Expiration date: 01/2025

The composition and form of issue:

Tablets. 1 tablet contains:

glimepiride 1 mg

excipients: lactose monohydrate carboximetilkrahmal sodium (type A) povidone 25000 MCC magnesium stearate colorant iron oxide red (E172) 

in a contour cells packing 15 PCs per cartons 2, 4, 6 or 8 packs.

Tablets. 1 tablet contains:

glimepiride 2 mg

excipients: lactose monohydrate carboximetilkrahmal sodium (type A) povidone 25000 MCC magnesium stearate colorant iron oxide yellow (E172) Indigo Carmine (E132) 

in a contour acheikova packing 15 PCs per cartons 2, 4, 6 or 8 packs.

Tablets. 1 tablet contains:

glimepiride 3 mg

excipients: lactose monohydrate carboximetilkrahmal sodium (type A) povidone 25000 MCC magnesium stearate colorant iron oxide yellow (E172) 

in a contour acheikova packing 15 PCs per cartons 2, 4, 6 or 8 packs.

Tablets. 1 tablet contains:

glimepiride 4 mg

excipients: lactose monohydrate carboximetilkrahmal sodium (type A) povidone 25000 MCC magnesium stearate Indigo Carmine (E132). 

in a contour acheikova packing 15 PCs per cartons 2, 4, 6 or 8 packs.

Description pharmaceutical form:

Amaryl 1 mg: tablets are pink, oblong, flat, with break line on both sides. Engraving "NMK" and the stylized "h" on two sides.

Amaryl 2 mg: tablets are green, oblong, flat, with break line on both sides. Engraving "NMM" and the stylized "h" on two sides.

Amaryl 3 mg: tablets are pale yellow, oblong, flat, with break line on both sides. Engraving "NMN" and the stylized "h" on two sides.

Amaryl 4 mg: blue tablets, oblong, flat, with break line on both sides. Engraving "NMO" and the stylized "h" on two sides.

Feature:

Hypoglycemic agent for oral administration, group III generation sulfonylurea.

Pharmacokinetics:

When multiple doses of glimepiride in a daily dose of 4 mg Cmax in serum is reached after about 2.5 hours and is 309 ng/ml. There is a linear relationship between dose and Cmax of glimepiride in plasma, and between dose and AUC. The ingestion of glimepiride its absolute bioavailability is complete. Food intake has no significant effect on absorption, with the exception of the slight slowing of its velocity. For glimepiride characterized by very low distribution volume (approximately 8.8 liter), approximately equal to the volume of distribution of albumin, a high degree of binding to plasma proteins (99%) and low clearance (approximately 48 ml/min). The average T1/2, defined by serum concentrations in case of multiple doses, is approximately 5-8 hours After ingestion of high doses, a slight increase in T1/2.

After a single dose of glimepiride inside 58% of the dose is excreted by the kidneys and 35% of the dose through the intestine. Glimepiride unchanged in the urine not detected.

In the urine and feces were identified two metabolites resulting from metabolism in the liver (mainly through CYP2C9), one of them was hydroxypropane and the other carboxyperitoneum. After ingestion of glimepiride terminal T1/2 of these metabolites were 3 to 5 and 5-6 h, respectively.

Glimepiride is excreted in breast milk and crosses the placental barrier.

Comparison of single and multiple (once daily) glimepiride did not reveal any significant differences in pharmacokinetic parameters are recorded their very low variability between different patients. Significant accumulation of the drug is absent.

The pharmacokinetic parameters are similar in patients of different sex and different age groups. In patients with impaired renal function (low creatinine clearance), there is a tendency to increase clearance glimepirida and reduce its average concentrations in the blood serum, which is likely due to more rapid excretion of the drug due to lower binding it to protein. Thus, in this category of patients, there is no additional risk of drug accumulation.

Description pharmacological action:

Glimepiride reduces the concentration of glucose in the blood, mainly by stimulating insulin release from the beta cells of the pancreas. Its effect is primarily associated with the improved ability of the beta cells of the pancreas to respond to physiological stimulation of glucose. Compared with glibenclamide, a low-dose of glimepiride causes the release of smaller quantities of insulin while achieving approximately the same reduction in the concentration of glucose in the blood. This fact testifies in favor of the presence of glimepiride extrapancreatic hypoglycemic effects (increased sensitivity of tissues to insulin and insulinomimetic effect).

The secretion of insulin. Like all other sulfonylureas, glimepiride regulates insulin secretion by interactions with ATP-sensitive potassium channels in the membranes of beta cells. Unlike other derivatives of sulfonylurea, glimepiride selectively binds to the protein with molecular weight 65, kilodalton (kDa) located in the membranes of the beta cells of the pancreas. This interaction of glimepiride with communicating with him protein regulates the opening or closing of ATP-sensitive potassium channels.

