Amaryl M - instructions for use, dose, side effects, contraindications

Active substanceGlimepiride + MetforminGlimepiride + Metformin

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Amaryl® M

pills inwards

Sanofi-Aventis SA Spain

Dosage form: & nbspfilm coated tablets

Composition:

Tablets 1 mg + 250 mg

One tablet contains:

active ingredients: glimepiride micronized - 1 mg, metformin hydrochloride - 250 mg;

Excipients: lactose monohydrate - 25 mg, sodium carboxymethyl starch - 7.5 mg, povidone-K30 - 12.5 mg, microcrystalline cellulose 25 mg, crospovidone 5 mg, magnesium stearate 2.5 mg; film sheath: hypromellose - 4.7 mg, macrogol-6000 - 0.85 mg, titanium dioxide (E 171) - 0.85 mg, carnauba wax 0.1 mg.

Tablets 2 mg + 500 mg One tablet contains:

active ingredients: glimepiride micronized - 2 mg, metformin hydrochloride - 500 mg;

Excipients: lactose monohydrate - 50 mg, sodium carboxymethyl starch - 15 mg, povidone-K30 - 25 mg, microcrystalline cellulose - 50 mg, crospovidone - 10 mg, magnesium stearate - 5 mg; film sheath: hypromellose - 9.4 mg, macrogol-6000 - 1.7 mg, titanium dioxide (E 171) 1.7 mg, carnauba wax 0.2 mg.

Description:

Tablets 1 mg + 250 mg

Oval biconvex tablets, covered with a white film shell, engraved HD125 on one side.

Tablets 2 mg + 500 mg

Oval biconvex tablets, coated with a film sheath of white color, with engraving HD25 on one side and risk on the other side.

Pharmacotherapeutic group:hypoglycemic agent for oral administration combined (biguanide + sulfonylurea derivative).

ATX: & nbsp

A.10.B.D.02 Metformin and sulfonamides

Pharmacodynamics:

The drug Amaryl® M is a combined hypoglycemic drug, which includes glimepiride and metformin.

Pharmacodynamics of glimepiride

Glimepiride, one of the active substances of Amaril® M, is a hypoglycemic agent for oral use, a derivative of the sulfonylurea of the third generation.

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

Influence on secretion of insulin.

Derivatives of sulfonylureas increase the secretion of insulin by closing ATP-dependent potassium channels located in the cytoplasmic membrane of the pancreatic beta cells. Closing the potassium channels, they cause depolarization of beta cells, which helps to open calcium channels and increase the intake of calcium inside the cells. Glimepiride with high replacement speed joins and detaches from the beta-cell protein of the pancreas (molecular weight 65 kD / SURX), which is associated with ATP-dependent potassium channels, but differs from the binding site of the usual derivatives of sulfonylurea (protein with a molecular weight of 140 kD / SURl).

This process results in the release of insulin by exocytosis, while the amount of insulin secreted is significantly less than that of the sulfonylurea derivatives of the second generation (eg, glibenclamide).

The minimal stimulating effect of glimepiride on the secretion of insulin provides a lower risk of hypoglycemia.

Extrapancreatic activity

Like the traditional derivatives of sulfonylureas, but to a much greater extent, glimepiride has pronounced extrapancreatic effects (decreased insulin resistance, anti-atherogenic, antiplatelet and antioxidant effect).

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 into these tissues in type 2 diabetes is a rate-limiting step in the utilization of glucose. Glimepiride very quickly increases the number and activity of molecules transporting glucose (GLUT1 and GLUT4), contributing to an increase in the assimilation of glucose by peripheral tissues. Glimepiride has a weaker inhibitory effect on ATP-dependent potassium channels of cardiomyocytes. When glimepiride is taken, the ability of metabolic adaptation of the myocardium to ischemia remains.

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 stimulation of glucose metabolism.

Glimepiride inhibits glucose output from the liver by increasing

intracellular concentrations of fructose-2,6-bisphosphate, which in

In turn, it inhibits gluconeogenesis.

Glimepiride selectively inhibits cyclooxygenase and reduces

conversion of arachidonic acid into thromboxane A2, an important endogenous platelet aggregation factor.

Glimepiride helps to reduce the lipid content, significantly

reduces lipid peroxidation, with what its antiatherogenic effect is connected. Glimepiride increases the content of endogenous a-tocopherol, catalase activity, glutathione peroxidase and superoxide dismutase, which contributes to the reduction of the oxidative stress that is constantly present in the body of patients with type 2 diabetes.

Pharmacodynamics of metformin

Metformin is a hypoglycemic agent from the biguanide group. Its hypoglycemic The action is possible only under condition of preservation of secretion of insulin (though also reduced). Metformin does not affect the beta cells of the pancreas and does not increase the secretion of insulin. Metformin in therapeutic doses does not cause hypoglycemia in humans. The mechanism of action of metformin has not yet been fully clarified. It is assumed, what metformin can potentiate the effects of insulin or that it can increase the effects of insulin in the peripheral receptor zones. Metformin Increases the sensitivity of tissues to insulin by increasing the number of insulin receptors on the surface of cell membranes. Besides 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), low density lipoproteins (LDL) and very low density lipoproteins (LNAP).

