Amaryl M pills 2 mg + 500 mg N30
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Active ingredients
Glimepiride + Metformin
Release form
Pills
Composition
Active ingredient: Glimepiride micronized, Metformin hydrochloride Concentration of active ingredient (mg): 502
Pharmacological effect
Amaryl M is a combined hypoglycemic drug, which consists of glimepiride and metformin. Pharmacodynamics of glimepiride Glimepiride, one of the active substances of the drug Amaryl M, is a hypoglycemic drug for oral administration, a third-generation sulfonylurea derivative. glands (pancreatic action), improves the sensitivity of peripheral tissues (muscle and fat) to the action of endogenous insulin (extrapank reathic action). Effect on insulin secretion. The sulfonylurea derivatives increase insulin secretion by closing the ATP-dependent potassium channels located in the cytoplasmic membrane of the β-cells of the pancreas. By closing the potassium channels, they cause β-cells to depolarize, which contributes to the opening of calcium channels and an increase in the calcium supplement, which causes β-cells to depolarize, which promotes the opening of calcium channels and an increase in calcium supplementation. inside the cells. Glimepiride connects and detaches from the pancreatic β-cell protein (mol. Mass 65 kD / SURX), which is associated with ATP-dependent potassium channels, but differs from the site of binding of the usual sulfonylurea derivatives (protein with mol. Mass 140 kD / SUR1). This process leads to the release of insulin by exocytosis, while the amount of secreted insulin is much less than under the action of sulfonylurea derivatives of the second generation (for example, glibenclamide). The minimal stimulating effect of glimepiride on insulin secretion provides a lower risk of hypoglycemia. Extrapancreatic activity As traditional sulfonylurea derivatives, but to a much greater extent, glimepiride has pronounced extrapancreatic effects (reduction of insulin resistance, anti-atherogenic, anti-aggrescent, and an anti-aggreptant, and an anti-agroante anesthetic, reduces anti-aggregants, and has a pronounced extrapancreatic effect (reduction of insulin resistance, anti-atherogenic, anti-aggre- Utilization of glucose by peripheral tissues (muscle and fat) occurs with the help of special transport proteins (GLUT1 and GLUT4) located in cell membranes.The transport of glucose to these tissues in type 2 diabetes mellitus is a speed-limited step of glucose utilization. Glimepiride very quickly increases the number and activity of glucose transporting molecules (GLUT1 and GLUT4), increasing glucose uptake by peripheral tissues. Glimepiride has a weaker inhibitory effect on the ATP-dependent potassium channels of cardiomyocytes. When glimepiride is taken, the ability of metabolic myocardial adaptation to ischemia is preserved. Glimepiride increases the activity of phospholipase C, as a result of which the intracellular calcium concentration in muscle and fat cells decreases, causing a decrease in the activity of protein kinase A, which in turn leads to the stimulation of glucose metabolism. Glimepiride inhibits glucose output from the liver by increasing the intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis. Glimepiride selectively ing It inhibits cyclo-oxygenase and reduces the conversion of arachidonic acid to thromboxane A2, an important endogenous platelet aggregation factor. Glimepiride helps reduce lipid content, significantly reduces lipid peroxidation, and its anti-atherogenic effect is associated with it. that reduces the severity of oxidative stress in the patient’s body, which is constantly present in the patient’s body ntov 2 diabetes tipa.Farmakodinamika metforminaMetformin is a hypoglycemic drug from the group of biguanides. Its hypoglycemic effect is possible only if insulin secretion is maintained (albeit reduced). Metformin does not affect the β-cells of the pancreas and does not increase insulin secretion. Therapeutic doses of metformin do not cause hypoglycemia in humans. The mechanism of action of metformin is not yet fully understood. It is assumed that metformin can potentiate the effects of insulin or that it can increase the effects of insulin in the areas of peripheral receptors. Metformin increases the sensitivity of tissues to insulin by increasing the amount of insulin receptors on the surface of cell membranes.In addition, metformin inhibits gluconeogenesis in the liver, reduces the formation of free fatty acids and the oxidation of fats, reduces the concentration in the blood of triglycerides (TG), LDL and LDLP. Metformin slightly reduces appetite and reduces the absorption of carbohydrates in the intestines. It improves blood fibrinolytic properties by suppressing the inhibitor of tissue plasminogen activator.
