Glimepiride

Pharmacological properties

glimepiride is a hypoglycemic agent that is active when taken orally, which belongs to the sulfonylurea group. it is used for type II diabetes mellitus.

Glimepiride acts primarily by stimulating the release of insulin from pancreatic β-cells. As with other sulfonylureas, this effect is based on increasing the sensitivity of pancreatic cells to physiological stimulation of glucose. In addition, glimepiride has a pronounced extra-pancreatic effect, which is also characteristic of other sulfonylureas.

Insulin release. Sulfonylurea preparations regulate insulin secretion by closing the ATP-dependent potassium channel located in the pancreatic β-cell membrane. Closing the potassium channel causes depolarization of the β-cell and by opening the calcium channels leads to an increase in the influx of calcium into the cell, which, in turn, causes the release of insulin by exocytosis. Glimepiride, with a high rate of substitution, binds to a protein of the β-cell membrane bound to the ATP-dependent potassium channel, however, the location of its binding site is different from the usual binding site of sulfonylurea preparations.

Extra-pancreatic activity. Extrapancreatic effects include, for example, improving the sensitivity of peripheral tissues to insulin and reducing the utilization of insulin by the liver.

Utilization of blood glucose by peripheral tissues (muscle and fat) occurs using special transport proteins located in the cell membrane. The transport of glucose into these tissues is limited by the speed of the glucose utilization step. Glimepiride very quickly increases the number of active molecules that transport glucose on the plasma membranes of muscle and adipose tissue cells, which leads to stimulation of glucose uptake.

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

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

General characteristics. In healthy individuals, the minimum effective oral dose is ≈0.6 mg. The effect of glimepiride is dose dependent and reproducible. The physiological reaction to acute physical exertion, that is, a decrease in insulin secretion, is preserved under the conditions of glimepiride.

There was no significant difference in the effect of glimepiride when taking the drug 30 minutes before meals or immediately before meals. In patients with diabetes, proper metabolic control for 24 hours was ensured when taking the drug 1 time per day.

Although hydroxylated metabolites cause an insignificant but significant decrease in blood glucose in healthy individuals, this is only an insignificant component of the overall effect of the drug.

Use in combination with metformin. One study demonstrated an improvement in metabolic control with concomitant glimepiride therapy compared with metformin monotherapy in patients whose diabetes is not adequately controlled with maximum doses of metformin.

Use in combination with insulin. Data on the use of the drug in combination with insulin are limited. In patients whose diabetes is not properly controlled with the maximum doses of glimepiride, concomitant insulin treatment may be initiated.In two studies, this combination made it possible to achieve the same improvement in metabolic control as with monotherapy with insulin, but combination therapy requires a lower average dose of insulin.

Special categories of patients

Children, including teenagers. In a 24-week clinical trial with active control (glimepiride at a dose of up to 8 mg / day or metformin at a dose of up to 2000 mg / day), 285 children (aged 8-17 years) with type II diabetes participated. Both glimepiride and metformin led to a significant decrease in HbA1c compared to the initial value (glimepiride - 0.95 [CI 0.41], metformin - 1.39 [CI 0.40]). However, for glimepiride, a higher efficiency was not demonstrated compared with metformin relative to the average change in HbA1c compared to the initial value. The difference between the two treatments was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not lower than 0.3% of the limit of no less efficiency. According to the results of treatment with glimepiride, no new safety problems were detected in children compared with adult patients with type II diabetes mellitus. There is no evidence of long-term efficacy and safety in children.

Pharmacokinetics Suction. Following oral administration, glimepiride has 100% bioavailability. Eating does not have a significant effect on absorption, but only slightly slows down the rate of absorption. C_max achieved 2.5 hours after oral administration of the drug (the average is 0.3 μg / ml when taking a multiple daily dose of 4 mg). There is a linear relationship between dose and C_maxas well as dose and AUC.

Distribution. Glimepiride has a small distribution volume (≈8.8 L), which is approximately equal to the volume of albumin distribution, a high degree of binding to blood plasma proteins (99%) and low clearance (≈48 ml / min).