Metformin slightly reduces appetite and decreases absorption

carbohydrates in the intestine. It improves the fibrinolytic properties of the blood by suppressing the inhibitor of the tissue plasminogen activator.

Pharmacokinetics:

Pharmacokinetics of glimepiride

With repeated administration of glimepiride in a daily dose of 4 mg, the maximum concentration in the blood plasma (Cmax) is reached after approximately 2.5 hours and is 309 ng / ml; there is a linear relationship between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve). When ingested glimepiride, its absolute bioavailability is complete.

Eating does not have a significant effect on absorption, except for a slight slowing of its speed. Glimepiride is characterized by a very low volume of distribution (about 8.8 liters), approximately equal to the volume of distribution of albumin, a high degree of binding to plasma proteins (more than 99%) and low clearance (about 48 ml / min).

After a single glimepiride intake, 58% of the dose taken is excreted by the kidneys (in the form of metabolites), and 35% of the accepted dose is excreted through the intestine.The half-life at plasma concentrations of glimepiride in the blood plasma corresponding to multiple intake is 5-8 hours. After taking high doses, the half-life period increases somewhat.

In urine and in stool, two inactive metabolites are identified, formed as a result of metabolism in the liver, one of them is a hydroxy derivative, and the other is a carboxy derivative. After ingestion of glimepiride, the terminal half-life of these metabolites is 3-5 hours and 5-6 hours, respectively.

Glimepiride penetrates into breast milk and through the placental barrier.

Glimepiride poorly penetrates the blood-brain barrier.

Comparison of a single and multiple (2 times a day) reception

glimepiride revealed no significant differences in pharmacokinetic

indicators, and their variability in different patients was insignificant. A significant accumulation of glimepiride was absent.

In patients of different sex 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 reduce its average concentrations in blood plasma, which in all likelihood,is due to the faster elimination of glimepiride due to its lower binding to plasma proteins. Thus, in this category of patients there is no additional risk of cumulating glimepiride.

Pharmacokinetics of metformin

After oral administration metformin It is absorbed from the gastrointestinal tract quite fully. Absolute bioavailability is 50-60%. Stam, averaging 2 μg / ml, is achieved after 2.5 hours. With simultaneous intake of food, the absorption of metformin decreases and slows down.

Metformin is rapidly distributed into tissues, practically does not bind to blood plasma proteins. Exposed to a very weak degree of metabolism and excreted by the kidneys. Clearance in healthy volunteers is 440 ml / min (4 times more than creatinine clearance), which indicates the presence of active canaliculosis secretion of metformin. The half-life is approximately 6.5 hours.

With renal failure, there is a risk of cumulation of metformin.

Pharmacokinetics Amaril® M with fixed doses of glimepiride and metformin. The values of Cmax and AUC when taking a combination drug with fixed doses (tablet containing glimepiride 2 mg + metformin 500 mg) meet the bioequivalence criteria when compared with the same indicators when taking the same combination as separate preparations (glimepiride tablet 2 mg and metformin 500 mg tablet).

In addition, a dose-proportional increase in Cmax and AUC of glimepiride was shown with an increase in its dose from 1 mg to 2 mg in fixed-dose combination preparations with a constant dose of metformin (500 mg) in these preparations. In addition, there were no significant differences in safety, including the profile of adverse effects, between patients taking Amaril® M 1 mg + 500 mg and patients taking Amaril® M 2 mg + 500 mg.

Indications:

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

when glycemic control can not be achieved with monotherapy with glimepiride or metformin;

when replacing the combined therapy with glimepiride and metformin for the administration of one combined drug Amaryl® M.

Contraindications:

Type 1 diabetes mellitus;
Diabetic ketoacidosis, incl. in anamnesis, diabetic coma and precoma, acute or chronic metabolic acidosis;
Hypersensitivity to derivatives of sulfonylurea, sulfonylamide preparations or biguanides, as well as to any of the excipients of the preparation;
Severe impairment of liver function (no experience of use, such patients need insulin treatment to ensure adequate glycemic control);
Patients on hemodialysis (no experience of use);
Renal failure and impaired renal function (creatinine concentration in the blood plasma:> 1.5 mg / dL (135 μmol / L) in men and> 1.2 mg / dl (110 μmol / L) in women or decreased creatinine clearance (elevated risk of lactic acidosis and other side effects of metformin);
Acute conditions in which renal dysfunction is possible (dehydration, severe infections, shock, intravascular injection of iodine-containing contrast agents, (see section "Special instructions");
Acute and chronic diseases that can cause tissue hypoxia (cardiac 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 fever, septicemia);
Exhaustion, starvation, compliance with hypocaloric diet (less than 1000 kcal / day);
Disruption of absorption of food and drugs in the gastrointestinal tract (with intestinal obstruction, intestinal paresis, diarrhea, vomiting);
Chronic alcoholism,
acute alcohol intoxication;
Deficiency lactase,
intolerance to galactose, glucose galactose malabsorption;
Pregnancy, pregnancy planning;
Period breastfeeding;
Children and adolescents under 18 years of age (inadequate clinical experience).

