Amaryl m pills 2mg + 500mg №30

Coated tablets

Composition

In 1 tablet, film coated, contains:
Active ingredients
Glimepiride micronized 2 mg.
Metformin hydrochloride 500 mg.
Excipients
Lactose monohydrate 50 mg, sodium carboxymethyl starch 15 mg, povidon-KZO 25 mg, microcrystalline cellulose 50 mg, crospovidone 10 mg, Magnesium stearate 5 mg.
Film shell
Hypromellose 9.4 mg, macrogol-6000 1.7 mg, titanium dioxide (E 171) 1.7 mg, carnauba wax 0.2 mg.

Packing

30 pieces

Mechanism of action

Amaryl M is a combined hypoglycemic drug, which consists of Glimepiride and Metformin.
Glimepiride
Glimepiride is an oral hypoglycemic drug - a derivative of the third generation sulfonylurea.
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 (extra pancreatic 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 beta cells of the pancreas.Closing the potassium channels, they cause the depolarization of beta cells, which contributes to the opening of Calcium channels and an increase in calcium intake inside the cells. Glimepiride connects and detaches from the protein of the beta cells of the pancreas (mol. Mass 65 kD / SURX), which is associated with ATP-dependent potassium channels, but differs from the binding site of the usual sulfonylurea derivatives (protein with mol. Mass 140 kD / SURI).
This process leads to the release of insulin by exocytosis, while the amount of secreted insulin is much less than under the action of conventional (traditionally used) sulfonylurea derivatives (for example, glibenclamide). The minimal stimulating effect of glimepiride on insulin secretion provides a lower risk of hypoglycemia.
Extrapancreatic activity
Like traditional sulfonylurea derivatives, but to a much greater extent, glimepiride has pronounced extrapancreatic effects (decreased insulin resistance, less effect on the cardiovascular system, anti-atherogenic, antiplatelet and antioxidant effects).
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 mellitus is a speed-limited step 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 the ATP-dependent K + channels of cardiomyocytes. When taking glimepirida retains the ability of metabolic myocardial adaptation to ischemia.
It increases the activity of phospholipase C, with which, in isolated muscle and fat cells, lipogenesis and glycogenesis caused by the preparation can correlate.
Inhibits the production of glucose in the liver by increasing the intracellular concentrations of fructose 2,6-bisphosphate, which in turn inhibits gluconeogenesis.
Selectively inhibits cyclooxygenase and reduces the conversion of arachidonic acid to thromboxane A2, which promotes platelet aggregation, thus exerting an antithrombotic effect. Glimepiride helps to reduce the content of lipids, significantly reduces lipid peroxidation, it contributes to the anti-atherogenic effect of the drug.
Increases the content of endogenous α-tocopherol, the activity of catalase, glutathione peroxidase and superoxide dismutase, which helps reduce the severity of oxidative stress in the patient's body, which is constantly present in type 2 diabetes.
Metformin
Metformin is a hypoglycemic drug from the biguanide group.Its hypoglycemic effect is possible only if insulin secretion is maintained (albeit reduced). Metformin does not affect the beta 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 may potentiate the effects of insulin or that it may increase the effects of insulin in peripheral receptor areas. Metformin increases the sensitivity of tissues to insulin due to an increase in 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 the oxidation of fats, reduces the concentration of triglycerides (TG) and low density lipoproteins (LDL) and very low density lipoproteins (LDLP) in the blood. Metformin slightly reduces appetite and reduces the absorption of carbohydrates in the intestines. It improves blood fibrinolytic properties by suppressing a tissue-type plasminogen activator inhibitor.

Indications and usage

Type 2 diabetes:
When glycemic control cannot be achieved with a combination of diet, exercise, weight loss and monotherapy with glimepiride or metformin.
In the case of replacement of the combination therapy with glimepiride and metformin to receive one combination drug Amaryl M.

