Endial Met

Endial Met

Glimepiride, Metformin Hydrochloride

Treatment of type 2 diabetes (in addition to diet, exercise, and weight loss):

in cases where glycemic control cannot be achieved by a combination of diet, exercise, weight loss, and glimepiride or metformin monotherapy,

when replacing combination therapy with glimepiride and metformin with a single combination drug.

As a rule, the dose of the drug Amaryl^® M should be determined by the target concentration of glucose in the patient's blood. The lowest dose, sufficient to achieve the necessary metabolic control, should be used.

During treatment with Amaryl^® M it is necessary to regularly determine the concentration of glucose in the blood and urine. In addition, regular monitoring of the percentage of glycosylated hemoglobin in the blood is recommended.

Incorrect drug administration, such as skipping the next dose, should never be made up for by taking a higher dose later.

The patient's actions in case of errors when taking the drug (in particular, when skipping the next dose or when skipping a meal), or in situations where it is not possible to take the drug, should be discussed by the patient and the doctor in advance.

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

The drug should be taken 1 or 2 times a day during meals.

The maximum dose of metformin per dose 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 greater than 6 mg is more effective.

In order to avoid the development of hypoglycemia, the initial dose of the drug Amaryl^® M should not exceed the daily doses of glimepiride and metformin that the patient is already taking. When transferring patients from taking a combination of individual drugs glimepiride and metformin to the drug Amaryl^® M its dose is determined on the basis of already taken doses of glimepiride and metformin in the form of separate drugs.

If necessary, increase the dose of the daily dose of the drug Amaryl^® M should be titrated in increments of only 1 table of the preparation Amaryl^® M 1 mg/250 mg or 1/2 table of the preparation Amaryl^®M 2 mg/500 mg.

Duration of treatment. Usually treatment with the drug Amaryl^® M is carried out for a long time.

type 1 diabetes mellitus,

history of diabetic ketoacidosis, diabetic ketoacidosis, diabetic coma and precoma, acute or chronic metabolic acidosis,

hypersensitivity to sulfonylurea derivatives, sulfonamide preparations or biguanides, as well as to any of the excipients of the drug,

severe hepatic impairment (lack of experience of use, such patients should be treated with insulin to ensure adequate glycemic control),

patients on hemodialysis (lack of experience with the use of),

renal insufficiency and impaired renal function (serum creatinine concentration: ≥1.5 mg/dl (135 mmol/l) in men and ≥1.2 mg/dl (110 µmol/l) in women or decreased creatinine clearance (increased risk of lactic acidosis and other side effects of metformin),

acute conditions in which renal function may be impaired (dehydration, severe infections, shock, intravascular administration of iodine-containing contrast agents, see the section " Special instructions»),

acute and chronic diseases that can cause tissue hypoxia (heart or respiratory failure, acute and subacute myocardial infarction, shock),

propensity to develop lactic acidosis, lactic acidosis in the anamnesis,

stressful situations (severe injuries, burns, surgical interventions, severe infections with a febrile state, septicemia),

exhaustion, starvation, compliance with a hypocaloric diet (less than 1000 cal/day),

violation of the absorption of food and drugs in the gastrointestinal tract (with intestinal obstruction, intestinal paresis, diarrhea, vomiting),

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 (lack of clinical experience).

With caution:

with the simultaneous use of certain medications (see " Interaction»),

in elderly patients (they often have an asymptomatic decrease in kidney function), in situations where kidney function may deteriorate, such as the start of taking antihypertensive drugs or diuretics, as well as NSAIDs (increased risk of lactic acidosis and other side effects of metformin),

when performing heavy physical work (increases the risk of lactic acidosis when taking metformin),

if there are no symptoms of adrenergic anti-glycemic regulation in response to developing hypoglycemia (in elderly patients, with neuropathy of the autonomic nervous system, or with simultaneous therapy with beta-blockers, clonidine, guanethidine and other sympathotics) (in such patients, more careful monitoring of blood glucose concentration is necessary),

with glucose-6-phosphate dehydrogenase deficiency (in such patients, when taking sulfonylurea derivatives, hemolytic anemia may develop, so the use of alternative hypoglycemic drugs that are not sulfonylurea derivatives in such patients should be considered).