Carefully:

In the first weeks of treatment with Amaril® M, the risk of hypoglycemia increases, which requires particularly careful monitoring.

- In conditions that increase the risk of developing hypoglycemia (patients who do not want or are not able (usually elderly patients) to cooperate with a doctor, malnourished, irregularly taking food, skipping meals, patients with a disparity between physical activity and carbohydrate intake; when you change the diet, with drinks containing ethanol, especially in combination with skipping meals; with violations of liver function andkidney; with some uncompensated endocrine disorders, such as thyroid dysfunction, insufficiency of the hormones of the anterior pituitary or adrenal cortex that affect the metabolism of carbohydrates or the activation of mechanisms aimed at increasing the glucose concentration in the blood with hypoglycemia; with the development of intercurrent diseases during treatment or with lifestyle changes). In such patients more thorough control of glucose concentration in blood and signs of hypoglycemia, they may require a dose adjustment Amaril M);

- With simultaneous application of some medicines (see section "Interaction with other medicinal products ");

- In elderly patients (such patients often have asymptomatic decrease in function kidney);

- In situations where the kidney function, such as beginning of patient acceptance antihypertensive drugs or duretics, as well as nonsteroidal anti-inflammatory drugs (NSAIDs) (increased risk of developing lactic acidosis and other side effects of metformin);

- When performing heavy physical work (increases risk of lactic acidosis taking metformin);

- With or without symptoms of adrenergic hypoglycemic regulation in response to developing hypoglycemia (in elderly patients, with autonomic neuropathy or with concomitant therapy with beta-blockers, clonidine, guanethidine, and others sympathetic) (these patients need a more thorough monitoring of blood glucose concentration);

- In the absence of glucose-6-phosphate dehydrogenase (in such patients, when taking sulfonylurea derivatives, it is possible development of hemolytic anemia, therefore, consideration should be given to the use of alternative hypoglycemic drugs other than derivatives sulfonylureas).

Pregnancy and lactation:

Pregnancy

This drug should not be taken during pregnancy because of the possible adverse effects on the fetal development of the fetus. Pregnant women and women planning pregnancy should report this to the treating doctor.During pregnancy, women with impaired carbohydrate metabolism, not correcting one diet and physical exertion, should receive insulin therapy.

Breastfeeding period

To avoid getting the drug with breast milk in the baby's body, women who breastfeed should not take this medication. If hypoglycemic therapy is necessary, the patient should be transferred to insulin treatment, otherwise she should stop breastfeeding.

Dosing and Administration:As a rule, the dose of Amaril® M should be determined by the target glucose concentration in the patient's blood. Use the smallest dose sufficient to achieve the required metabolic control.

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

Incorrect drug intake, such as skipping the next dose, should never be replenished by the subsequent administration of a higher dose.

The patient's actions in case of mistakes in taking the drug (in particular, if you skip the next dose of Amaril® M or when you skip meals), or in situations where it is not possible to take the drug, should Consult patient and physician beforehand. Since the improvement of metabolic control is associated with an increase in the sensitivity of tissues to insulin, then during treatment with Amaril® M, the demand for glimepiride may decrease. In order to avoid the development of hypoglycemia, it is necessary to reduce doses in a timely manner or stop taking Amaril® M.

The drug Amaryl® M should be taken once or twice a day during meals.

The maximum single dose of metformin is 1000 mg. The maximum daily dose: for glimepiride - 8 mg, for metformin - 2000 mg.

Only a small number of patients have a more effective daily glimepiride dose of more than 6 mg.

In order to avoid the development of hypoglycemia, the initial dose of Amaril® M should not exceed per diems doses glimepiride and metformin, which the patient is already taking. When translating patients with a combination of individualpreparations of glimepiride and metformin on Amaril® M preparation, the dose of Amaril® M is determined on the basis of the already taken doses of glimepiride and metformin in the form of separate preparations.

If you need to increase the dose, the daily dose of Amaril® M should be titrated in steps of only 1 tablet of Amaril® M 1 mg + 250 mg or 1/2 tablet of Amaryl® M 2 mg + 500 mg. Duration of treatment Usually treatment with Amaril® M is carried out for a long time.

Use in children

Study security and effectiveness of the drug in children with type 2 diabetes mellitus was not performed.

Use in elderly patients

Metformin is excreted mainly by the kidneys. Because the risk of developing severe unwanted reactions to metformin in patients with impaired renal function above, his can only be used in patients with normal kidney function. Due with the fact that with age, kidney function decreases in elderly patients age of metformin should be use with caution. Should carefully select the dose and ensure a thorough and regular monitoring of kidney function.

Side effects:

The frequency of adverse events was determined in accordance with the classification of the World Health Organization (WHO): very often (> 10%), often (> 1%, <10%); infrequently (>0.1%, <1%); rarely (>0.01%, <0.1%) and very rarely, including individual reports (<0.01%), the frequency is unknown (it is not possible to determine the frequency from the available data).

Glimepiride + metformin

The combination of these two drugs, both in the form of free combinations, from individual preparations glimepiride and metformin, and in as a combined preparation with fixed doses of glimepiride and metformin, is associated with the same characteristics security as the application of each of these drugs in isolation.