Contraindications

Type 1 diabetes.
History of diabetic ketoacidosis, diabetic ketoacidosis, diabetic coma and precomatose state, acute or chronic metabolic acidosis.
Hypersensitivity to sulfonylurea derivatives, sulfonamides or biguanides, as well as to any of the excipients of the drug.
Severe abnormal liver function (lack of experience; insulin treatment is necessary to ensure adequate glycemic control).
Impaired renal function, including patients on hemodialysis. Serum creatinine concentration:> 1.5 mg / dL in men and> 1.4 mg / dL in women or reduced creatinine clearance (increased risk of developing lactic acidosis and other side effects of metformin).
Tendency to the development of lactic acidosis, lactic acidosis in history.
Stressful situations (severe injuries, burns, surgeries, severe infections with fever, septicemia.).
Heart failure, collapse (shock), acute myocardial infarction.
Exhaustion, fasting, dehydration, adherence to a low-calorie diet (less than 10OO cal / day).
Impaired absorption of food and drugs in the gastrointestinal tract (with intestinal obstruction, intestinal paresis; diarrhea, vomiting).
Pituitary or adrenal insufficiency.
Severe violation of pulmonary function, and other hypoxic conditions, including tissue hypoxia (cardiac or respiratory failure, acute myocardial infarction, etc.).
Chronic alcoholism, acute alcohol poisoning.
Intravenous administration of Iodine contrast agents, since they can cause acute renal failure (the drug is not prescribed 48 hours before and 48 hours after the study).
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
Pregnancy, pregnancy planning.
Lactation.
Children's age up to 18 years (lack of clinical data).
If you have one of the listed diseases or conditions, be sure to consult your doctor before taking the drug.
Carefully:
In conditions that increase the risk of hypoglycemia (patients who are unwilling or unable to cooperate with the doctor, most often, elderly patients; poorly nourished, not regularly taking meals, skipping meals of patients; with a discrepancy between exercise and carbohydrate intake; with changing diet ; when drinking alcohol, especially in combination with skipping meals; in cases of impaired liver and kidney function; in some uncompensated endocrine disorders, such as impaired function itovidnoy gland insufficiency hormones of the anterior pituitary and the adrenal cortex, affecting carbohydrate metabolism or activation mechanisms aimed at increasing blood glucose concentrations during hypoglycemia (such patients, a more careful control of blood glucose concentration and symptoms of hypoglycemia).
With the simultaneous use of some other drugs.
With a decrease in kidney function in such conditions as advanced age, collapse, shock (increased risk of developing lactic acidosis and other side effects of metformin).
When performing heavy physical work (the risk of lactic acidosis increases when taking metformin).
With smoothing or absence of symptoms of hypoglycemia associated with the activation of the sympathetic nervous system (in elderly patients, with neuropathic lesions of the autonomic nervous system, or with simultaneous therapy with beta-adrenergic blockers, clonidine, guanethidine and other sympatholytic agents) (in such patients more careful monitoring of concentration is necessary) blood glucose).
If you have one of the listed diseases or conditions, be sure to consult your doctor before taking the drug.

Pregnancy
This drug should not be taken during pregnancy because of the possible adverse effects on fetal development.
Pregnant women and women planning a pregnancy should report this to their doctor.
During pregnancy, women with impaired carbohydrate metabolism, not corrected by a single diet and exercise, should receive insulin therapy.
Lactation
In order to avoid getting the drug with breast milk in the body of a child to women who are breastfeeding,You can not take this drug. If necessary, the patient should be transferred to insulin, or stop breastfeeding.

Adults: dosing of hypoglycemic drugs should be carried out individually, taking into account the concentration of glucose in the blood of the patient. As a rule, it is recommended to begin treatment with the smallest effective dose and, depending on the glucose concentration in the patient’s blood, increase the dose. For this, it is necessary to conduct an appropriate monitoring of the concentration of glucose in the blood. The drug should be administered 1 or 2 times a day, before or during the meal.
Children: the study, the safety and efficacy of the drug in children with type 2 diabetes has not been conducted.
Elderly patients: it is known that metformin is excreted mainly by the kidneys, and since the risk of severe adverse reactions to the drug in patients with impaired renal function is higher, the drug can only be used in patients with normal renal function, due to the fact that with age renal function decreases, with age metformin should be used with caution. Care should be taken to carefully select the dose and to ensure careful and regular monitoring of renal kidney function.