Glimepiride

Based on the experience of using glimepiride and known data on other sulfonylurea derivatives, it is possible to develop the following side effects of the drug.

From the side of metabolism and diet: the development of hypoglycemia, which can be prolonged (as with the use of other sulfonylurea derivatives). Symptoms of developing hypoglycemia include: headache, acute hunger, nausea, vomiting, lethargy, lethargy, sleep disturbance, anxiety, aggressiveness, decreased concentration, decreased alertness, delayed psychomotor reactions, depression, confusion, speech disorder, aphasia, visual impairment, tremor, paresis, impaired sensitivity, dizziness, helplessness, loss of self-control, delirium, convulsions, drowsiness and loss of consciousness up to coma, superficial breathing, bradycardia. In addition, there may be signs of an adrenergic reaction to hypoglycemia: increased sweating, sticky skin, increased anxiety, tachycardia, increased blood pressure, a feeling of increased heartbeat, angina and arrhythmia. The clinical picture of an attack of severe hypoglycemia may resemble an acute violation of cerebral circulation. Symptoms almost always resolve after the glycemia is eliminated

On the part of the visual organ: visual impairment (especially at the beginning of treatment due to fluctuations in the concentration of glucose in the blood).

From the gastrointestinal tract: nausea, vomiting, feeling of full stomach, abdominal pain and diarrhea.

From the liver and biliary tract: increased liver enzyme activity and impaired liver function (such as cholestasis and jaundice), as well as hepatitis, which can progress to liver failure.

From the blood and lymphatic system: thrombocytopenia, in some cases-leukopenia, hemolytic anemia or erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia. Careful monitoring of the patient's condition is necessary, since cases of aplastic anemia and pancytopenia have been reported during treatment with sulfonylureas. If these phenomena occur, the drug should be discontinued and appropriate treatment should be initiated.

On the part of the immune system: allergic or pseudoallergic reactions (for example, itching, urticaria, or rashes). Such reactions almost always occur in a mild form, but can turn into a severe form, with shortness of breath or a decrease in blood pressure, up to the development of anaphylactic shock. If urticaria occurs, you should immediately consult a doctor. Possible cross-allergy with other sulfonylurea derivatives, sulfonamides or similar substances. Allergic vasculitis.

Other: photosensitization, hyponatremia.

Metformin

From the side of metabolism and nutrition: lactic acidosis (see "Special instructions"), hypoglycemia.

From the gastrointestinal tract: diarrhea, nausea, abdominal pain, vomiting, increased gas formation, lack of appetite are the most common reactions with metformin monotherapy. These symptoms are almost 30% more common than in patients taking placebo, especially at the beginning of treatment. These symptoms are mostly transient and go away on their own. In some cases, a temporary dose reduction may be useful. During clinical trials, metformin was discontinued in almost 4% of patients due to the occurrence of gastrointestinal reactions.

Since the development of symptoms from the gastrointestinal tract at the beginning of treatment was dose-dependent, their manifestations can be reduced by gradually increasing the dose and taking the drug with a meal.

Since diarrhea and / or vomiting can lead to dehydration and prerenal renal failure, if they occur, the drug should be temporarily discontinued.

At the beginning of treatment with metformin, approximately 3% of patients may experience an unpleasant or metallic taste in the mouth, which usually passes on its own.

On the skin side: erythema, itching, rash.