In animals, glimepiride is excreted in breast milk. Glimepiride crosses the placenta. Penetration through the BBB is low.

Biotransformation and excretion. Medium core T_½ at plasma drug concentrations corresponding to a multiple dosing regimen, is approximately 5–8 hours. After taking the drug in high doses, a slight increase in T was observed_½.

After taking a single dose of glimepiride labeled with a radioactive isotope, 58% of the radioactive substance was detected in urine and 35% in feces. Unchanged substance in the urine is not detected. In the urine and feces, two metabolites are determined that are most likely formed as a result of metabolism in the liver (the main enzyme CYP 2C9), one of which is a hydroxy derivative, and the other is a carboxy derivative. After oral administration of glimepiride, terminal T_½ of these metabolites were 3–6 and 5–6 hours, respectively.

When comparing the pharmacokinetics after a single dose and multiple doses of the drug 1 time per day, no significant differences were revealed. Interindividual variability was very low. Cumulation, which would be important, is not noted.

Special categories of patients. The pharmacokinetic parameters in men and women, as well as in young and elderly people (over 65), were similar. In patients with decreased creatinine clearance, there was a tendency to increase the clearance of glimepiride and a decrease in its average plasma concentrations, which is most likely due to faster excretion due to the lower degree of protein binding. The renal clearance of both metabolites increased. In general, these patients do not expect an additional risk of cumulation of the drug.

The pharmacokinetic parameters in 5 patients who underwent surgery on the biliary tract were similar to those in healthy volunteers.

Children, including teenagers.A study that examined the pharmacokinetics, safety, and tolerability after a single dose of 1 mg of glimepiride in a satiated state in 30 children (4 children aged 10-12 years and 26 children 12-17 years old) with type II diabetes showed that average AUC performance_{0 – last}, C_max and T_½ were similar to those previously observed in adults.

Preclinical safety data. The effects observed during preclinical studies occurred at exposure levels that far exceeded the maximum exposure levels in humans, indicating their insignificant value for clinical practice, or were caused by the pharmacodynamic effect of the drug (hypoglycemia). These results were obtained as part of traditional pharmacological safety studies, repeated dose toxicity studies, tests for genotoxicity, oncogenic potential and reproductive toxicity. Side effects identified in the course of the latter (which covered the study of embryotoxicity, teratogenicity, and toxic effects on the development of the body) were considered to be the result of hypoglycemic effects caused by the drug in females and cubs.

Indications

Type II diabetes mellitus in adults, if blood glucose cannot be supported only by diet, exercise and weight loss.

Application

The successful treatment of diabetes depends on the patient following an appropriate diet, regular physical activity, and constant monitoring of blood and urine glucose levels. patient non-compliance with the diet cannot be compensated by taking pills or insulin.

Dosing depends on the results of an analysis of the level of glucose in the blood and urine.

The initial dose is 1 mg (¹/₂ 2 mg tablets) of glimepiride per day. If such a dose allows for control of the disease, it should be used for maintenance therapy.

If glycemic control is not optimal, the dose should be increased to 2; 3 or 4 mg of glimepiride per day in stages (with intervals of 1–2 weeks).

A dose exceeding 4 mg / day gives the best results only in individual cases. The maximum recommended dose is 6 mg of Amaril^® per day.

If the maximum daily dose of metformin does not provide sufficient glycemic control, concomitant therapy with the patient with glimepiride can be started.

Adhering to the previous dosage of metformin, the use of glimepiride should begin with a low dose, which can then be gradually increased to the maximum daily dose, focusing on the desired level of metabolic control. Combination therapy should be carried out under close medical supervision.

If the maximum daily dose of Amaril^® does not provide sufficient glycemic control, if necessary, concomitant insulin therapy can be started. Following the previous dosing of glimepiride, insulin treatment should begin with a low dose, which can then be increased, focusing on the desired level of metabolic control. Combination therapy should be carried out under close medical supervision.

Usually one dose of glimepiride per day is enough. It is recommended to take it shortly before or during a hearty breakfast or (in the absence of breakfast) shortly before or during the first main meal. Errors in the use of the drug, for example, skipping the next dose, can never be corrected by the subsequent intake of a higher dose. The tablet should be swallowed without chewing, washed down with liquid.