Pharmacokinetics
Glimepiride Absorption When repeated administration of the drug inside the daily dose of 4 mg Cmax in serum is reached after about 2.5 hours 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 glimepiride its absolute bioavailability is complete. 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 48 ml / min). Glimepiride is excreted in breast milk and penetrates the placental barrier. Glimepiride poorly penetrates through the BBB. A comparison of a single and multiple (2 times / day) intake of glimepiride did not reveal significant differences in pharmacokinetic parameters, and their variability in different patients was insignificant. There was no significant accumulation of glimepiride. Metabolism Glimepiride is metabolized in the liver to form two metabolites — hydroxylated and carboxylated derivatives, which are found in urine and in feces. Excretion of T1 / 2 at plasma concentrations of the drug in serum corresponding to a multiple dose is approximately 5–8 hours. glimepiride in high doses of T1 / 2 increases slightly. After a single oral administration, 58% of glimepiride is excreted by the kidneys (as metabolites) and 35% through the intestines. There is no unchanged active substance in the urine. The terminal T1 / 2 hydroxylated and carboxylated glimepiride metabolites are 3-5 h and 5-6 h, respectively. Pharmacokinetics in special clinical situations in patients of different sexes and different age groups have pharmacokinetic parameters in glimepiride are the same. In patients with impaired renal function (with low QC), there was a tendency to an increase in the clearance of glimepiride and to a decrease in its average concentrations in blood serum, which, most likely,due to the more rapid elimination of glimepiride due to its lower binding to plasma proteins. Thus, in this category of patients there is no additional risk of glimepiride cumulation. Methformin Absorption After oral administration, metformin is absorbed from the gastrointestinal tract completely. Absolute bioavailability is 50-60%. Cmax in plasma is about 2 mcg / ml and is reached after 2.5 h. With simultaneous ingestion, the absorption of metformin decreases and slows down. Distribution and metabolismMetformin is rapidly distributed in the tissue, practically does not bind to plasma proteins. Metabolized to a very low degree. Excretion of T1 / 2 is approximately 6.5 hours. Excreted by the kidneys. The clearance of healthy volunteers is 440 ml / min (4 times more than QC), which indicates the presence of active tubular secretion of metformin. Pharmacokinetics in special clinical situations. In case of renal insufficiency, the risk of drug accumulation appears. Cmax and AUC when taking a fixed-dose combination drug (tablet containing glimepiride 2 mg + metformin 500 mg) meet the criteria for bioequivalence when compared with this The same indicators when taking the same combination in the form of separate drugs (glimepiride tablet 2 mg and metformin tablet 500 mg). In addition, a dose-proportional increase in Cmax and AUC of glimepiride was shown while increasing its dose in fixed-dose combination drugs from 1 mg to 2 mg at a constant dose of metformin (500 mg) in the composition of these drugs. In addition, there were no significant differences in safety, including the profile of undesirable effects, between patients taking Amaryl M 1 mg + 500 mg patients taking medication Amaryl M 2 mg + 500 mg.
Indications
Hormone replacement therapy (HRT) for menopausal disorders associated with estrogen deficiency: involutional changes of the skin and urinary tract, decrease in bone density, psychoemotional lability, vegeto-vascular disorders. Experience with women over 65 is limited.
