dose or when skipping a meal), or in situations where it is not possible to take the drug.

Amaryl tablets should be taken whole, without chewing, with a sufficient amount of liquid (about 1/2 cup). If necessary, Amaryl ® tablets can be divided along the line into two equal parts.

The initial dose of Amaryl® is 1 mg 1 time / day. If necessary, the daily dose can be gradually increased (at intervals of 1-2 weeks) under regular monitoring of blood glucose and in the following order: 1 mg-2 mg-3 mg-4 mg-6 mg (-8 mg) per day.

In patients with well-controlled type 2 diabetes, the daily dose of the drug is usually 1-4 mg. A daily dose of more than 6 mg is more effective only in a small number of patients.

The doctor determines the time of taking Amaryl® and the distribution of doses throughout the day, taking into account the patient’s lifestyle (meal time, amount of physical activity). The daily dose is prescribed in 1 dose, usually immediately before a full breakfast or, if the daily dose was not taken, immediately before the first main meal. It is very important not to skip meals after taking Amaryl tablets.

Since improved metabolic control is associated with increased insulin sensitivity, treatment may reduce the need for glimepiride. In order to avoid the development of hypoglycemia, it is necessary to reduce the dose or stop taking Amaryl®in a timely manner.

Conditions that may also require dose adjustment of glimepiride:

• weight loss;
• lifestyle changes (changes in diet, meal times, amount of physical activity);
• the occurrence of other factors that lead to a predisposition to the development of hypoglycemia or hyperglycemia.

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

Transfer of a patient from taking another oral hypoglycemic drug to taking Amaryl®

There is no exact correlation between the dosage of Amaryl® and other oral hypoglycemic drugs. When transferring from such drugs to Amaryl®, the recommended initial daily dose of the latter is 1 mg (even if the patient is transferred to Amaryl® from the maximum dose of another oral hypoglycemic drug). Any increase in the dose should be carried out in stages, taking into account the reaction to glimepiride in accordance with the recommendations given above. It is necessary to take into account the intensity and duration of the effect of the previous hypoglycemic agent. Discontinuation of treatment may be necessary to avoid an additive effect that increases the risk of hypoglycemia.

Use in combination with metformin

In patients with insufficiently controlled diabetes mellitus, when taking glimepiride or metformin in the maximum daily doses, treatment with a combination of these two drugs can be initiated. At the same time, the previous treatment with either glimepiride or metformin continues in the same doses, and the additional intake of metformin or glimepiride begins with a low dose, which is then titrated depending on the target level of metabolic control, up to the maximum daily dose. Combination therapy should be initiated under strict medical supervision.

Use in combination with insulin

Patients with insufficiently controlled diabetes mellitus who are taking glimepiride at the maximum daily dose may be simultaneously prescribed insulin.In this case, the last dose of glimepiride prescribed to the patient remains unchanged. In this case, insulin treatment begins with low doses, which are gradually increased under the control of blood glucose concentrations. Combined treatment is carried out under close medical supervision.

Patients with impaired renal function may be more sensitive to the hypoglycemic effect of glimepiride. Data on the use of Amaryl in patients with renal insufficiency are limited.

Data on the use of Amaryl in patients with hepatic insufficiency are limited.

Overdose

Symptoms: acute overdose, as well as long-term treatment with glimepiride in excessively high doses, may lead to severe life-threatening hypoglycemia.

Treatment: hypoglycemia can almost always be quickly relieved by an 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 g of glucose (4 lumps of sugar). Sweeteners are ineffective in treating hypoglycemia.

Until the doctor decides that the patient is out of danger, the patient needs careful medical supervision. It should be borne in mind that hypoglycemia may resume after the initial restoration of blood glucose concentration.

If a patient suffering from diabetes is treated by different doctors (for example, during a hospital stay after an accident, during a weekend illness), they must inform them about their illness and previous treatment.

