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Active ingredients
Glimepiride
Release form
Pills
Composition
1 tablet contains: Glimepiride 4 mg Supplementary substances: lactose monohydrate - 135.85 mg, sodium carboxymethyl starch (type A) - 8 mg, povidone 25 000 - 1 mg, microcrystalline cellulose - 20 mg, magnesium stearate - 1 mg, indigo carmine (E132) - 0.15 mg.
Pharmacological effect
Oral hypoglycemic drug is a third generation sulfonylurea derivative. Glimepiride reduces the concentration of glucose in the blood, mainly due to the stimulation of insulin release from β-cells of the pancreas. Its effect is primarily related to the improved ability of the β-cells of the pancreas to respond to physiological stimulation with glucose. Compared to glibenclamide, glimepiride in low doses causes the release of a smaller amount of insulin when approximately the same decrease in blood glucose concentration is achieved. This fact argues in favor of the presence of extrapancreatic hypoglycemic effects in glimepiride (increased sensitivity of tissues to insulin and insulinomimetic effect). Secretion of insulin. Like all other sulfonylurea derivatives, glimepiride regulates insulin secretion by interacting with ATP-sensitive potassium channels on β-cell membranes. Unlike other sulfonylurea derivatives, glimepiride selectively binds to a protein with a molecular mass of 65 kilodalton, located in the membranes of β-cells of the pancreas. This interaction of glimepiride with a protein that binds to it regulates the opening or closing of ATP-sensitive potassium channels. Glimepiride closes the potassium channels. This causes β-cell depolarization and leads to the discovery of voltage-sensitive calcium channels and the entry of calcium into the cell. As a result, an increase in the intracellular calcium concentration activates insulin secretion by exocytosis. Glimepiride is much faster and, accordingly, more often enters the bond and is released from the bond with the protein bound to it than glibenclamide. It is assumed that this property of the high rate of exchange of glimepiride with a protein binding to it causes its pronounced effect of β-cell sensitization to glucose and their protection from desensitization and premature depletion. The effect of increasing tissue sensitivity 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 the release of glucose 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 molecules transporting glucose in plasma membranes of muscle cells and adipocytes. Increased glucose ingestion of cells leads to activation of glycosylphosphatidylinositol-specific phospholipase C. As a result, the intracellular calcium concentration decreases, causing a decrease in the activity of protein kinase A, which in turn stimulates glucose metabolism. 2,6-bisphosphate, which inhibits gluconeogenesis. Effect on platelet aggregation. Glimepiride reduces platelet aggregation in vitro and in vivo. This effect appears to be associated with selective inhibition of COX, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor. Anti-atherogenic effect. Glimepiride contributes to the normalization of lipids, reduces the level of malondialdehyde in the blood, which leads to a significant decrease in lipid peroxidation. In animals, glimepiride leads to a significant decrease in the formation of atherosclerotic plaques. Reducing the severity of oxidative stress, which is constantly present in patients with type 2 diabetes. Glimepiride increases the level of endogenous α-tocopherol, catalase activity, glutathione peroxidase and superoxide dismutase. Cardiovascular effects. Through the ATP-sensitive potassium channels, sulfonylurea derivatives also affect the cardiovascular system. Compared with traditional sulfonylurea derivatives, glimepiride has a significantly lower effect on the cardiovascular system, which can be explained by the specific nature of its interaction with the ATP-sensitive potassium channels that bind 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 physical exertion (decrease in insulin secretion) while taking glimepiride persists. There are no significant differences in 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, in 12 of 16 patients with renal insufficiency (CC 4–79 ml / min), sufficient metabolic control was also achieved. Combined therapy with metformin. In patients with insufficient metabolic control when using the maximum dose of glimepiride, combination therapy with glimepiride and metformin can be initiated. In two studies, the combination therapy has been shown to improve metabolic control compared with that in the treatment of each of these drugs separately. Combined therapy with insulin. In patients with insufficient metabolic control while taking glimepiride in maximum doses, simultaneous insulin therapy can be initiated. According to the results of two studies with the use of this combination, the same improvement in metabolic control is achieved as with the use of only one insulin. However, a lower dose of insulin is required in combination therapy.