Glimepiride

Based on the clinical experience with the use of glimepiride and known data on other sulfonylurea derivatives, it is possible development of the following adverse reactions.

Disorders from the metabolism and nutrition

Hypoglycaemia

Possible development of hypoglycemia, which can be protracted. Symptoms developing hypoglycemia include: headache, acute hunger, nausea, vomiting, weakness, lethargy, sleep disorders, anxiety, aggressiveness, decreased concentration, decreased vigilance and slowing of psychomotor reactions, depression, confused consciousness, speech disorders, aphasia, visual impairment, tremor, paresis, impaired sensitivity, dizziness, helplessness, loss of self-control, delirium, cramps, drowsiness and loss of consciousness until coma develops , shallow breathing and bradycardia. In addition, the development of symptoms of adrenergic antihyperglycemic regulation in response to developing hypoglycemia, such as increased sweating, stickiness of skin cover, increased anxiety, tachycardia, increased blood pressure, feeling increased heart rate, angina and heart rhythm disturbances. The clinical picture of an attack of severe hypoglycemia can remind acute violation of cerebral circulation.

Symptoms are almost always resolved after elimination of hypoglycemia.

Disturbances on the part of the organ of sight

Temporal deterioration of vision, especially at the beginning of treatment, due to fluctuations in the concentration of glucose in the blood. The cause of visual impairment is a temporary change in the swelling of the lens, depending on the concentration of glucose in the blood, and due to this the change in their refractive index.

Disorders from the gastrointestinal tract

Development of gastrointestinal Symptoms such as nausea, vomiting, a feeling of stomach overflow, abdominal pain and diarrhea.

Disturbances from the liver and bile ducts

Hepatitis, increased activity of "hepatic" enzymes and / or cholestasis and jaundice, which can progress to life-threatening liver failure, but may undergo reverse development after glimepiride cancellation.

Violations of the blood and lymphatic system

Changes in the picture of blood: thrombocytopenia, in some cases - leukopenia or hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis, or pancytopenia. After the release of the drug on the market, cases of severe thrombocytopenia (with a platelet count of less than 10,000 / μL) and thrombocytopenic purpura (the frequency is unknown).

Immune system disorders

Allergic or pseudoallergic reactions (eg, itching, hives, or rashes). These reactions are almost always of an easy form, however, they can go into severe form with shortness of breath or a decrease arterial pressure, up to the development of anaphylactic shock. If urticaria develops, the doctor should be informed immediately. A cross-allergy with other derivatives of sulfonylurea, sulfonamides or the like may occur. In some cases, allergic vasculitis.

Disturbances from the skin and subcutaneous tissues

In some cases, photosensitization.

Laboratory and instrumental data

In some cases, hyponatremia.

Metformin

Violations from the exchange substances and nutrition

Lactic acidosis (see section "Special instructions ").

Disorders from the gastro-intestinal tract

Gastrointestinal Symptoms (nausea, vomiting, diarrhea, pain in the stomach, increased gas production, meteorism and anorexia) - the most frequent reactions with monotherapy metformin - occur approximately 30 % more often than taking placebo, especially in initial period of treatment. These symptoms, mainly temporary, while continuing treatment spontaneously resolved. In separate cases can be useful temporary dose reduction. In connection with The fact that the development of gastro-intestinal symptoms in the initial period of treatment is dose-dependent, these symptoms can be reduce by gradual increasing the dose and taking the drug while eating. Since a strong Diarrhea and / or vomiting can lead to dehydration and prerenal azotemia, when they appear temporarily stop taking the drug Amaril M. Appearance nonspecific gastrointestinalintestinal symptoms in patients with diabetes mellitus type 2, with stabilized state at background of the drug Amaryl® M can be associated not only with therapy, but also with intercurrent diseases or development lactic acidosis.

At the beginning of metformin treatment about 3% of patients are the appearance of an unpleasant or "metallic" taste in the mouth, which, usually, spontaneously disappears.

Disturbances from the skin and subcutaneous tissue

Very rarely (<0.01%) of erythema in patients with hypersensitivity, pruritus, rash.

Violations from the blood and lymphatic system

Anemia, hemolytic anemia (frequency unknown), leukocytopenia or thrombocytopenia.

If the patient has megaloblastic anemia, consideration should be given to reducing the absorption of vitamin B12 associated with taking metformin (see below).

Disorders from the liver and bile ducts

Deviation from the norm norm functional "hepatic" tests or hepatitis that were reversed at discontinuation of admission metformin.

Laboratory and instrumental data

Reduction of the thyroid-stimulating hormone concentration in patients with hypothyroidism (frequency unknown) (see section "Special instructions"). Hypomagniemia (with diarrhea) (the frequency is unknown).

Reduction of vitamin B12 concentration in the blood: <0.01% of patients taking long-term metformin, a decrease in the absorption of vitamin B12 was observed, usually accompanied by a clinically insignificant decrease in its serum concentration.

Disturbances from the nervous system

Encephalopathy (frequency unknown).

In postmarketing metformin use, patients with vitamin B12 deficiency have been observed cases of peripheral neuropathy (the frequency is unknown) (see section "Special instructions").