If the patient develops a hypoglycemic reaction to taking glimepiride at a dose of 1 mg / day, this means that diabetes can be controlled only by following a diet.Improving diabetes control is accompanied by an increase in insulin sensitivity, so the need for glimepiride may decrease during the course of treatment. To avoid hypoglycemia, the dose should be gradually reduced or therapy should be interrupted altogether. The need for a dosage review may also arise if the patients body weight or lifestyle changes or other factors increase the risk of hypo- or hyperglycemia.

Transition from oral hypoglycemic agents to Amaril^®

From other oral hypoglycemic drugs, you can usually switch to taking Amaril.^®. During such a transition, the force of action and T_½ previous funds. In some cases, especially if the antidiabetic drug has a long T_½ (e.g. chlorpropamide), before taking Amaril^® It is recommended to wait a few days. This will reduce the risk of hypoglycemic reactions due to the additive effect of the two drugs.

The recommended starting dose is 1 mg of glimepiride per day. As noted above, the dose can be gradually increased taking into account the reaction to the drug.

Transition from insulin to Amaril^®

In exceptional cases, patients with type II diabetes mellitus receiving insulin may be shown to replace it with Amaryl^®. Such a transition should be carried out under close medical supervision.

Contraindications

Amaril® is not intended for the treatment of insulin-dependent type I diabetes mellitus, diabetic ketoacidosis, and diabetic coma. the use of the drug is contraindicated in patients with severe impaired renal or hepatic function. in case of severe impaired renal or hepatic function, the patient must be transferred to insulin.

Amaril^® should not be taken by patients with hypersensitivity to glimepiride or any auxiliary ingredient that is part of the drug, to sulfonylurea derivatives or other sulfonamide drugs (risk of hypersensitivity reactions).

The period of pregnancy and lactation (see. Use during pregnancy and lactation).

Side effects

Based on the experience of using the drug amaryl® and other sulfonylurea derivatives, the following adverse reactions were observed during clinical trials, which are given below for the classes of organs and systems in order of decreasing incidence: very often - ≥1 / 10; often - ≥1 / 100 to 1/10; infrequently - ≥1 / 1000 to 1/100; rarely - ≥1 / 10,000 to 1/1000; very rarely - 1/10 000); the frequency is unknown (cannot be calculated from the available data).

From the blood and lymphatic systems: rarely - thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia and pancytopenia, which are usually reversible after drug withdrawal; the frequency is unknown - during post-registration observation, cases of severe thrombocytopenia with a platelet count of 10,000 / μl and thrombocytopenic purpura were recorded.

On the part of the immune system: very rarely - leukocytoclastic vasculitis, moderate hypersensitivity reactions that can progress to severe forms, accompanied by shortness of breath, a sharp decrease in blood pressure and sometimes shock; frequency unknown - cross-allergy with sulfonylurea, sulfonamides or related substances is possible.

Metabolic and nutritional disorders: rarely - hypoglycemia. Such hypoglycemic reactions predominantly occur immediately, can be severe and not always easily corrected. The occurrence of such reactions, as in the case of the use of other hypoglycemic agents, depends on individual factors, such as eating habits and dose (see SPECIAL INSTRUCTIONS for details). The clinical presentation of a severe attack of hypoglycemia may resemble the clinical presentation of a stroke.

From the side of the organ of vision: the frequency is unknown - transient visual disturbances may occur, especially at the beginning of treatment, due to a change in the level of glucose in the blood.

From the gastrointestinal tract: very rarely - nausea, vomiting, diarrhea, a feeling of heaviness and discomfort in the abdomen, abdominal pain, which rarely lead to the need to stop treatment.

From the hepatobiliary system: frequency unknown - increased activity of liver enzymes; very rarely - impaired liver function (e.g. cholestasis or jaundice), hepatitis and liver failure.

On the part of the skin and subcutaneous tissue: the frequency is unknown - allergic and pseudo-allergic reactions may occur, including pruritus, rash, urticaria and sensitivity to light.