Glimepiride closes potassium channels. This causes depolarization of beta cells and leads to opening of voltage-sensitive calcium channels and influx of calcium into the cell. As a result, the increase in intracellular concentration of calcium activates the secretion of insulin through exocytosis.

Glimepiride is much faster and therefore more frequently comes into contact and is released from connection with communicating with him in protein than glibenclamide. It is expected that this property of high exchange rate of glimepiride from communicating with him protein is responsible for its pronounced effect of sensitization of beta cells to glucose and their protection from desensitization and premature exhaustion.

The effect of increasing the sensitivity of tissues to insulin. Glimepiride increases the effects of insulin on glucose uptake by peripheral tissues.

Insulinomimetic effect. Glimepiride has effects similar to the effects of insulin on glucose uptake by peripheral tissues and glucose output from the liver.

Glucose uptake by peripheral tissues is carried out by its transport inside muscle cells and adipocytes. Glimepiride directly increases the number of glucose transport molecules in the plasma membranes of muscle cells and adipocytes. The increase in revenues inside the cells of glucose leads to the activation of glycosylphosphatidylinositol-specific phospholipase C. as a result, intracellular calcium concentration is reduced, causing a decrease in the activity of protein kinase A, which in turn leads to stimulation of glucose metabolism.

Glimepiride inhibits the glucose output from the liver by increasing the concentration of fructose-2,6-bisphosphate, which inhibits gluconeogenesis.

Influence on platelet aggregation and atherosclerotic plaque formation. Glimepiride reduces platelet aggregation in vitro and in vivo. This effect is apparently associated with selective inhibition of COX, which is responsible for the formation of thromboxane A, an important endogenous factor of platelet aggregation.

Antiatherogenic effect of the drug. Glimepiride helps to normalize lipid content, reduces the level of malonic aldehyde in the blood, which leads to a significant decrease in lipid peroxidation.

Reducing the severity of oxidative stress, which is always present in patients with saharnym for type 2 diabetes. Glimepiride increases the level of endogenous &alpha-tocopherol, catalase, and superoxide dismutase glutationperoxydasy.

The cardiovascular effects. Via ATP-sensitive potassium channels (see above) sulfonylureas also have an impact on the cardiovascular system. Compared with conventional sulfonylureas, glimepiride has a significantly smaller effect on the cardiovascular system. It reduces platelet aggregation and leads to a significant decrease in the formation of atherosclerotic plaques.

In healthy volunteers the minimum effective dose of glimepiride is 0.6 mg. the Effect of glimepiride is dose-dependent and reproducible. Physiological response to physical activity (reduced insulin secretion) while taking glimepiride persists.

No significant differences in the effect depending on was adopted the drug 30 minutes before meals or just before eating. Patients with diabetes can achieve adequate metabolic control within 24 h after a single reception of the drug. Moreover, in a clinical study in 12 of 16 patients with renal insufficiency (Cl creatinine 4-79 ml/min) was also achieved adequate metabolic control.

Combination therapy with Metformin. Patients who have not achieved adequate metabolic control when using the maximum dose of glimepiride may be initiated combination therapy with glimepiride and Metformin. In two studies, combination therapy was shown to improve the metabolic control compared with that in the treatment of each of these drugs separately.

Combination therapy with insulin. Patients who have not achieved adequate metabolic control when using the maximum dose of glimepiride may be initiated concurrent therapy with insulin. According to the results of two studies in the application of this combination achieved the same improvement in metabolic control as when using only one insulin, however, in combination therapy requires a lower dose of insulin.

The use in children. Data for long-term effectiveness and safety of using the drug in children are missing.

Indications:

Diabetes mellitus type 2 (monotherapy or in combination therapy with Metformin or insulin).

Contraindications:

• hypersensitivity to glimepiride or any subsidiary of the drug substance, other sulfonylureas or sulfa drugs (risk of hypersensitivity reactions)
  
• diabetes mellitus type 1
  
• diabetic ketoacidosis, diabetic precoma and coma
  
• severe violations of liver function (no clinical experience)
  
• severe renal dysfunction, including patients on hemodialysis (without clinical experience)
  
• pregnancy
  
• lactation
  
• children's age (no clinical experience)
  
• rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
  

With caution:

• the condition in the first week of treatment (increasing the risk of hypoglycemia). In the presence of risk factors for hypoglycemia (see "Special indications"), you may need to adjust doses of glimepiride or the entire therapy
  
• intercurrent disease during treatment or when you change the lifestyle of patients (changing your diet and time food intake, increase or decrease in physical activity)
  
• deficiency of glucose-6-phosphate dehydrogenase
  
• malabsorption of food and drugs in the gastrointestinal tract (intestinal obstruction, intestinal paresis).
  