Disturbances from the skin and subcutaneous tissues

Photosensitivity (frequency unknown).

Since some unwanted reactions, including hypoglycemia, lactic acidosis, hematologic disorders,severe allergic and pseudo allergic reactions and liver failure may threaten the life of the patient, if such reactions develop, the patient should immediately notify his doctor and stop taking the drug further until he receives instructions from the doctor.

Overdose:

Overdose of glimepiride

Since the preparation Amaryl M contains glimepiride, overdose (both acute and prolonged taking the drug in high doses) can cause severe, life-threatening hypoglycemia.

Once installed an overdose of glimepiride, you must immediately inform this doctor. Before the arrival of a doctor, the patient must Take sugar immediately if perhaps, in the form of dextrose (glucose). Patients who took life-threatening quantity glimepiride, it is necessary to carry out gastric lavage and give Activated carbon. Sometimes, as a preventive measure, hospitalization is necessary. An easily expressed hypoglycemia without loss of consciousness and neurological manifestations should be treated with oral dextrose (glucose) and adjusting the dose of Amaril® M and / or the patient's diet.Intensive monitoring should continue until the doctor is satisfied that the patient is out of danger (it should be borne in mind that hypoglycemia can occur repeatedly after initial recovery to normal blood glucose levels). Significant overdose and severe hypoglycemic reactions with symptoms such as loss of consciousness or other serious neurologic disorders are critical conditions requiring immediate hospitalization of the patient. When the unconscious state of the patient is shown, the introduction concentrated solution glucose (dextrose) intravenously for example, for adults start with 40 ml of a 20% solution glucose (dextrose).

Alternative treatment for adults is considered administration of glucagon, for example, in a dose from 0.5 to 1 mg intravenously, subcutaneously or intramuscularly. The patient is carefully observed in for at least 24-48 hours, since after visible clinical recovery hypoglycemia may repeat. Danger of recurrence hypoglycemia in severe cases with protracted current may persist for several days.

In the treatment of hypoglycemia in children when they are accidentally admitted glimepiride should be very carefully adjust the dose dextrose under constant control concentration of glucose in the blood, because of possible development of dangerous hyperglycemia.

Metformin overdose

When metformin enters stomach up to 85 g hypoglycemia was not observed, although in some cases lactic acidosis.

Significant overdose metformin or available patient, the associated risks may lead to the development of lactic acidosis, requiring urgent medical care in the hospital.

The most effective way removal of lactate and metformin from the patient's body is hemodialysis. With good hemodynamics metformin is able by hemodialysis with clearance to 170 ml / min.

With an overdose of metformin, it is possible to develop acute pancreatitis.

Interaction:

The interaction of glimepiride with other medicinal means

When the patient receiving glimepiride, at the same time prescribe or cancel other medicines, unwanted reactions are possible: strengthening or weakening of hypoglycemic action glimepiride.Based on clinical experience with the use of glimepiride and other drugs sulfonylureas, it should be noted that consider the following drug interactions.

- With drugs that are inducers and inhibitors of the isoenzyme CYP2C9:

Glimepiride is metabolized by cytochrome P450 2C9 (isoenzyme CYP2C9). Its metabolism is affected by the simultaneous use of isoenzyme inducers CYP2C9, for example, rifampicin (the risk of a decrease in the hypoglycemic effect of glimepiride when used simultaneously with CYP2C9 isoenzyme inducers and an increased risk of hypoglycemia if it is abolished without correction of glimepiride dose) and inhibitors of the CYP2C9 isoenzyme, for example, fluconazole (increased risk of hypoglycemia and side effects of glimepiride in its simultaneous admission with inhibitors of the isoenzyme CYP2C9 and the risk of reducing its hypoglycemic effect when they are withdrawn without correction of the dose of glimepiride).

- With drugs that enhance the hypoglycemic effect of glimepiride: insulin and hypoglycemic drugs for oral use, inhibitors angiotensin-converting enzyme (ACE), anabolic steroids, male sex hormones, chloramphenicol, indirect anticoagulants, coumarin derivatives, cyclophosphamide,disopyramide, fenfluramine, pheniramidol, fibrates, fluoxetes, guanethidine, ifosfamide, monoamine oxidase inhibitors (MAO), miconazole, fluconazole, aminosalicylic acid acid, pentoxifylline (high doses parenterally), phenylbutazone, azapresen, oxyphenbutazo, probenecid, antimicrobial agentsreagents - derivatives of quinolone, salicylates, sulfinopyrazone, clarithromycin, sulfonamide antimicrobial drugs, tetracyclines, tritvaline, trophosphamide.

Increased risk of hypoglycemia with the simultaneous use of these drugs with glimepiride and the risk of worsening glycemic control when they are withdrawn without correction of the dose of glimepiride.

- With drugs that reduce hypoglycemic effects: acetazolamide, barbiturates, glucocorticosteroids, diazoxide, diuretics, epinephrine (adrenaline) or other sympathomimetics, glucagon, laxatives (long-term use), a nicotinic acid (high doses), estrogens, progestogen, phenothiazines, phenytoin, rifampicin, thyroid hormones.