Laboratory indicators: very rarely - a decrease in the level of sodium in the blood plasma.

Reported suspected adverse reactions. Reporting suspected adverse reactions after approval of the drug by the licensing authorities is an important procedure. This allows constant monitoring of the benefit / risk ratio of the use of this drug. Health care providers are asked to report all suspected adverse reactions through national reporting systems.

special instructions

Amaril® must be taken shortly before or during meals.

In the first weeks of treatment, there may be an increased risk of hypoglycemia, therefore it is necessary to carry out especially careful monitoring.

In case of irregular nutrition or skipping meals, treatment with Amaril^® may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, severe hunger, nausea, vomiting, fatigue, apathy, drowsiness, sleep disorders, increased physical activity, aggression, impaired concentration, anxiety and delayed reaction time, depression, confusion, speech and visual impairment disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cramps, drowsiness and loss of consciousness up to coma, shallow breathing and brady Diya. In addition, signs of adrenergic counter-regulation may be present, such as sweating, cold and wet skin, anxiety, tachycardia, hypertension, tachycardia, angina pectoris and arrhythmia.

The clinical presentation of a severe attack of hypoglycemia may resemble the clinical presentation of a stroke. Symptoms of hypoglycemia can almost always be quickly eliminated by the immediate consumption of carbohydrates (sugar). Artificial sugar substitutes are ineffective.

From the experience of using other sulfonylurea derivatives, it is known that, despite the initial effectiveness of measures to eliminate hypoglycemia, it can occur again. Severe or prolonged hypoglycemia, which is only temporarily eliminated with normal amounts of sugar, requires immediate treatment, sometimes hospitalization. Factors contributing to the development of hypoglycemia include:

- unwillingness or (especially in old age) the patients inability to cooperate with a doctor;

- malnutrition, irregular eating or skipping meals or a period of fasting;

- violation of the diet;

- mismatch between physical activity and carbohydrate intake;

- drinking alcohol, especially in combination with skipping meals;

- impaired renal function;

- severe liver dysfunction;

- overdose of Amaril^®;

- Certain decompensated diseases of the endocrine system that affect carbohydrate metabolism or counterregulation of hypoglycemia (for example, with some dysfunctions of the thyroid gland and insufficiency of the function of the anterior pituitary or adrenal cortex);

- simultaneous use of other drugs (see INTERACTIONS).

Amaril treatment^® requires regular monitoring of blood and urine glucose levels. In addition, it is recommended to determine the content of glycosylated hemoglobin.

During treatment with Amaril^® it is necessary to regularly monitor indicators of liver function and hematological parameters (especially the number of leukocytes and platelets).

In stressful situations (for example, trauma, unplanned surgery, infections accompanied by fever), a temporary transfer of the patient to insulin may be indicated.

Amaril experience^® in people with severely impaired liver function or in patients on dialysis, no. Patients with severe impaired renal or hepatic function are indicated for insulin transfer. Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylurea preparations can lead to the development of hemolytic anemia. Since glimepiride belongs to the class of sulfonylurea preparations, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. They should be prescribed alternative drugs that do not contain sulfonylurea.

Amaril^® contains lactose monohydrate. This medication should not be taken in patients with rare hereditary galactose intolerance, Lapp lactase deficiency or impaired glucose-galactose absorption.

Pregnancy period

The risk associated with diabetes. Deviation from normal blood glucose levels during pregnancy can increase the likelihood of congenital malformations and perinatal mortality. Therefore, it is necessary to carefully control glycemia during pregnancy in order to avoid teratogenic risk. A pregnant woman with diabetes should be switched to insulin. Women with diabetes should inform their doctor about their planned pregnancy to correct treatment and switch to insulin.

Risk associated with glimepiride. There is no data on the use of glimepiride during pregnancy. According to the results of animal experiments, the drug has a toxic effect on reproductive function, probably associated with the pharmacological (hypoglycemic) effect of glimepiride.

Therefore, throughout the entire period of pregnancy, glimepiride is contraindicated (see CONTRAINDICATIONS).