Sometimes it may be necessary to hospitalize the patient, if only as a precautionary measure. A significant overdose and severe reaction with symptoms such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and hospitalization.

In case of loss of consciousness, intravenous use of a concentrated dextrose (glucose) solution (for adults, starting with 40 ml of a 20% solution) is necessary. As an alternative, adults may be given intravenous, subcutaneous or intramuscular glucagon, for example, at a dose of 0.5-1 mg.

When treating hypoglycaemia due to accidental use of Amaryl® by children or young children, the dextrose dose should be carefully adjusted to avoid the possibility of dangerous hyperglycaemia; dextrose use should be carried out under constant monitoring of blood glucose concentrations.

In case of overdose of Amaryl®, gastric lavage and use of activated charcoal may be required.

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

As soon as an overdose is detected, it is necessary to inform the doctor immediately.

Special instructions

In special clinical stressful conditions, such as trauma, surgery, or infections with febrile fever, metabolic control may be impaired in patients with diabetes mellitus, so a temporary switch to insulin therapy may be required to maintain adequate metabolic control.

In the first weeks of treatment, there may be an increased risk of hypoglycemia, which requires particularly careful monitoring of blood glucose concentrations.

Factors contributing to the risk of hypoglycemia include::

• the unwillingness or inability of the patient (more frequently observed in elderly patients) to cooperate with the doctor;
• malnutrition, irregular mealtimes or omissions meal;
• the imbalance between physical exertion and carbohydrate intake;
• dietary advice;
• use of alcohol, especially in combination with skipped meals;
• severe kidney problems;
• severe disturbances of liver function (in patients with severely impaired liver function shown on insulin therapy, at least, to achieve metabolic control);
• an overdose of glimepiride;
• some decompensated endocrine disorders, in violation of carbohydrate metabolism or adrenergic contraregulatory in response to hypoglycemia (e. g. some dysfunction of the thyroid and anterior pituitary, and adrenal insufficiency);
• simultaneous reception of certain drugs;
• receiving glimepiride in absence of evidence for its reception.

Treatment with sulfonylurea derivatives, including glimepiride, can lead to the development of hemolytic anemia, so in patients with glucose-6-phosphate dehydrogenase deficiency, special care should be taken when prescribing glimepiride, preferably using hypoglycemic agents that are not sulfonylurea derivatives.

If the above risk factors for hypoglycaemia are present, if intercurrent diseases occur during treatment or if the patient’s lifestyle changes, it may be necessary to adjust the dose of glimepiride or the entire therapy.

Symptoms of hypoglycemia resulting from adrenergic counterregulation of the body in response to hypoglycemia may be mild or absent with the gradual development of hypoglycemia, in elderly patients, in patients with disorders of the autonomic nervous system, or in patients receiving beta-blockers, clonidine, reserpine, guanethidine and other sympatholytic agents.

Hypoglycemia can be quickly eliminated with immediate intake of fast-digesting carbohydrates (glucose or sucrose). As with other sulfonylureas, hypoglycaemia may resume despite initial successful relief of hypoglycaemia. Therefore, patients should remain under constant supervision. In case of severe hypoglycemia, immediate treatment and medical supervision are additionally required, and in some cases, the patient is hospitalized.

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

Such side effects as severe hypoglycemia, serious changes in the blood picture, severe allergic reactions, liver failure can be life-threatening, so if such reactions develop, the patient should immediately inform the attending physician about them, stop taking the drug and do not resume taking it without a doctor’s recommendation.

Use in pediatrics

There are no data on the long-term efficacy and safety of the drug in children.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Hypo – or hyperglycaemia-related decreases in concentration and speed of psychomotor reactions may occur at the beginning of treatment, after treatment changes, or with irregular glimepiride use. This may negatively affect your ability to drive vehicles or manage various machines and mechanisms.

Form of production

Tablets

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Glimepiride

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults

Indications

Type 2 Diabetes