The risk of worsening glycemic control when combined with these drugs and increasing the risk of hypoglycemia in the event of their withdrawal without correction of the dose of glimepiride.

- With blockers of H2-histamine receptors, beta-adrenoblockers, clonidine, reserpine, guanethidine.

Perhaps both the enhancement and reduction of the hypoglycemic effect of glimepiride. A careful monitoring of the concentration of glucose in the blood is necessary.

- With beta-blockers, clonidine, guanethidine and reserpine Beta-blockers, clonidine, guanethidine and reserpine can weaken or completely eliminate adrenergic counterregulation reactions (reactions of the sympathetic nervous system in response to hypoglycemia aimed at increasing blood glucose concentration), which leads to a weakening of hypoglycemia (makes its development more imperceptible to the patient and the doctor) and therefore makes it more difficult to detect and treatment.

- With ethanol

Acute and chronic consumption of alcoholic beverages can, and 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.

FROM bile acid sequestrants: kolezevels bind to glimepiride and reduce the absorption of glimepiride from the gastrointestinal tract. In the case of using glimepiride, at least 4 hours before the administration of colevelam, no interaction is observed. therefore glimepiride must be taken at least 4 hours prior to the intake of Wheezevelum.

Interaction of metformin with other drugs

Unrecommended combinations

- With ethanol

In acute alcohol intoxication, the risk of developing lactic acidosis increases, especially in the case of missing or inadequate food intake, the presence of liver failure. Avoiding alcohol (ethanol) and containing ethanol preparations.

- With iodine-containing contrast agents

Intravascular administration of iodine-containing contrast agents may 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 within 48 hours after it; resumption of metformin is possible only after research and obtaining of normal indicators of kidney function (see section "Special instructions").

- With antibiotics having a pronounced nephrotoxic effect (gentamicin)

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

Combinations of metformin preparations that require caution

- With glucocorticosteroids (systemic or topical), beta2-adrenostimulants and diuretics with internal hyperglycemic activity.

The patient should be informed of the need for more frequent monitoring of the morning blood glucose concentration, especially at the onset of combination therapy. It may be necessary to correct the dose of hypoglycemic drugs during the application or after the abolition of the above drugs.

- With antihypertensive drugs

Hypotensive drugs, including ACE inhibitors, can change the concentration of glucose in the blood.If necessary, the dose of metformin should be adjusted. However, it should be borne in mind that when metformin was used in monotherapy in combination with ACE inhibitors, there was no development of hypoglycemia.

- With fenprokoumonom

Metformin can reduce the anticoagulant effect of fenprocoumone. Therefore, careful monitoring of the International Normalized Relationship (MHO) is recommended.

- With levothyroxine sodium

Levothyroxine sodium may reduce the hypoglycemic effect of metformin. It is recommended to monitor blood glucose concentrations, especially when starting treatment or stopping treatment with thyroid hormone drugs, if necessary, adjust the dose of metformin.

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

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

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

In the case of simultaneous application of the above drugs with metformin, careful monitoring of the patient and control of the glucose concentration in the blood are necessary, since hypoglycemic action may be weakened.

Interactions that should be taken into account

- With furosemide

In a clinical study of the interaction of metformin and furosemide in their single administration in healthy volunteers, it was shown that the simultaneous use of these drugs affects their pharmacokinetic performance. Furosemide increased C_max metformin in the blood plasma by 22%, a AUC by 15% without any significant changes in the renal clearance of metformin. When used with metformin C_max and AUC furosemide were reduced by 31% and 12%, respectively, compared with furosemide monotherapy, and the final elimination half-life decreased by 32% without any significant changes in furosemide renal clearance. Information on the interaction of metformin and furosemide with long-term use is absent.

- With nifedipine

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

With cationic preparations: amiloride, dicogsin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin. Cationic drugs, derived from tubular secretion in the kidneys, are theoretically able to interact with metformin as a result of competition for the common tubular transport system. This interaction between metformin and oral cimetidinewere observed in healthy volunteers in clinical studies on the interaction of metformin and cimetidine in single and multiple applications, where a 60% increase in the maximum plasma concentration and total concentration of metformin in the blood and a 40% increase in plasma and total AUC metformin. With a single admission of changes in the half-life was not. 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 and correction of the dose of metformin and / or the drug interacting with it should be ensured the case of simultaneous reception of cationic drugs that are excreted from the body by the secretory system of the proximal tubules of the kidneys.

- With propranolol, ibuprofen

- In healthy volunteers, studies of a single dose of metformin and propranolol, as well as metformin and ibuprofen, showed no change in their pharmacokinetic performance.

Special instructions:

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 the assessment of glycemic control. Lactic acidosis

Lactic acidosis is a rare but severe (with high mortality in the absence of proper treatment) metabolic complication, which develops as a result of the accumulation of metformin during treatment. The incidence of reported cases of lactic acidosis in patients taking metformin, very low (about 0.03 cases per 1000 patient-years). The reported cases of lactic acidosis have been found mainly in patients with diabetes mellitus with severe renal failure, including congenital kidney disease and kidney hypoperfusion, often in the presence of numerous concomitant conditions requiring medical and / or surgical treatment.