From the blood and lymphatic system: anemia, leukocytopenia, or thrombocytopenia. Approximately 9% of patients who received monotherapy with Amaryl^® M, and 6% of patients who were treated with metformin or metformin/a drug from the sulfonylurea group have an asymptomatic decrease in vitamin B levels₁₂ in the blood plasma (the level of folic acid in the blood plasma did not significantly decrease). Despite this, while taking the drug Amaryl^® M only megaloblastic anemia was registered, and no increase in the incidence of neuropathy was detected. Therefore, it is necessary to carry out appropriate monitoring of the level of vitamin B₁₂ in blood plasma (periodic parenteral administration of vitamin B may be required₁₂).

From the liver: impaired liver function.

All cases of the above adverse reactions or other adverse reactions should be reported to the patient immediately. Due to the fact that some adverse reactions, including hypoglycemia, hematological disorders, severe allergic and pseudoallergic reactions and liver failure can threaten the patient's life, if they develop, the patient should immediately inform the doctor about them and stop further taking the drug until receiving instructions from the doctor. Unexpected adverse reactions to Amaryl^® M, with the exception of the already known reactions to glimepiride and metformin, was not observed during phase I clinical trials and open phase III trials.

Glimepiride metformin

Taking a combination of these two drugs, either as a free combination composed of separate glimepiride and metformin, or as a combination drug with fixed doses of glimepiride and metformin, is associated with the same safety characteristics as using each of these drugs separately.

Amaryl^® M is a combined hypoglycemic drug, which includes 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.

Glimepiride stimulates the secretion and release of insulin from the beta cells of the pancreas (pancreatic action), improves the sensitivity of peripheral tissues (muscle and fat) to the action of endogenous insulin (extrapancreatic action).

Effect on insulin secretion

Sulfonylurea derivatives increase insulin secretion by closing ATP-dependent potassium channels located in the cytoplasmic membrane of pancreatic beta cells. By closing the potassium channels, they cause depolarization of beta cells, which helps to open the calcium channels and increase the intake of calcium into the cells.

Glimepiride binds and detaches at a high replacement rate from the protein of pancreatic beta cells (mol. mass 65 kD / SURX), which is associated with ATP-dependent potassium channels, but differs from the binding site of conventional sulfonylurea derivatives (mol. weighing 140 cD/SUR1).

This process leads to the release of insulin by exocytosis, while the amount of insulin secreted is significantly less than with the action of conventional (traditionally used) derivatives of sulfonylureas (for example, glibenclamide). The minimal stimulating effect of glimepiride on insulin secretion also provides a lower risk of hypoglycemia.

Extrapancreatic activity

Like traditional sulfonylureas, but to a much greater extent, glimepiride has pronounced extrapancreatic effects (reduction of insulin resistance, antiatherogenic, antiplatelet and antioxidant effects).

The utilization of glucose from the blood by peripheral tissues (muscle and fat) occurs with the help of special transport proteins (GLUT1 and GLUT4) located in the cell membranes. The transport of glucose to these tissues in type 2 diabetes is a speed-limited stage of glucose utilization. Glimepiride very quickly increases the number and activity of glucose-transporting molecules (GLUT1 and GLUT4), which leads to an increase in glucose uptake by peripheral tissues.

Glimepiride has a weaker inhibitory effect on ATP-dependent K - channels of cardiomyocytes. When taking glimepiride, the ability of the metabolic adaptation of the myocardium to ischemia is preserved.

Glimepiride increases the activity of phospholipase C, with which the drug-induced lipogenesis and glycogenesis can correlate in isolated muscle and fat cells.

Glimepiride inhibits the release of glucose from the liver by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis.

Glimepiride selectively inhibits cyclooxygenase and reduces the conversion of arachidonic acid to thromboxane A2, an important endogenous platelet aggregation factor.

Glimepiride helps to reduce the content of lipids, significantly reduces the peroxidation of lipids, which is associated with its anti-atherogenic effect

Glimepiride increases the content of endogenous alpha-tocopherol, the activity of catalase, glutathione peroxidase and superoxide dismutase, which helps to reduce the severity of oxidative stress in the patient's body, which is constantly present in type 2 diabetes mellitus.