Glimepiride
Based on clinical experience with glimepiride and known data on other sulfonylurea derivatives, adverse reactions listed below may develop.
Metabolic and nutritional disorders
Hypoglycemia: the development of hypoglycemia, which, judging by other sulfonylurea drugs, may be protracted. Symptoms of developing hypoglycemia include: headache, an acute feeling of hunger, nausea, vomiting, lethargy, lethargy, sleep disturbance, anxiety, aggressiveness, decreased concentration, decreased alertness and slowed down psychomotor reactions, depression, confusion, speech disorders, aphasia, disturbances of vision, tremor, paresis, impaired sensitivity, dizziness, helplessness, loss of self-control, delirium, convulsions, drowsiness and loss of consciousness, even coma, shallow breathing and bradycardia. In addition, signs of an adrenergic reaction to hypoglycemia may develop, such as increased sweating, skin stickiness, increased anxiety, tachycardia, increased blood pressure, a feeling of palpitations, angina and arrhythmias. The clinical picture of an attack of severe hypoglycemia may resemble acute cerebrovascular accident. Symptoms are almost always resolved after the elimination of hypoglycemia.
Violations by the organ of vision
Visual impairment, especially at the beginning of treatment, due to fluctuations in glucose concentration in the blood.
Disorders of the gastrointestinal tract
The development of gastrointestinal symptoms, such as nausea, vomiting, a feeling of fullness in the stomach, abdominal pain and diarrhea.
Disorders of the liver and biliary tract
Increased activity of “liver” enzymes and abnormal liver function (for example, cholestasis and jaundice), as well as hepatitis, which can progress to liver failure.
Violations of the blood and lymphatic system
Thrombocytopenia, in some cases - leukopenia or hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis or pancytopenia. Due to the fact that during the treatment with sulfonylureas aplastic anemia and pancytopenia were recorded, careful monitoring should be carried out. With their development, the drug should be discontinued and appropriate treatment should be initiated.
Immune system disorders (hypersensitivity reactions)
Allergic or pseudo-allergic reactions (eg, pruritus, urticaria, or rash). These reactions almost always have a light form, however, they 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 develops, you should immediately inform your doctor. Possible cross-allergy with other sulfonylurea derivatives, sulfonamides or similar substances.
Allergic vasculitis.
Other
Photosensitization, hyponatremia.
Metformin
Metabolic and nutritional disorders
Lactic acidosis, hypoglycemia.
Disorders of the gastrointestinal tract
Gastrointestinal symptoms (diarrhea, nausea, abdominal pain, vomiting, increased flatulence, flatulence and lack of appetite) are the most frequent reactions with metformin monotherapy, occurring approximately 30% more often than when taking placebo, especially in the initial period of therapy. These symptoms are predominantly temporary, with continued treatment they are spontaneously resolved. In some cases, it may be useful to temporarily reduce the dose. In clinical studies due to gastrointestinal reactions, this drug was withdrawn in about 4% of patients. Due to the fact that the development of gastrointestinal symptoms in the initial period of treatment is dose-dependent, these symptoms can be reduced by gradually increasing the dose and taking the drug during a meal. Since severe diarrhea and / or vomiting can lead to dehydration and prerenal renal failure, when they appear, you should temporarily stop taking this drug.
At the beginning of treatment with metformin, approximately 3% of patients may develop an unpleasant or metallic taste in the mouth, which usually spontaneously disappears.
Violations of the skin and subcutaneous tissues
Skin reactions: erythema, pruritus, rash.
Violations of the blood and lymphatic system
Anemia, leukocytopenia or thrombocytopenia. Approximately 9% of patients with monotherapy with this drug and 6% of patients receiving metformin or metformin / drug from the sulfonylurea group, have an asymptomatic decrease in serum vitamin B 12 concentration (serum folate concentration does not significantly decrease). Despite this, in connection with the intake of this drug, only interregional anemia was registered, and there was no increase in the incidence of neuropathy. Therefore, it is necessary to carry out appropriate monitoring of the concentration of vitamin B 12 in serum, it may be necessary to periodically parenteral replenishment of vitamin B 12.
Disorders of the liver and biliary tract
With the development of the above or other adverse reactions, the patient should immediately notify your doctor. Since some adverse reactions, including hypoglycemia, hematological disorders, severe allergic and pseudo-allergic reactions and hepatic insufficiency can threaten the patient’s life, if such reactions develop, the patient should immediately inform your doctor and stop taking the drug further before receiving instructions from the doctor.
With the exception of the already known reactions to glimepiride and metformin, there were no unexpected undesirable reactions to Amaryl M in phase I clinical trials and in open phase III trials.