The risk of developing lactic acidosis increases with the severity of renal dysfunction, as well as with age.The likelihood of lactic acidosis with metformin can be significantly reduced with regular monitoring of renal function and the use of minimal effective doses of metformin. The frequency 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, and intensive use of drinks containing ethanol, liver failure and conditions accompanied by tissue hypoxia.

Diagnosis of lactic acidosis

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 the pH of the blood, a violation of the water-electrolyte balance with an increase in the anion deficiency and a lactate / pyruvate ratio. In cases where the cause of lactic acidosis is metformin, the plasma concentration of metformin is generally> 5 μg / ml. If lactic acidosis is suspected, metformin should be discontinued immediately and the patient should be immediately hospitalized.

Due to the fact that a violation of liver function can significantly limit the excretion of lactate, the use of Amaril® M in patients with clinical or laboratory signs of liver disease should be avoided.

In addition, the drug Amaril® M should be temporarily discontinued before x-ray studies with intravascular injection of iodine-containing contrast media and before surgery. The use of metformin should be interrupted for a period of 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 abnormalities from the gastrointestinal tract. With more severe acidosis, it is possible to develop hypothermia, lower blood pressure, and resistant bradyarrhythmia. Both the patient and the attending physician should know how important these symptoms can be. It should be instructed the patient about the need to inform the doctor about the occurrence of such symptoms.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, the concentration of lactate and metformin in the blood. In patients receiving metformin plasma concentration of lactate in venous blood on an empty stomach exceeding the upper limit of the norm (but below 5 mmol / l) does not necessarily indicate lactic acidosis. Its increase can be explained by other mechanisms, such as poorly controlled diabetes mellitus or obesity, intense physical stress or technical errors when taking blood 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 in-patient treatment. In the case of diagnosing lactic acidosis, immediately stop taking Amaril^F M and proceed to general supportive measures. Metformin is removed from the blood by hemodialysis with a clearance of up to 170 ml / min, therefore, in the absence of hemodynamic disorders, immediate hemodialysis is recommended to remove accumulated metformin and lactate.Such measures often lead to the rapid disappearance of symptoms and to recovery.

Hypoglycaemia

In the first weeks of treatment, careful monitoring of the patient's condition is necessary because of the risk of developing hypoglycemia, especially if there is an increased risk of developing it (patients who are unwilling or unable to follow the doctor's recommendations, most often in elderly patients, undernourished meals, irregular meals, in case of a mismatch between exercise and consumption of carbohydrates, with changes in diet, with the use of alcoholic beverages, especially in combination with skipping meals, renal function, severe liver function abnormalities, glimepiride overdose, with certain uncompensated disorders of the endocrine system (for example, with some thyroid dysfunction and insufficiency of the hormones of the anterior pituitary or adrenal cortex), while using several other drugs that affect carbohydrate metabolism (see the section "Interactions with other drugs"), with the use of glimepiride in the absence of indications.In such cases, a careful monitoring of the concentration of glucose in the blood is necessary.

The patient should inform the doctor about these risk factors and the symptoms of hypoglycemia, if any. If there are risk factors for hypoglycemia, you may need to adjust the dose of the drug or the entire therapy. This approach is used whenever a disease develops during a therapy or a patient's lifestyle changes. Symptoms of hypoglycemia reflecting adrenergic antihyperglycemic regulation in response to developing hypoglycemia (see the section "Side effect") may be less pronounced or absent if hypoglycemia develops gradually, as well as in elderly patients, with autonomic neuropathy or with concomitant therapy beta-

adrenoblockers: clonidine, reserpine, guanethidine and other sympatholytic drugs.

Almost always hypoglycemia can be quickly quenched with the immediate intake of carbohydrates (glucose or sugar, for example, a piece of sugar, fruit juice containing sugar, tea with sugar, etc.).To this end, the patient must carry at least 20 grams of sugar. He may need help from others to avoid complications. Sugar substitutes are ineffective.

In the experience with other sulfonylureas, it is known that, despite the initial efficacy of the countermeasures undertaken, hypoglycemia may recur, so patients should remain under close supervision. The development of severe hypoglycemia requires immediate treatment and medical supervision, in some cases - inpatient treatment.

General instructions

It is necessary to maintain the target glycemia with the help of complex measures: diet and exercise, weight loss, and if necessary, regular intake of hypoglycemic drugs. Patients should be informed of the importance of adhering to dietary requirements and conducting regular exercise.

Clinical symptoms of inadequately regulated glycemia in the blood include oliguria, thirst, including pathologically severe thirst, dry skin and others.

If the treatment is not done by the attending physician (for example, hospitalization, accident,the need for a visit to a doctor on a day off, etc.), the patient should inform him about the diabetes and about the treatment.

In stressful situations (for example, trauma, surgery, infectious disease with fever), glycemic control may be impaired, and a temporary transition to insulin therapy may be required to ensure the necessary metabolic control.