Pharmacodynamics of metformin

Hypoglycemic drug from the group of biguanides. Its hypoglycemic effect is possible only if the insulin secretion is preserved (although reduced). Metformin has no effect on the beta cells of the pancreas and does not increase the secretion of insulin, in therapeutic doses does not cause hypoglycemia in humans.

The mechanism of action is not fully understood. It is suggested that metformin may potentiate the effects of insulin or increase these effects in the peripheral receptor areas. Metformin increases the sensitivity of tissues to insulin by increasing the number of insulin receptors on the surface cell membranes. In addition, metformin inhibits gluconeogenesis in the liver, reduces the formation of free fatty acids and fat oxidation, reduces the concentration of triglycerides (TG) and LDL and VLDL in the blood. Metformin slightly reduces appetite and reduces the absorption of carbohydrates in the intestine. It improves the fibrinolytic properties of the blood by suppressing the tissue type plasminogen activator inhibitor

Pharmacokinetics of glimepiride

When taken repeatedly in a daily dose of 4 mg C_max the blood plasma level is reached approximately 2.5 hours after oral administration and is 309 ng / ml, there is a linear ratio between the dose and C_max, as well as between the dose and the AUC. When glimepiride is taken orally, its absolute bioavailability is complete. Food intake does not significantly affect the absorption, except for a slight slowdown in its speed. Glimepiride is characterized by a very low V_d (about 8.8 l), approximately equal to the volume of albumin distribution, high degree of binding to plasma proteins (more than 99%) and low clearance (about 48 ml/min).

After a single oral dose of glimepiride, 58% of the drug is excreted by the kidneys (only in the form of metabolites) and 35% - through the intestine. T_1/2 at plasma concentrations in the serum corresponding to repeated administration, it is 5-8 hours. After taking the drug in high doses, there was an elongation of T_1/2.

In the urine and feces, 2 inactive metabolites are detected, formed as a result of metabolism in the liver, one of them is hydroxy- , and the second is a carboxyl derivative. After oral administration of glimepiride, terminal T_1/2 these metabolites were 3-5 and 5-6 hours, respectively.

Glimepiride is excreted in breast milk and penetrates the placental barrier. It penetrates poorly through the BBB. A comparison of single and multiple (2 times a day) administration of glimepiride did not reveal significant differences in pharmacokinetic parameters, their variability was different in different patients. There was no significant accumulation of glimepiride.

In patients of different genders and different age groups, the pharmacokinetic parameters of glimepiride are the same. In patients with impaired renal function (with low creatinine clearance), there was a tendency to increase the clearance of glimepiride and to decrease its average serum concentrations, which is most likely due to faster elimination of glimepiride due to its lower binding to plasma proteins. Thus, there is no additional risk of accumulation of glimepiride in this category of patients.

Pharmacokinetics of metformin

After oral administration, metformin is absorbed from the gastrointestinal tract quite completely. The absolute bioavailability of metformin is about 50-60%. C_max (approximately 2 µg / ml or 15 µmol) in plasma is reached after 2.5 hours. With simultaneous food intake, the absorption of metformin decreases and slows down.

Metformin is rapidly distributed in the tissues, practically does not bind to plasma proteins. It is metabolized to a very weak degree and is excreted by the kidneys. The clearance in healthy subjects is 440 ml / min (4 times greater than that of creatinine), which indicates the presence of active tubular secretion. After oral administration, terminal T_1/2 it is about 6.5 hours. With renal failure, it increases, there is a risk of accumulation of the drug.

Pharmacokinetics of the drug Amaryl^® M with fixed doses of glimepiride and metformin

Values of C_max and AUC when taking a combination drug with fixed doses (a tablet containing glimepiride 2 mg metformin 500 mg) meet the criteria for bioequivalence when compared with the same indicators when taking the same combination as separate drugs (a tablet of glimepiride 2 mg and a tablet of metformin 500 mg).