Pharmacokinetics
When comparing the data obtained with a single and multiple (1 time / day) administration of glimepiride, there were no significant differences in pharmacokinetic parameters, and their variability between different patients was very low. Significant accumulation of the drug is absent. Absorption When repeated administration of the drug inside the daily dose of 4 mg Cmax in serum is reached after about 2.5 h and is 309 ng / ml. There is a linear relationship between the dose and Cmax of glimepiride in the blood plasma, as well as between the dose and AUC. When ingested, the bioavailability of glimepiride is 100%. Meal does not have a significant effect on absorption, except for a slight slowing down of its speed. Distribution For glimepiride, a very low Vd (about 8.8 l), approximately equal to Vd albumin, a high degree of plasma protein binding (over 99%) and low clearance (about 48Glimepiride is excreted in breast milk and penetrates the placental barrier. Metabolism Glemepiride is metabolized in the liver (mainly with the participation of the CYP2C9 isoenzyme) to form 2 metabolites - hydroxylated and carboxylated derivatives, which are found in the urine and in the feces. T1 / 2 metabolites - T1 / 2 plasma concentrations of the drug in serum, corresponding to the multiple dosing regimen, is approximately 5-8 hours. After taking glimepiride in high doses, T1 / 2 increases slightly. After a single dose ingestion of 58% of glimepiride is excreted by the kidneys and 35% through the intestines. Unchanged active substance is not detected in the urine. The T1 / 2 hydroxylated and carboxylated glimepiride metabolites were about 3-5 hours and 5-6 hours, respectively. Pharmacokinetics in special clinical situations Pharmacokinetic parameters are similar in patients of different sexes and different age groups. In patients with impaired function kidney disease (low QC), there is a tendency to an increase in the clearance of glimepiride and to a decrease in its average concentrations in blood serum, which is likely due to a more rapid elimination arat due to lower its binding with proteins. Thus, in this category of patients there is no additional risk of glimepiride cumulation.
Indications
- diabetes mellitus type 2 (as monotherapy or as part of combination therapy with metformin or insulin).
Contraindications
- type 1 diabetes; - diabetic ketoacidosis, diabetic precoma and coma; - severe liver dysfunction (lack of clinical experience); - severe kidney dysfunction, including patients on hemodialysis (lack of clinical experience); - pregnancy; - lactation (breastfeeding); - children's age (lack of 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 sulfonylurea derivatives and sulfa drugs (the risk of developing hypersensitivity reactions).
Precautionary measures
With caution should use the drug in the first weeks of treatment (increased risk of hypoglycemia); if there are risk factors for the development of hypoglycemia (may require a dose adjustment of glimepiride or the whole therapy); with intercurrent diseases during treatment or with a change in the lifestyle of patients (change in diet and meal times, increase or decrease in physical activity); in case of insufficiency of glucose-6-phosphate dehydrogenase; in violation of the absorption of food and medicines from the gastrointestinal tract (intestinal obstruction, intestinal paresis).
Use during pregnancy and lactation
Amaryl is contraindicated for use in pregnancy. In the case of a planned pregnancy or pregnancy, a woman should be transferred to insulin therapy. It is established that glimepiride is excreted in breast milk. During lactation, you should transfer a woman to insulin or stop breastfeeding.
Dosage and administration
As a rule, the dose of Amaryl is determined by the target concentration of glucose in the blood. The drug should be used in 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, it is recommended to regularly monitor the level of glycated hemoglobin. Disruption of the drug intake, for example, skipping the next dose, should not be replenished by subsequent administration of the drug in a higher dose. (in particular, when skipping a regular dose or skipping a meal), or in situations where it is not possible to take the drug. t accept a whole, without chewing, with a sufficient amount of liquid (about 1/2 cup). If necessary, pills of Amaryl can be divided along the risks 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 the regular control 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 diabetes mellitus type 2, 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 dose distribution during the day taking into account the patient's lifestyle (meal time, amount of exercise). The daily dose is prescribed in 1 reception, as a rule, 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 a meal after taking the pills of Amaryl. Because Improved metabolic control is associated with increased insulin sensitivity, and during treatment it is possible to reduce the need for glimepiride. In order to avoid the development of hypoglycemia, it is necessary to reduce the dose in a timely manner or stop taking Amaryl. Conditions in which dose adjustment of glimepiride may also be required: - weight loss; - lifestyle changes (change in diet, meal times, amount of exercise); the occurrence of other factors that lead to susceptibility to the development of hypoglycemia or hyperglycemia. The treatment with glimepiride is usually carried out for a long time. The transfer of a patient from taking another oral hypoglyce nical drug on the drug AmarilNe there is an exact relation between the doses of the drug Amaryl and other oral hypoglycemic agents. 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 dose increase should be carried out in stages, taking into account the reaction to glimepiride in accordance with the above recommendations. It is necessary to take into account the intensity and duration of the effect of the previous hypoglycemic agent. Interruption of treatment may be required to avoid an additive effect that increases the risk of hypoglycemia. Use in combination with metformin Patients with poorly controlled diabetes mellitus while taking glimepiride or metformin at maximum daily doses can be started with a combination of these two drugs.In this case, earlier treatment with either glimepiride or metformin continues at the same doses, and the additional administration of metformin or glimepiride is started from 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 started under strict medical supervision. Use in combination with insulinPatients with insufficiently controlled diabetes mellitus while taking glimepiride at the maximum daily dose can be simultaneously administered insulin. In this case, the last dose of glimepiride assigned to the patient remains unchanged. In this case, insulin treatment begins with low doses, which gradually increase under the control of the concentration of glucose in the blood. 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 the drug Amaryl in patients with renal insufficiency is limited. Data on the use of the drug Amaryl in patients with liver failure is limited.