Contraindications
Type 1 diabetes; diabetic ketoacidosis (in t.including history), diabetic coma and precoma; acute or chronic metabolic acidosis; severe impaired liver function (lack of experience with the use of insulin; treatment with insulin is necessary to ensure adequate glycemic control); patients on hemodialysis (lack of experience with the application); renal failure and impaired renal function (plasma creatinine concentration ≥1.5 mg / dL (135 mcmol / L) in men and ≥1.2 mg / dL (110 mcmol / L) in women or decreased QC (increased risk of developing lactic acidosis and other side effects of metformin); acute conditions in which impaired renal function is possible (dehydration, severe infections, shock, intravascular injection of iodine-containing contrast agents); acute and chronic diseases that can cause tissue hypoxia (cardiac or respiratory failure, acute and subacute th myocardial infarction, shock); a tendency to the development of lactic acidosis, lactic acidosis in history; stressful situations (severe injuries, burns, surgical operations, severe infections with fever, septicemia); ; impaired absorption of food and drugs in the gastrointestinal tract (with intestinal obstruction, intestinal paresis, diarrhea, vomiting); chronic alcoholism, acute alcohol intoxication; lactase deficiency, galactose intolerance, glucose-galactose malabsorption; pregnancy, pregnancy planning; breastfeeding period; children and adolescents under 18 years of age (insufficient experience in clinical use); hypersensitivity to the drug; Hypersensitivity to sulfonylurea derivatives, sulfa drugs, or biguanides.
Use during pregnancy and lactation
Lactic acidosis Lactic acidosis is a rare, but severe (with high mortality in the absence of proper treatment) metabolic complication that develops as a result of accumulation of metformin during treatment. Cases of lactic acidosis while taking metformin were observed mainly in patients with diabetes mellitus with severe renal insufficiency. The incidence of lactic acidosis can and should be reduced by assessing the presence in patients of other associated risk factors for the development of lactic acidosis, such as poorly controlled diabetes mellitus, ketoacidosis, prolonged fasting, intensive use of ethanol-containing beverages, liver failure and conditionsaccompanied by tissue hypoxia. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia, followed by the development of coma. Diagnostic laboratory manifestations are an increase in the concentration of lactate in the blood (> 5 mmol / l), a decrease in blood pH, impaired water-electrolyte balance with an increase in anion deficiency and the lactate / pyruvate ratio. In cases where lactacidosis is caused by metformin, the plasma concentration of metformin is typically> 5 μg / ml. If lactacidosis is suspected, metformin should be immediately discontinued and the patient should be immediately hospitalized. The frequency of reported cases of lactic acidosis in patients taking metformin is very low (about 0.03 cases / 1000 patient-years). Reported cases occurred mainly in diabetic patients with severe renal insufficiency, including with congenital kidney disease and hypoperfusion of the kidney, often in the presence of numerous concomitant conditions requiring medical and surgical treatment. The risk of lactic acidosis increases with the severity of renal impairment and with age. The probability of lactic acidosis when taking metformin can be significantly reduced with regular monitoring of renal function and the use of minimal effective doses of metformin. For the same reason, in conditions associated with hypoxemia or dehydration, it is necessary to avoid taking the drug Amaryl M. Due to the fact that the liver dysfunction can significantly limit the excretion of lactate, the use of the drug Amaryl M should be avoided in patients with clinical or laboratory signs of liver disease In addition, the administration of Amaryl M should be temporarily discontinued before x-ray examinations with intravascular iodine-containing contrast agents and before surgical interventions. Metformin should be discontinued for 48 hours before and 48 hours after surgery with general anesthesia. Often lactic acidosis develops gradually and is manifested only by nonspecific symptoms, such as poor health, myalgia, respiratory disorders, increasing drowsiness and nonspecific disorders of the gastrointestinal tract.With a more pronounced acidosis, hypothermia, a decrease in blood pressure and resistant bradiarrhythmia are possible. Both the patient and the treating physician should know how important these symptoms may be. The patient should be instructed to immediately notify the doctor if such symptoms occur. To clarify the diagnosis of lactic acidosis, it is necessary to determine the concentration of electrolytes and ketones in the blood, the concentration of glucose in the blood, blood pH, the concentration of lactate and metformin in the blood. Plasma lactate concentration in venous blood on an empty stomach, exceeding the upper limit of normal, but below 5 mmol / l in patients taking metformin does not necessarily indicate lactacidosis; its increase can be explained by other mechanisms, such