In addition, a dose-proportional increase in C was shown_max and the AUC of glimepiride with an increase in its dose in combination drugs with fixed doses from 1 to 2 mg with 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 adverse effects, between patients taking the drug Amaryl^® M 1 mg/500 mg and patients taking the drug Amaryl^® M 2 mg/500 mg.

• Hypoglycemic synthetic and other drugs in combinations

Glimepiride

If a patient who takes glimepiride is simultaneously prescribed or canceled other medications, both an undesirable increase and a weakening of the hypoglycemic effect of glimepiride is possible. Based on the experience of using glimepiride and other sulfonylurea derivatives, it is necessary to take into account the drug interactions listed below.

With drugs that are inducers or inhibitors of CYP2C9

Glimepiride is metabolized by cytochrome P450 CYP2C9. It is known that its metabolism is affected by the simultaneous use of CYP2C9 inducers, for example, rifampicin (the risk of reducing the hypoglycemic effect of glimepiride when used simultaneously with CYP2C9 inducers and an increased risk of hypoglycemia in the case of withdrawal of CYP2C9 inducers without dose adjustment of glimepiride) and CYP2C9 inhibitors, for example, fluconazole (increased risk of hypoglycemia and side effects of glimepiride when taken simultaneously with these drugs and the risk of reducing hypoglycemic effect of glimepiride on the withdrawal of CYP2C9 inhibitors without dose adjustment of glimepiride)

With drugs that enhance the hypoglycemic effect

Insulin and oral hypoglycemic agents, ACE inhibitors, allopurinol, anabolic steroids, male sex hormones, chloramphenicol, coumarin anticoagulants, cyclophosphamide, disopyramide, fenfluramine, pheniramidol, fibrates, fluoxetine, guanetidine, ifosfamide, MAO inhibitors, miconazole, fluconazole, aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), phenylbutazone, probenecid, antimicrobial agents of the quinolone group, salicylates, sulfinpyrazone, sulfonamide derivatives, tetracyclines, tritoxvaline, trophosfamide, azapropazone, oxyphenbutazone.

The risk of hypoglycemia increases with the simultaneous use of the above drugs with glimepiride and the risk of deterioration of glycemic control when they are discontinued without adjusting the dose of glimepiride.

With drugs that reduce the hypoglycemic effect

Acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine or sympathomimetics, glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens, progestogens, phenothiazines, phenytoin, rifampicin, thyroid hormones.

The risk of deterioration of glycemic control increases with the combined use of glimepiride with the listed drugs and the risk of hypoglycemia in the case of their withdrawal without adjusting the dose of glimepiride.

With drugs that can both enhance and reduce the hypoglycemic effect

Histamine H blockers₂- receptors, clonidine and reserpine.

With simultaneous use, both an increase and a decrease in the hypoglycemic effect of glimepiride is possible. Careful monitoring of the concentration of glucose in the blood is necessary.

With beta-blockers

Beta-blockers, clonidine, guanetidine, and reserpine, as a result of blocking the reactions of the sympathetic nervous system in response to hypoglycemia, can make the development of hypoglycemia more invisible to the patient and the doctor, and thereby increase the risk of its occurrence.

With sympatholytic agents

They can reduce or block the sympathetic nervous system's response to hypoglycemia, which can make the development of hypoglycemia more invisible to the patient and the doctor, and thus increase the risk of its occurrence.

With ethanol

Acute and chronic use of ethanol can unpredictably either weaken or enhance the hypoglycemic effect of glimepiride.

With indirect anticoagulants, coumarin derivatives

Glimepiride can both enhance and reduce the effects of indirect anticoagulants, coumarin derivatives.