Side effects
On the part of the metabolism: hypoglycemia is possible, which, as with the use of other sulfonylurea derivatives, can be prolonged. Symptoms of hypoglycemia - headache, hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, anxiety, aggressiveness, impaired concentration, alertness and reaction rate, depression, confusion, speech disorders, aphasia, visual disorders, tremor, paresis , sensory disturbances, dizziness, loss of self-control, delirium, cerebral seizures, 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 cold sticky sweat, anxiety, tachycardia, arterial hypertension, angina pectoris, palpitations, and heart rhythm disturbances. The clinical picture of severe hypoglycemia may resemble a stroke. Symptoms of hypoglycemia almost always disappear after its elimination. From the organ of vision: transient visual disturbances due to changes in blood glucose concentration are possible (especially at the beginning of treatment).Their cause is a temporary change in the swelling of the lens, depending on the concentration of glucose in the blood, and due to this change in the index of refraction of the lens. On the part of the digestive system: rarely - nausea, vomiting, 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 can progress to life-threatening liver failure, but may undergo a reverse development when the drug is withdrawn. From the hematopoietic system: rarely - thrombocytopenia; in some cases, leukopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia. With post-marketing use of the drug, cases of severe thrombocytopenia with platelet count <10,000 / μl and thrombocytopenic purpura (frequency unknown) were reported. Allergic reactions: rarely allergic and pseudo-allergic reactions such as itching, urticaria, skin rash. Such reactions almost always have a mild form, but 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. Others: in some cases - hyponatremia, photosensitization. If symptoms appear, the urticaria should immediately consult a doctor.
Overdose
In particular clinical stressful conditions, such as trauma, surgery, infections with febrile temperature, metabolic control may worsen in patients with diabetes, therefore, to maintain adequate metabolic control, it may be necessary to temporarily switch to insulin therapy. hypoglycemia, which requires particularly careful monitoring of blood glucose concentrations. To factors that contribute to the risk of hypoglycemia are reported: - unwillingness or inability of the patient (more often observed in elderly patients) to cooperate with the doctor; - malnutrition, irregular food intake or skipping meals; - an imbalance between exercise and carbohydrate consumption; - changing diet; - alcohol consumption,especially in combination with skipping meals; severe renal dysfunction; severe liver dysfunction (in patients with severely impaired liver function, insulin therapy is indicated, at least until metabolic control is achieved); overdose of glimepiride; some decompensated endocrine Disorders that interfere with carbohydrate metabolism or adrenergic counterregulation in response to hypoglycemia (for example, some dysfunctions of the thyroid gland and the anterior pituitary gland, insufficiency of the cortex adrenal glands); - simultaneous intake of certain drugs; - glimepiride in the absence of indications to receive it. Treatment of sulfonylurea derivatives, which include glimepiride, can lead to the development of hemolytic anemia, therefore, in patients with glucose-6-phosphate dehydrogenase deficiency, a special caution in the appointment of glimepiride, it is preferable to use hypoglycemic agents that are not derivatives of sulfonylurea. In the case of the above risk factors The development of hypoglycemia, as well as the occurrence of intercurrent diseases during treatment or a change in the patient’s lifestyle, may require dose adjustment of glimepiride or the whole therapy. in elderly patients, in patients with disorders of the autonomic nervous system, or in patients receiving beta-adrenoblockato p, clonidine, reserpine, guanethidine, and other sympatholytic drugs. Hypoglycemia can be quickly eliminated by immediately taking fast-digesting carbohydrates (glucose or sucrose). As with the intake of other sulfonylurea derivatives, despite initial successful relief of hypoglycemia, hypoglycemia can resume. Therefore, patients should remain under constant surveillance. When severe hypoglycemia additionally requires immediate treatment and observation by a physician, and in some cases hospitalization of the patient. During treatment with glimepiride, regular monitoring of liver function and peripheral blood picture (especially the number of leukocytes and platelets) is required. Such side effects as severe hypoglycemia, serious changes blood pictures, severe allergic reactions,liver failure can be life-threatening, therefore, if such reactions develop, the patient should immediately inform the attending physician about them, stop taking the drug and not resume taking it without a doctor's recommendation. Pediatric use. There are no data on the long-term efficacy and safety of using the drug. on the ability to drive vehicles and control mechanisms. At the beginning of treatment, after a change in treatment or with an irregular reception of glimepiride, lovlennoe hypo- or hyperglycemia decreased concentration and psychomotor speed. This may adversely affect the ability to drive motor vehicles or to control various machines and mechanisms.