Monitoring of kidney function

Metformin is excreted mainly by the kidneys. If the kidney function is impaired, the risk of cumulation of metformin and the development of lactic acidosis increase. When the serum creatinine concentration exceeds the upper age limit of the norm, it is not recommended to take Amaril® M. For elderly patients, a careful titration of the dose of metformin is necessary to select the minimum effective dose, since with age, the kidney function decreases. Renal function in patients with normal renal function should be checked at least once a year, and in patients with a concentration of creatinine in the blood at the upper limit of the norm and in elderly patients 2-4 times a year.In elderly patients, decreased renal function often occurs asymptomatically. Special care should be taken in cases of possible impairment of kidney function, for example, with the initiation of antihypertensive or diuretic therapy or the administration of NSAIDs. In elderly patients, as a rule, do not increase the dose of metformin to its maximum daily dose.

Simultaneous administration of other medications may affect kidney function or metformin excretion or cause significant changes in hemodynamics, including renal blood flow.

X-ray studies with intravascular injection of iodine-containing contrast agents [eg, intravenous urography, intravenous cholangiography, angiography and computed tomography (CT) using contrast medium]

Contrastive intravenous iodine-containing substances intended for carrying out X-ray examinations can cause acute disruption of kidney function; their use is associated with the development of lactic acidosis in patients taking metformin (see section "Contraindications").If such a study is planned, Amaril® M should be discontinued before or during the study and glimepiride is not resumed for the next 48 hours after the procedure. The treatment with Amaril® M can be resumed only after the renal function is re-examined and the normal renal function is obtained.

The states under which hypoxia development is possible

A collapse or shock of any origin, acute heart failure, acute myocardial infarction and other conditions characterized by hypoxemia and tissue hypoxia can also cause prenatal kidney failure and increase the risk of lactic acidosis. If patients experiencing Amaryl M experience these conditions, immediately discontinue the drug.

Surgical interventions

With any planned surgical intervention, it is necessary to stop therapy with Amaril® M for 48 hours (except for small procedures that do not require restriction of food and liquid intake), therapy can not be resumed until the oral intake of food is restored and the renal function is not recognized normal.

Reception of ethanol-containing drugs and alcoholic beverages

Ethanol enhances the effect of metformin on the metabolism of lactate. Patients should be cautioned against the use of drugs and beverages that contain ethanol, during the reception of Amaril® M.

Impaired liver function

Since in some cases lactic acidosis was associated with impaired liver function, patients with clinical or laboratory signs of liver damage should avoid using this drug.

Change in the clinical state of a patient with previously controlled diabetes mellitus

A patient with diabetes mellitus, previously a well-controlled metformin, is subject to immediate examination, especially if the disease is unclear and poorly recognized, to exclude ketoacidosis and lactic acidosis. The study should include: the determination of the content of electrolytes and ketone bodies in the blood serum, the determination of the concentration of glucose in the blood and, if necessary, the pH of the blood, the concentration of lactate, pyruvate and metformin in the blood. In the case of any form of acidosis, you should immediately stop taking Amaril® M and use other drugs to maintain glycemic control.

Information for patients

Patients should be informed of the possible risks and benefits of the drug, as well as alternative methods of treatment. It is also important to explain the importance of following dietary guidelines and regular exercise, regular monitoring of blood glucose concentration, glycosylated hemoglobin concentration, renal function and hematological parameters, as well as the risk of hypoglycemia, its symptoms and treatment, and conditions predisposing to its development.

Concentration of the vitamin AT 2 in blood

Long-term treatment with metformin was associated with a decrease in serum concentrations of vitamin B₁₂, which can cause the development of peripheral neuropathy. It is recommended to monitor the concentration of vitamin B₁₂ in the blood (see section "Side effect").

Laboratory safety monitoring

Periodically monitor hematological parameters (hemoglobin or hematocrit, the number of erythrocytes) and renal function (serum creatinine concentration). If necessary, the patient is shown appropriate examination and treatment of any obvious pathological changes.

Despite the fact that when metformin was taken, the development of megaloblastic anemia was rarely observed, if suspected, a check should be performed to exclude vitamin deficiency B₁₂.

Patients with hypothyroidism need regular monitoring of the thyroid-stimulating hormone concentration in the blood (see section "Side effect").

Effect on the ability to drive transp. cf. and fur:

The rate of patient reactions may worsen as a result of hypoglycemia and hyperglycemia, especially at the beginning of treatment or after changes in treatment, or with an irregular intake of the drug. This can affect the ability to manage vehicles and engage in other potentially hazardous activities. Patients should be warned about the need to observe caution in managing especially in the case of a tendency to develop hypoglycemia and / or reduce the severity of its precursors.

Form release / dosage:

Tablets, film-coated, 1 mg + 250 mg and 2 mg + 500 mg.

Packaging:

For 10 tablets in PVC / Aluminum blister.

For 3 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the product after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000130

Date of registration:11.01.2011 / 30.03.2016

The owner of the registration certificate: Sanofi-Aventis SA Sanofi-Aventis SA Spain

Manufacturer: & nbsp

HANDOK PHARMACEUTICALS, Co. Ltd. The Republic of Korea

Representation: & nbspSanofi Aventis GroupSanofi Aventis Group

Information update date: & nbsp22.04.2016

Illustrated instructions

Instructions

Amaryl® M (Amaryl® M)