Application of pregnancy and breast-feeding:

Glimepiride is contraindicated in pregnant women. In the case of planned pregnancy or when pregnancy occurs, the woman should be transferred to insulin therapy.

Glimepiride passes into breast milk, so it is impossible to take during breastfeeding. In this case, you need to go to insulin or cease breastfeeding.

Side effects:

From the metabolism: the result of hypoglycemic action of the drug Amaryl can develop hypoglycemia, which, like the application of other sulfonylurea derivatives, can be long-lasting.

Symptoms of hypoglycemia are: headache, hunger, nausea, vomiting, fatigue, sleepiness, sleep disturbance, anxiety, aggressiveness, impaired concentration, vigilance and speed of reactions, depression, confusion, speech disorders, aphasia, visual disorders, tremor, paresis, sensory disturbance, dizziness, loss of self-control, delirium, cerebral convulsions, somnolence or loss of consciousness up to coma, shallow breathing, bradycardia.

In addition, you may experience adrenergic manifestations of contraregulatory in response to hypoglycemia, such as the appearance of cold sticky sweat, anxiety, tachycardia, hypertension, angina, palpitations and heart rhythm disorders.

The clinical picture of severe hypoglycemia can be similar to a stroke. The symptoms of hypoglycemia nearly always disappear after its removal.

Side of body: during treatment (especially at the beginning) may experience transient visual disturbances caused by changes in the concentration of glucose in the blood. Their cause is a temporary change in swelling of the lens, depending on the concentration of glucose in the blood, and thereby changing the refractive index of the lens.

Gastrointestinal: rarely — nausea, vomiting, feeling of heaviness or overfilling in epigastria, abdominal pain, diarrhoea in some cases, — hepatitis, increased liver enzymes and/or cholestasis and jaundice which may progress to life-threatening liver failure but can be subjected to reverse development with the elimination of the drug.

From the hematopoietic system and lymphatic system: rarely — thrombocytopenia in some cases — leukopenia, hemolytic anemia, erythropenia, granulocytopenia, agranulocytosis and pancytopenia.

General disorders: in rare cases, possible allergic and pseudoallergic reactions such as itching, urticaria, skin rash. Such reactions can go into a severe reaction with shortness of breath, sudden decrease in blood pressure, which sometimes can progress up to anaphylactic shock. If you have symptoms of hives, you should immediately consult a doctor. In some cases, may experience a decrease in serum concentrations of sodium, allergic vasculitis, photosensitivity.

Drug interactions:

Glimepiride is metabolized by cytochrome P4502C9 (CYP2C9), which should be considered when concomitant use with inducers (e.g. rifampicin) or inhibitors (e.g. fluconazole) of CYP2C9.

Potentiation of the hypoglycemic action and in some cases associated with the possible development of hypoglycemia may occur when combined with one of the following drugs: insulin and other hypoglycemic drugs for oral administration, ACE inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fenyramidol, fibrates, fluoxetine, guanetidin, ifosfamide, MAO inhibitors, fluconazole, para-aminosalicylic acid, pentoxifylline (high dose parenteral), phenylbutazone, azapropazon, oxyphenbutazone, probenecid, chinolone, salicylates, sulfinpirazon, clarithromycin, sulfonamides, tetracyclines, tritoqualine, trofosfamide.

The weakening of the hypoglycemic action and the consequent increase in the concentration of glucose in the blood can be observed in combination with one of the following drugs: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics, epinephrine and other sympathomimetic funds, glucagon, laxatives (long-term use), nicotinic acid (in high doses), estrogens and progestogen, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones.

Blockers H2-histamine receptors, beta-blockers, clonidine and reserpine can potentiate or weaken the hypoglycemic action of glimepiride. Under the influence of simpatoliticheskih such as beta-blockers, clonidine, guanetidin, and reserpine, the signs of adrenergic kontrrevolyutsiei in response to hypoglycemia may be reduced or absent.

While taking glimepiride, you may experience strengthen or weaken the effect of coumarin derivatives.

Single or chronic use of alcohol may potentiate or weaken the hypoglycemic action of glimepiride.

Method of application and dose:

Inside, alone with liquid, squeezed enough liquid (about 0.5 cups).