Interaction with other drugs
Glimepiride is metabolized with the participation of CYP2C9 isoenzyme, which should be considered when using the drug simultaneously with inducers (for example, rifampicin) or inhibitors (for example, fluconazole) CYP2C9. one of the following drugs: insulin, other hypoglycemic agents for oral administration, ACE inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarinas , tetracyclines, tritoqualine, trophosphamide. Reduction of hypoglycemic action and the associated increase in the concentration of glucose in the blood is possible when combined with one of the following drugs: acetazolamide, barbitur you, GCS, diazoxide, diuretics, sympathomimetic agents (including epinephrine), glucagon, laxatives (with long-term use), nicotinic acid (in high doses), estrogens and progestogens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones. Blockers of histamine H2-receptors, beta-adrenergic 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 counter-regulation in response to hypoglycemia may be reduced or absent. weakening of the effect of coumarin derivatives. Simultaneous or chronic drinking of alcohol can both strengthen and weaken the hypoglycemic effect of glimepiride. Sequestrants elchnyh acids: colesevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. In the case of glimepiride, at least 4 hours before ingestion of the wheelwheel, no interaction is observed. Therefore, glimepiride must be taken at least 4 hours before taking the wheelchair.
special instructions
In particular clinical stressful conditions, such as trauma, surgery, infections with febrile temperature, metabolic control may worsen in patients with diabetes, therefore, to maintain adequate metabolic control, it may be necessary to temporarily switch to insulin therapy. hypoglycemia, which requires particularly careful monitoring of blood glucose concentrations. To factors that contribute to the risk of hypoglycemia are reported: - unwillingness or inability of the patient (more often seen in elderly patients) to cooperate with the doctor; - malnutrition, irregular eating or skipping meals; - an imbalance between physical activity and carbohydrate consumption; - changing diet; - alcohol consumption, especially in conjunction with eating habits; severe renal dysfunction; severe hepatic dysfunction (in patients with severely impaired liver function, insulin therapy is indicated, at least until a metabolic pressure is reached matic control); - an overdose of glimepiride - some decompensated endocrine disorders, violating the carbohydrate metabolism or adrenergic kontrregulyatsii in response to hypoglycemia (eg certain disorders of thyroid function and anterior part of the pituitary gland,adrenal insufficiency); - simultaneous intake of certain drugs; - glimepiride in the absence of indications for its reception. Treatment of sulfonylurea derivatives, which include glimepiride, can lead to hemolytic anemia, therefore in patients with glucose deficiency 6-phosphate dehydrogenase should Take special care when prescribing glimepiride, it is preferable to use hypoglycemic agents that are not sulfonylurea derivatives. In the case of the above Risk factors for hypoglycemia, as well as intercurrent diseases occurring during treatment or a change in the patient’s lifestyle, may require dose adjustment of glimepiride or the entire therapy. development of hypoglycemia, in elderly patients, in patients with disorders of the autonomic nervous system or in patients, I get their beta-blockers, clonidine, reserpine, guanethidine or other sympatholytic sredstva.Gipoglikemiya can be quickly eliminated by the immediate acceptance quickly digestible carbohydrates (glucose or sucrose). As with the intake of other sulfonylurea derivatives, despite initial successful relief of hypoglycemia, hypoglycemia can resume. Therefore, patients should remain under constant surveillance. When severe hypoglycemia additionally requires immediate treatment and observation by a physician, and in some cases hospitalization of the patient. During treatment with glimepiride, regular monitoring of liver function and peripheral blood picture (especially the number of leukocytes and platelets) is required. Such side effects as severe hypoglycemia, serious changes blood picture, severe allergic reactions, liver failure can be life-threatening, so if such reactions develop, the patient should en immediately inform their doctor, stop taking the drug and not to renew the appointment without the recommendation vracha.Ispolzovanie in pediatriiDannye on long-term efficacy and safety of the drug in children otsutstvuyut.Vliyanie on ability to drive vehicles and management mehanizmamiV the beginning of treatment,after a change in treatment or with an irregular reception of glimepiride, a decrease in the concentration of attention and speed of psychomotor reactions caused by hypo- or hyperglycemia may occur. This may adversely affect the ability to drive motor vehicles or to control various machines and mechanisms.