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 the assessment of glycemic control.
During the first week of treatment, careful monitoring is necessary because of the risk of hypoglycemia, especially when there is an increased risk of its development (patients who are unwilling or unable to follow the doctor's recommendations, most often elderly patients; with poor nutrition, irregular meals, with skipping meals; when there is a discrepancy between exercise and carbohydrate consumption, with changes in diet, with alcohol consumption, especially in combination with skipping meals, with kidney dysfunction, with severe dysfunction liver, with an overdose of the drug Amaryl M; with some uncompensated disorders of the endocrine system (for example, dysfunction of the thyroid gland lack of function of the anterior pituitary or adrenal glands; while some other drugs that affect carbohydrate metabolism.
In such cases, careful monitoring of glucose concentration in the blood is necessary.
The patient should inform the doctor about these factors and the symptoms of hypoglycemia, if any. If there are risk factors for hypoglycemia, a dose adjustment of this drug or the whole therapy may be required. This approach is used whenever a disease develops during therapy and when the patient's lifestyle changes. Symptoms of hypoglycemia, reflecting adrenergic anti-hypoglycemic regulation, may be less pronounced or completely absent,if hypoglycemia develops gradually, as well as in elderly patients, with neuropathy of the autonomic nervous system, or with simultaneous therapy with beta-blockers, clonidine, guanethidine and other sympatholytic agents.
It is necessary to maintain target glycemia with the help of complex measures: with the help of diet and exercise, and if necessary, due to weight loss and with the help of regular intake of this drug. The clinical symptoms of inadequately regulated blood glucose include: oliguria, thirst, pathologically strong thirst, dry skin, and others.
Patients should be informed about the possible side effects of this drug. Patients should also be informed about the importance of dietary compliance and regular exercise.
Almost always, hypoglycemia can be stopped quickly with the help of an immediate carbohydrate intake (glucose or sugar, for example, a lump of sugar, fruit juice, containing sugar, tea with sugar, etc.). To this end, the patient should carry with him 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 of using other sulfonylurea drugs, it is known that, despite the initial efficacy of the taken countermeasures, hypoglycemia can recur. Therefore, patients should remain under close supervision.The development of severe hypoglycemia requires immediate treatment and medical observation, in some cases - inpatient treatment.
If a patient is treated by a non-attending physician (for example, hospitalization, accident, need for a visit to the doctor on a day off, etc.), the patient should inform him about the diabetes and the treatment being carried out.
In stressful situations (for example, trauma, surgery, infectious disease with temperature), glycemic control may be impaired, and a temporary transition to insulin therapy may be required to ensure the necessary control over metabolism.
Monitoring kidney function: it is known that metformin is excreted mainly by the kidneys. If kidney damage occurs, the risk of metformin cumulation and the development of lactic acidosis increases. Therefore, when serum creatinine concentration exceeds the upper age limit of the norm, it is not recommended to take this drug. For elderly patients, careful titration of the dose of this drug is necessary in order to select the minimum dose to provide the corresponding glycemic effect, since the kidney function decreases with age. Renal function in elderly patients should be monitored regularly, and, as a rule, this drug should not be titrated to the maximum dose.
Taking other medicines at the same time can affect kidney function or the removal of metformin.Simultaneous use of other medicines may affect kidney function or cause significant changes in hemodynamics, or affect the release of this drug. X-ray examinations with intravascular injection of iodine-containing contrast agents (for example, intravenous urography, intravenous cholangiography, angiography and computed tomography (CT) using a contrast agent): contrast intravenous iodine-containing substances intended for research can cause acute impairment of renal function, their use is associated with lactic acidosis in patients taking this drug. Therefore, if you plan to conduct such a study, this drug should be canceled 48 hours before the procedure and not to resume its appointment in the next 48 hours after the procedure. It is possible to resume treatment with this drug only after monitoring renal function, if the latter turns out to be normal.
Conditions of hypoxia: collapse or shock of any origin, acute heart failure, acute myocardial infarction and other conditions characterized by hyoxemia are accompanied by lactic acidosis and can also cause prerenal renal failure. If such conditions arise in patients taking this drug, the drug should be discontinued immediately.
Surgical operations: for any surgical intervention, it is necessary to temporarily discontinue therapy with this drug (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 recognized as normal.
Alcohol intake: it is known that alcohol enhances the effect of metformin on lactate metabolism. Therefore, patients should be cautioned against consuming alcohol while taking this drug.
Changes in the clinical condition of a patient with previously controlled diabetes mellitus: a patient with diabetes mellitus, a previously well-controlled metformin is subject to immediate examination, especially for a poorly and poorly recognized disease, to exclude ketoacidosis and lactic acidosis. The study should include: determination of electrolytes and ketone bodies of serum, blood glucose and, if necessary, blood pH, lactate, pyruvate and metformin concentrations. If any form of acidosis is present, this drug should be immediately discontinued and other means should be prescribed to maintain glycemic control. Information for patients: Patients should be informed about the possible risks and advantages of this drug, as well as alternative treatment methods. The importance of following dietary guidelines, regular exercise and regular monitoring of blood glucose, glycated hemoglobin, kidney function and hematological parameters should also be well explained.