As a rule, the dose of Amaryl is determined by the target concentration of glucose in the blood. Should apply the lowest dose that is sufficient to achieve the desired metabolic control.

During treatment, the drug Amaryl, you should regularly determine the concentration of glucose in the blood. In addition, it is recommended that regular monitoring of glycosylated hemoglobin.

Wrong drug, for example, to skip taking the next dose should never be replenished by the subsequent acceptance of a higher dose.

The patient's errors while taking the drug (particularly if you skip taking the next dose or skipping a meal) or situations where there is no possibility to take the drug, should be negotiated by the patient and physician in advance.

The drug

Initial dose and dose selection

The initial dose is 1 mg of glimepiride once a day 1.

If necessary, the daily dose may be gradually (at intervals of 1-2 weeks) is increased. It is recommended to increase dose to be under the regular control of the concentration of glucose in the blood and in accordance with the next step increase dose: 1 mg?2 mg?3 mg?4 mg?6 mg (?8 mg).

The dose range in patients with well-controlled diabetes

Usual daily dose in patients with well controlled diabetes is 1 to 4 mg of glimepiride. Daily dose of more than 6 mg are more effective only in a small number of patients.

The dosage regimen

The drug and the distribution of the doses during the day is determined by the doctor depending on the patient's lifestyle at a given time (time of food intake, amount of physical activity).

Usually, a single dose of the drug during the day. It is recommended that in this case, the full dose was taken just before a full Breakfast or if she was not adopted at this time — immediately before the first main meal. It is very important after taking the pills do not skip meals.

Because improved metabolic control is associated with higher insulin sensitivity during the treatment may decrease the need for glimepiride. In order to avoid hypoglycemia, it is necessary to reduce the dose or discontinue the drug Amaryl.

A condition in which may also require adjustment of the dose of glimepiride:

• reduction of body weight of the patient
  
• change the lifestyle of the patient (change of diet, time of meals, amount of physical activity)
  
• the emergence of other factors that lead to susceptibility to hypoglycemia or hyperglycemia (see "Special instructions").
  

The duration of treatment

Therapy with glimepiride is usually held for a long time.

The transfer of the patient with other hypoglycemic drugs for oral on Amaryl

There is no exact correlation between the doses of the drug Amaryl and other hypoglycemic agents for oral administration. When another hypoglycemic agent for oral administration is replaced with the drug Amaryl, it is recommended that the procedure for his appointment was the same as during the initial appointment of the drug Amaryl, ie, the treatment should begin with low doses of 1 mg (even if the patient is transferred to Amaryl maximum doses of other hypoglycemic drug for oral administration). Any increase in dose should be carried out gradually, taking into account the reaction to glimepiride in accordance with the recommendations above.

Consider the power and duration of the effect of previous hypoglycaemic agents for oral administration. You may need to interrupt treatment in order to avoid any summation of effects, which can increase the risk of hypoglycemia.

Use in combination with Metformin

In patients with poorly controlled diabetes while taking maximum daily dose or glimepiride or Metformin can be initiated treatment with the combination of these two drugs. While earlier treatment or glimepiride or Metformin is continued at the same dose level, and additional Metformin or glimepiride begin with a low dose which is then titrated depending on the target level of metabolic control up to the maximum daily dose. Combination therapy should begin under strict medical supervision.

Use in combination with insulin

Patients with poorly controlled diabetes while taking maximum daily dose of glimepiride can be simultaneously assigned to insulin. In this case, the last assigned patient the dose of glimepiride remains unchanged. While insulin treatment starts with low doses that are gradually increased under the control of the concentration of glucose in the blood. Combined treatment requires careful medical supervision.

Use in patients with renal insufficiency. There is a limited amount of information on the use of the drug in patients with renal insufficiency. Patients with impaired renal function may be more sensitive to hypoglycemic effect of glimepiride (see section "Pharmacokinetics", "Contraindications").

Use in patients with hepatic insufficiency. There is a limited amount of information on the use of the drug with hepatic failure (see section "Contraindications").

The use in children. Data on the use of the drug in children is not enough.

Overdose:

Symptoms: acute overdose and long-term treatment too high dose of glimepiride may lead to the development of severe life-threatening hypoglycemia.

Treatment: once you have found the overdose, you should immediately inform the doctor. Hypoglycaemia can almost always be quickly docked immediate intake of carbohydrates (glucose or sugar, sweet fruit juice or tea). In this regard, the patient should always carry not less than 20 g glucose (4 sugars). Sweeteners are ineffective in the treatment of hypoglycemia.