as poorly controlled diabetes mellitus or obesity, intense exercise or technical errors in blood sampling for analysis. It should be assumed that lactic acidosis is present in a patient with diabetes mellitus with metabolic acidosis in the absence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a critical condition requiring inpatient treatment. In the case of lactic acidosis, you should immediately discontinue taking Amaryl M and begin general supportive measures. Metformin is removed from the blood by hemodialysis with a clearance of up to 170 ml / min. Therefore, it is recommended that, if there are no hemodynamic disturbances, immediate hemodialysis is carried out to remove accumulated metformin and lactate. Such measures often lead to the rapid disappearance of symptoms and recovery. Monitoring the effectiveness of treatment The effectiveness of any hypoglycemic therapy should be monitored by periodically monitoring the concentration of glucose and glycosylated hemoglobin in the blood. The goal of treatment is the normalization of these indicators. The concentration of glycosylated hemoglobin allows glycemic control to be assessed. Hypoglycemia During the first week of treatment, careful monitoring is necessary because of the risk of hypoglycemia, especially if there is an increased risk of its development (patients who are not unwilling or unable to follow the recommendations of the doctor, most often elderly patients; with poor nutrition, irregular meals,when you skip meals; if there is a discrepancy between exercise and carbohydrate intake; with changes in diet, with the consumption of ethanol, especially in combination with skipping meals; in violation of renal function; in severe liver dysfunction; with some uncompensated disorders of the endocrine system (for example, some dysfunction of the thyroid gland and insufficiency of hormones of the anterior pituitary or adrenal cortex; with the simultaneous use of some other drugs that affect carbohydrate metabolism. In such cases, the patient must monitor blood glucose. report these risk factors and symptoms of hypoglycemia to your doctor, if any. If risk factors for hypoglycemia are present adjusting the dose of this drug or the entire therapy.This approach is used whenever the patient develops a disease or changes the patient’s lifestyle.Hypoglycemia symptoms reflecting adrenergic anti-hypoglycemic regulation in response to developing hypoglycemia may be less pronounced be absent if hypoglycemia develops gradually, as well as in elderly patients, with autonomic neuropathy or with beta therapy being simultaneously administered renoblokatorami, clonidine, guanethidine and other simpatolitikami.Pochti always hypoglycemia can be quickly cut short by means of immediate carbohydrate intake (glucose, or sugar, for example, a piece of sugar, fruit juices containing sugar, tea with sugar). To this end, the patient should carry with them at least at least 20 g of sugar. He may need the help of others to avoid complications. Sugar substitutes are ineffective. According to the experience with other sulfonylurea drugs, it is known that, despite the initial efficacy of the taken countermeasures, hypoglycemia can recur, therefore patients should remain under close observation. The development of severe hypoglycemia requires immediate treatment and medical observation, in some cases - inpatient treatment. General indications It is necessary to maintain target glycemia with the help of comprehensive measures: diet and exercise, weight loss, and, if necessary, regular intake of hypoglycemic drugs.Patients should be informed about the importance of dietary requirements and regular exercise. The clinical symptoms of inadequately controlled blood glucose include oliguria, thirst, pathologically strong thirst, dry skin, and others. If the patient is not treated by a doctor (for example, hospitalization, accident , the need for a visit to the doctor on a day off), the patient should inform him about diabetes and the treatment being carried out. In stressful situations (for example, trauma, surgery, infectious disease with fever) glycemic control may be impaired, and a temporary switch to insulin therapy may be required to provide the necessary metabolic control. Monitoring of renal functionIt is known that metformin is mainly excreted by the kidneys. In case of impaired renal function, the risk of metformin accumulation and the development of lactic acidosis increases. At concentration of creatinine in blood serum, exceeding the upper age limit of the norm, it is not recommended to take Amaryl M. For elderly patients, careful titration of the dose of metformin is necessary in order to select the minimum effective dose, since the renal function decreases with age. Renal function in elderly patients should be monitored regularly, and, as a rule, the dose of metformin should not be increased to its maximum daily dose. Simultaneous use of other drugs may affect kidney function or removal of metformin or cause significant changes in hemodynamics. the introduction of iodine-containing contrast agents (for example, intravenous urography, intravenous cholangiography, angiography and CT using a contrast