Usually metformin itself does not cause hypoglycemia, although the latter is possible if metformin is used in conjunction with sulfonylurea derivatives for oral administration.When starting a combination therapy, patients should be told about the risk of hypoglycemia, its symptoms and treatment, as well as the conditions that predispose to its development.
The concentration of vitamin B12
A decrease in the serum vitamin B12 concentration below normal in the absence of clinical manifestations was observed in about 7% of patients who took this drug during controlled clinical studies for a period of 29 weeks. Probably, this decrease is due to the effect of vitamin B 12 complex, the internal factor of Castle on the absorption of vitamin B 12, however, it is very rarely accompanied by anemia and when you cancel this drug or when prescribing vitamin B 12 quickly reversible. Some people (with inadequate intake or absorption of vitamin B 12) are prone to lower vitamin B 12 concentrations.
For such patients it may be useful to regularly determine serum vitamin B 12 every 2-3 years.
Hematological parameters (hemoglobin or hematocrit, red blood cell count) and kidney function indicators (creatinine) should be monitored periodically at least once a year and appropriate examination and treatment of any obvious pathological changes. In spite of the fact that development of megaloblastic anemia was rarely observed when taking metformin, if it is suspected, it should be examined to exclude vitamin B deficiency.
Lactic acidosis
Lactic acidosis is a rare but severe metabolic complication that develops as a result of accumulation of metformin during treatment.In approximately 50% of cases, lactic acidosis is fatal. Lactic acidosis can also occur due to certain pathophysiological conditions, including diabetes mellitus, as well as significant tissue ischemia and hypoxemia. Lactic acidosis is characterized by an increase in blood lactate concentration (> 5 mmol / l), a decrease in blood pH, electrolyte imbalance with an increase in anion deficiency and an increase in the ratio between lactate and pyruvate. In cases where the cause of lactic acidosis is metformin, the plasma concentration of metformin is typically> 5 μg / ml.
The frequency of reported cases of lactic acidosis in patients taking metformin is very low (about 0.03 cases / 1000 patient-years with an approximate death rate of 0.015 cases / 1000 patient-years). Reported cases have occurred mainly in diabetic patients with severe renal insufficiency, including congenital kidney disease and renal hypoperfusion, often in the presence of numerous concomitant conditions requiring conservative or surgical treatment and concomitant medical treatment.
The risk of developing lactic acidosis increases with the severity of renal dysfunction and with age. The chance 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 this drug.
As a rule, due to the fact that an abnormal liver function can significantly limit the excretion of lactate, it should be avoided that patients with clinical or laboratory signs of liver disease should be prescribed this drug.
In addition, the drug should be temporarily discontinued before conducting x-ray studies using intravascular contrast agents and before surgical interventions.
Often lactic acidosis develops gradually and manifests itself only with nonspecific symptoms, such as poor health, myalgia, respiratory disorders, increasing drowsiness and nonspecific disorders of the gastrointestinal tract. With more severe acidosis, hypothermia, lowering blood pressure and resistant bradiarrhythmia may occur. Both the patient and the treating physician should know how important these symptoms can be. The patient should be instructed to, in case of such symptoms, immediately notify the physician. 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, the pH of the blood, lactate and metformin in the blood. If the patient is already stabilized on any dose of this drug, then gastrointestinal symptoms, which often occur at the beginning of metformin therapy, may be due to the development of lactic acidosis or other serious illness.Plasma lactate concentration in the venous blood on an empty stomach, exceeding the upper limit of normal, but below 5 mmol / l, in patients taking this drug does not necessarily indicate lactic acidosis, it can be explained by other mechanisms, such as poorly controlled diabetes mellitus or obesity, intense physical stress or technical errors in blood sampling for analysis.
It should be assumed the presence of lactic acidosis 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 this drug and begin general supportive measures. Due to the fact that metformin is removed from the blood by hemodialysis with clearance up to 170 ml / min, provided there is no hemodynamic disturbance, immediate hemodialysis is recommended to correct acidosis and remove accumulated metformin. Such measures often lead to the rapid disappearance of symptoms and recovery.
Liver dysfunction
Since in some cases lactic acidosis was associated with impaired liver function, it is usually necessary to avoid using this drug in patients with clinical or laboratory signs of liver damage.
Influence on ability to drive motor transport and control mechanisms
The reaction rates of the patient may worsen as a result of hypoglycemia and hyperglycemia, especially at the beginning of treatment or after changes in treatment, or if the drug is taken irregularly. This may affect the ability to drive vehicles and other mechanisms.
Patients should be warned about the need for caution when driving vehicles, especially in the case of a tendency to develop hypoglycemia and / or reduce the severity of its precursors.

Glimepiride
When a patient receiving glimepiride is administered at the same time or from