Until that moment, until the doctor decides that the patient is out of danger, the patient should be careful medical supervision. It should be remembered that hypoglycemia may recur after initial recovery of the concentration of glucose in the blood.

If the patient suffering with diabetes mellitus, treated by different doctors (for example during a stay in the hospital after the accident, when the disease at the weekend), he should definitely inform them about their disease and previous treatment.

Sometimes you may require hospitalization of the patient, even if only as a precaution. A significant overdose and severe reactions with such manifestations as loss of consciousness or other serious neurological disorders are medical conditions emergency and require immediate treatment and hospitalization.

In the case of unconsciousness of the patient should/in the introduction of a concentrated solution of dextrose (glucose) (for adults, starting with 40 ml of 20% solution). Alternatively, adults may in/, p/or/m introduction of glucagon, e.g. at a dose of 0.5–1 mg.

When treating hypoglycaemia due to accidental intake of amaryl drug babies or younger children the dose of dextrose should be carefully adjusted in terms of the possibility of dangerous hyperglycemia, and infusion of dextrose should be under constant control of the concentration of glucose in the blood.

In case of overdose of the drug Amaryl may require gastric lavage and administration of activated charcoal.

After a quick recovery of the glucose concentration in the blood is necessary to conduct in I/V infusion of dextrose solution in a lower concentration to prevent recurrence of hypoglycemia. The concentration of glucose in blood at such patients should be continuously monitored for 24 h. In severe cases, prolonged hypoglycemia the risk of lower concentrations of blood glucose to hypoglycemic levels can persist for several days.

Special instructions:

In special clinical stress such as trauma, surgery, infection, occurring with febrile temperature, possibly deteriorating metabolic control in patients with diabetes diabetom, and they may need temporary transfer to insulin therapy to maintain adequate metabolic control.

In the first weeks of treatment may increase the risk of hypoglycemia and, therefore, at this time, requires particularly careful monitoring of the concentration of glucose in the blood.

The factors contributing to the risk of hypoglycemia include:

• the unwillingness or inability of the patient (often observed in elderly patients) to cooperate with the doctor
  
• malnutrition, irregular meals or skipping of meals
  
• imbalance between physical exertion and carbohydrate intake
  
• change diet
  
• the use of alcohol, especially in combination with skipped meals
  
• severe renal dysfunction
  
• severe disturbances of liver function (patients with severe liver dysfunction shown on insulin therapy, at least, to achieve metabolic control)
  

Overdose of glimepiride

some decompensated endocrine disorders, in violation of carbohydrate metabolism or contraregulatory in the adrenergic response to hypoglycemia (for example, certain disorders of thyroid function and anterior pituitary, adrenal insufficiency)

- concomitant use of certain medicines (see "Interactions")

- reception of glimepiride in the absence of testimony to its acceptance.

Treatment with sulfonylureas, which include glimepiride, can lead to the development of hemolytic anemia, and in patients with deficiency of glucose-6-phosphate dehydrogenase should be particularly careful in the appointment of glimepiride and better to use hypoglycemic agents non-sulfonylureas.

In the case of the above risk factors for development of hypoglycemia may require correction doses of glimepiride or the entire therapy. This also applies to the occurrence of intercurrent diseases during treatment or lifestyle change patients.

Those symptoms of hypoglycaemia which reflect adrenergic contraregulatory of the body in response to hypoglycemia (see "Side effects"), may be weakly expressed or absent during progressive hypoglycemia, elderly patients, patients with neuropathy of the autonomic nervous system, or patients receiving beta-blockers, clonidine, reserpine, guanetidin, and other simpatoliticescoe funds.

Hypoglycemia can be quickly treated with immediate ingestion of fast digestible carbohydrates (glucose or sucrose).

As with other sulfonylurea derivatives, despite initial successful relief of hypoglycemia, hypoglycemia may recur. Therefore patients should remain under constant surveillance.

When severe hypoglycemia is additionally required immediate treatment and supervision of a physician and in some cases, hospitalization of the patient.

During treatment with glimepiride requires regular monitoring of liver function and picture peripheral blood (especially the number of leukocytes and platelets).

Because some side effects such as severe hypoglycemia, major changes in the blood picture, severe allergic reactions, liver failure, can under certain circumstances represent a threat to the life, in the case of adverse or severe reactions, the patient should immediately inform the attending physician and in any case not to continue taking the drug without his recommendation.

Effects on ability to drive vehicles and other mechanisms. In the case of hypoglycemia or hyperglycemia, especially early in treatment or after changing treatment or when the drug is not taken regularly, may reduce attention and speed of psychomotor reactions. This may impair the patient's ability to drive vehicles or other mechanisms.