agent) : Contrast in / in iodine-containing substances intended for research can cause acute renal dysfunction, their use is associated with the development of lactic acidosis in patients taking metformin. If you plan to conduct such a study, Amaryl M must be canceled before the procedure and do not resume taking it in the next 48 hours after the procedure.It is possible to resume treatment with Amaryl only after monitoring and obtaining normal indicators of renal function. Conditions in which hypoxia can developCollapse or shock of any origin, acute heart failure, acute myocardial infarction and other conditions characterized by tissue hypoxemia and hypoxia can also cause prerenal renal failure and increase the risk of lactic acidosis. If such conditions arise in patients taking this drug, the drug should be discontinued immediately. Surgical interventions With any planned surgical intervention, therapy with this drug should be discontinued within 48 hours (except for small procedures that do not require restrictions in food and fluid intake), therapy cannot be resumed until oral ingestion is restored and renal function is not recognized as normal. Alcohol intake (beverages containing ethanol) It is known that ethanol enhances the action effect of metformin on lactate metabolism. Patients should be cautioned against consuming ethanol-containing drinks while taking Amaryl M. Liver function impairment. In some cases, liver dysfunction was accompanied by lactic acidosis, patients with clinical or laboratory signs of liver damage should avoid using this drug. diabetes mellitus; Patient diabetes mellitus, previously well controlled administration of metformin, should be examined immediately, especially but with ill-defined and poorly recognized disease, to exclude ketoacidosis and lactic acidosis. The study should include: determination of serum electrolytes and ketone bodies, the concentration of glucose in the blood and, if necessary, blood pH, blood concentration of lactate, pyruvate and metformin. If any of the forms of Amaryl M acidosis is present, you should immediately cancel and prescribe other drugs to maintain glycemic control. Information for patients It is necessary to inform patients of the possible risks and benefits of this drug, as well as alternative treatment methods.It is also necessary to explain well the importance of following dietary instructions, performing regular exercise and regularly monitoring blood glucose, glycosylated hemoglobin, kidney function and hematological parameters, as well as the risk of developing hypoglycemia, its symptoms and treatment, as well as predisposing to its development. The concentration of vitamin B12 in the blood. A decrease in the serum vitamin B12 concentration below the norm in the absence of clinical manifestations was observed in approximately 7% of patients Taking Amaryl M, nevertheless, it is very rarely accompanied by anemia and cancellation of the drug or by administration of vitamin B12 was quickly reversible. Patients with inadequate intake or absorption of vitamin B12 are prone to decreased vitamin B12 concentrations. For these patients, regular serum concentration of vitamin B12 may be useful every 2-3 years. Laboratory monitoring of treatment safety It should periodically monitor hematological parameters (hemoglobin or hematocrit, red blood cell count) and kidney function (serum creatinine concentration) of at least one once a year in patients with normal renal function, and at least 2-4 times a year in patients with serum creatinine concentration on VGN and in elderly patients. If necessary, the patient is shown appropriate examination and treatment of any apparent pathological changes. Although megaloblastic anemia was rarely observed when taking metformin, if you suspect it, you should be examined to rule out vitamin B12 deficiency. Effect on ability to drive and control machinery or after changes in treatment, or with an irregular drug intake. This may affect the ability to drive vehicles and engage in other potentially hazardous activities. Patients should be warned about the need to exercise caution when driving, especially if they are prone to developing hypoglycemia and / or reducing the severity of its precursors.
Dosage and administration
Amaryl M should be taken 1 or 2 times / day with meals. The maximum dose of metformin at a time is 1000 mg.The maximum daily dose: for glimepiride - 8 mg, for metformin - 2000 mg. Only in a small number of patients a daily dose of glimepiride more than 6 mg is more effective. In order to avoid the development of hypoglycemia, the initial dose of Amaryl M should not exceed the daily doses of glimepiride and metformin, which the patient is already taking. When transferring patients from taking a combination of individual drugs of glimepiride and metformin to Amaryl M, its dose is determined on the basis of the doses of glimepiride and metformin already taken as separate drugs. If it is necessary to increase the dose, the daily dose of Amaryl M should be titrated in increments of only 1 tablet of Amaryl M 1 mg + 250 mg or 1/2 tablet of Amaryl M 2 mg + 500 mg. Duration of treatment: usually treatment with Amaryl M is carried out for a long time.