Metformin

Not recommended combinations

With ethanol

With acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in the case of skipping or insufficient food intake, the presence of liver failure. Alcohol (ethanol) and ethanol-containing drugs should be avoided

With iodine-containing contrast agents

Intravascular administration of iodine-containing contrast agents can lead to the development of renal failure, which in turn can lead to the accumulation of metformin and an increased risk of lactic acidosis. Metformin should be discontinued before or during the study and not resumed for 48 hours after it, the resumption of metformin is possible only after the study and the normal indicators of renal function are obtained (see "Special instructions").

With antibiotics that have a pronounced nephrotoxic effect (gentamicin)

Increased risk of lactic acidosis (see "Special instructions").

Combinations of drugs with metformin that require caution

With GCS (systemic and topical), beta₂- adrenostimulants and diuretics with internal hyperglycemic activity. The patient should be informed about the need for more frequent monitoring of the morning blood glucose concentration, especially at the beginning of combination therapy. It may be necessary to adjust the doses of hypoglycemic therapy during the use or after the withdrawal of the above drugs.

With ACE inhibitors

ACE inhibitors can reduce the concentration of glucose in the blood. It may be necessary to adjust the dose of hypoglycemic therapy during the use or after the withdrawal of ACE inhibitors.

With drugs that enhance the hypoglycemic effect of metformin: insulin, sulfonylureas, anabolic steroids, guanetidine, salicylates (acetylsalicylic acid, etc.), beta-blockers (propranolol, etc.), MAO inhibitors

In the case of simultaneous use of these drugs with metformin, careful monitoring of the patient and monitoring of the concentration of glucose in the blood are necessary, since it is possible to increase the hypoglycemic effect of glimepiride.

With drugs that weaken the hypoglycemic effect of metformin: epinephrine, corticosteroids, thyroid hormones, estrogens, pyrazinamide, isoniazid, nicotinic acid, phenothiazines, thiazide diuretics and diuretics of other groups, oral contraceptives, phenytoin, sympathomimetics, blockers of "slow" calcium channels

In the case of simultaneous use of these drugs with metformin, careful monitoring of the patient and monitoring of the concentration of glucose in the blood are necessary, since it is possible to weaken the hypoglycemic effect.

Interactions to take into account

With furosemide

In a clinical study on the interaction of metformin and furosemide with their single administration in healthy volunteers, it was shown that the simultaneous use of these drugs affects their pharmacokinetic parameters. Furosemide increased C_max metformin in the blood plasma by 22%, and AUC-by 15% without any significant changes in the renal clearance of metformin. When used with metformin C_max and furosemide AUC decreased by 31 and 12%, respectively, compared with furosemide monotherapy, and the final half-life decreased by 32% without any significant changes in the renal clearance of furosemide. There is no information about the interaction of metformin and furosemide with long-term use.

With nifedipine

In a clinical study of the interactions of metformin and nifedipine with their single administration in healthy volunteers, it was shown that the simultaneous use of nifedipine increases C_max and the AUC of metformin in the blood plasma by 20 and 9%, respectively, and also increases the amount of metformin released by the kidneys. Metformin had minimal effect on the pharmacokinetics of nifedipine.

With cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin)

Cationic drugs excreted by tubular secretion in the kidneys are theoretically able to interact with metformin as a result of competition for a common tubular transport system. This interaction between metformin and oral cimetidine was observed in healthy volunteers in clinical studies of the interaction of metformin and cimetidine with single and multiple use, where there was a 60% increase in the maximum plasma concentration and total concentration of metformin in the blood and a 40% increase in the plasma and total AUC of metformin. With a single dose, there were no changes in the half-life. Metformin did not affect the pharmacokinetics of cimetidine. Despite the fact that such interactions remain purely theoretical (with the exception of cimetidine), careful monitoring of patients should be ensured and dose adjustment of metformin and/or the drug interacting with it should be carried out in the case of simultaneous administration of cationic drugs excreted from the body by the secretory system of the proximal tubules of the kidneys

With propranolol, ibuprofen

In healthy volunteers, no changes in their pharmacokinetic parameters were observed in studies on a single dose of metformin and propranolol, as well as metformin and ibuprofen.