Side effects
Interaction of glimepiride with other drugs When an patient taking glimepiride is simultaneously prescribed or canceled by other drugs, undesirable reactions are possible: the strengthening or weakening of the hypoglycemic action of glimepiride. Based on the clinical experience with glimepiride and other sulfonylurea drugs, the following drug interaction should be considered. With drugs that are inducers and inhibitors of the CYP2C9 isoenzyme: glimepiride is metabolized with the participation of the CYP2C9 isoenzyme. Its metabolism is influenced by the simultaneous use of CYP2C9 isoenzyme inducers, for example, rifampicin (the risk of reducing the hypoglycemic effect of glimepiride with simultaneous use of the isoenzyme CYP2C9 with inducers and an increase in the risk of developing hypoglycemia if they are canceled without dose correction of glimepiride) and inhibitors of the CYP2Cro isoenzyme and CYP2Cro isoenzyme inhibitors. increased risk of hypoglycemia and side effects of glimepiride when taken simultaneously with inhibitors of the CYP2C9 isoenzyme and the risk of reducing its hypoglycemia cesky effect when they are canceled without dose adjustment of glimepiride). With drugs that enhance the hypoglycemic effect of glimepiride: insulin and hypoglycemic preparations for oral administration, ACE inhibitors, anabolic steroids, male sex hormones, chloramphenicol,indirect cognacs , salicylates, sulfinpirazon, clarithromycin, sulfanilamide antimicrobials, tetracyclines, tritokvalin, trofosfamid: increased risk of hypoglycemia at the same time the use of these drugs with glimepiride and the risk of worsening of glycemic control if they are canceled without dose adjustment of glimepiride. application), nicotinic acid (high doses), estrogens, progestogens, phenothiazines, phenytoin, rifampicin, thyroid hormones: the risk of worsening glycemic control during joint enenii with these drugs and increased risk of hypoglycaemia in case of cancellation without dose adjustment glimepirida.S blockers of histamine H2-receptor, beta-blockers, clonidine, reserpine, guanethidine: probably both intensification and reducing hypoglycemic effect of glimepiride. Careful monitoring of blood glucose concentration is required. Beta-adrenergic blockers, clonidine, guanethidine and reserpine as a result of blocking reactions of the sympathetic nervous system in response to hypoglycemia can make the development of hypoglycemia more imperceptible for the patient and the doctor and thereby increase the risk of its occurrence. or enhance the hypoglycemic effect of glimepiride. With indirect anticoagulants, derivatives of coumarin: glimepiride can both enhance and reduce the effects of indirect anticoagulants, roizvodnyh kumarina.S bile acid sequestrants: colesevelam binds glimepiride glimepiride and reduces the absorption from the gastrointestinal tract. In the case of glimepiride, at least 4 hours before ingestion of the wheelwheel, no interaction is observed.Therefore, glimepiride should be taken at least 4 hours before taking the wheel. Interaction of metformin with other drugs. Recommended combinations with ethanol: acute alcohol intoxication increases the risk of lactic acidosis, especially in the case of skipping or insufficient food intake, the presence of liver failure. Intake of alcohol (ethanol) and preparations containing ethanol should be avoided. With iodine-containing contrast agents: intravascular administration of iodine-containing contrast preparations can lead to the development of renal failure, which in turn can lead to an accumulation of metformin and an increased risk of lactic acidosis. Metformin should be discontinued prior to or during the study and should not be resumed within 48 h after it; Resuming metformin is possible only after testing and obtaining normal indicators of kidney function. With antibiotics with a pronounced nephrotoxic effect (gentamicin): an increase in the risk of lactic acidosis. adrenergic stimulants and diuretics with internal hyperglycemic activity: the patient should be informed about the need for more frequent monitoring morning blood glucose levels, especially at the beginning of combined therapy. Correction of doses of hypoglycemic therapy may be required during use or after discontinuation of the above drugs. With ACE inhibitors: ACE inhibitors can reduce the concentration of glucose in the blood. It may be necessary to adjust doses of hypoglycemic therapy during use or after discontinuation of ACE inhibitors. With drugs that enhance the hypoglycemic effect