When using glimepiride and planning or becoming pregnant, the woman should be transferred to insulin therapy as soon as possible.

The period of breastfeeding. To avoid getting the drug Amaryl^® with mother’s breast milk into the baby’s body and possible harmful effects on it, this drug should not be taken by women during breast-feeding. If necessary, the patient should switch to the use of insulin or completely abandon breastfeeding (see CONTRAINDICATIONS).

Children. Existing data on the safety and efficacy of the drug in children are insufficient, therefore it is not recommended for use in patients of this category.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies on the effect of the drug on the ability to drive vehicles and work with mechanisms have not been conducted.

The ability to concentrate and the reaction rate may decrease due to hypoglycemia or hyperglycemia, or, for example, due to visual impairment. This can create a risk in situations where this ability is especially important (for example, driving vehicles or working with machinery).

The patient should be cautioned that they do not allow the development of hypoglycemia while driving. This is especially true for those individuals who are poorly or completely unable to recognize their symptoms - precursors of hypoglycemia, and those who often have hypoglycemia attacks.You must carefully weigh the need to drive vehicles or work with mechanisms in such circumstances.

Interactions

The concomitant use of amaryl® with certain drugs can cause both a decrease and an increase in the hypoglycemic effect of glimepiride. therefore, other drugs should be used only with the consent (or prescription) of the doctor. glimepiride is metabolized using cytochrome p450 2c9 (cyp 2c9). it is known that due to the simultaneous administration of inducers (e.g. rifampicin) or cyp 2c9 inhibitors (e.g. fluconazole), this metabolism may change. The results of the in vivo interaction study showed that fluconazole, one of the most powerful inhibitors of cyp 2c9, increases the auc of glimepiride by about 2 times. the existence of these types of interactions is evidenced by the experience of using the drug amaryl® and other sulfonylurea derivatives. potentiation of the hypoglycemic effect, which means, in some cases, hypoglycemia, can occur when drugs such as phenylbutazone, azapropazone and oxyphenbutazone, sulfin pyrazone, insulin and oral antidiabetic drugs, some prolonged-release sulfonamides, are used simultaneously with glimepiride and pask, MAO inhibitors, anabolic steroids and male sex hormones, quinolone antibiotics, chloramphenicol, probenecid, coumarin anticoag Yanta, miconazole, fenfluramine, disopyramide, pentoxifylline (for parenteral administration at a high dose), fibrates tritokvalin, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclo-, Trojan and ifosfamide.

A decrease in the hypoglycemic effect and, consequently, an increase in blood glucose levels can occur with the simultaneous use of such drugs: estrogens and progestogens, saluretics, thiazide diuretics, drugs that stimulate thyroid function, glucocorticoids, phenothiazine derivatives, chlorpromazine, epinephrine and sympathomimetics, nicotinic acid (high dose) and its derivatives, laxatives (long-term use), phenytoin, diazoxide, glucagon, barbiturates and rifampicin, acetosols d.

Antagonists H₂receptors, β-adrenoreceptor blockers, clonidine and reserpine can lead to both potentiation and a decrease in the hypoglycemic effect. Under the influence of sympatholytics, such as β-adrenoreceptor blockers, clonidine, guanethidine and reserpine, the manifestations of adrenergic counterregulation of hypoglycemia may be reduced or even absent. Drinking alcohol may increase or decrease the hypoglycemic effect of glimepiride in an unforeseen manner.

Glimepiride is able to both increase and decrease the effect of coumarin derivatives.

Kolesevelam binds to glimepiride and reduces the absorption of the latter in the digestive tract. No interactions were detected if glimepiride was taken at least 4 hours before taking wheel lovelam. In this regard, glimepiride should be taken no less than 4 hours before the use of wheel magnum.

Overdose

It can lead to hypoglycemia, which lasts from 12 to 72 hours, and after the first decrease in the severity of symptoms, it can reappear. symptoms may occur 24 hours after absorption of the drug. as a rule, for such patients observation in the clinic is recommended. nausea, vomiting, and pain in the epigastric region may occur. hypoglycemia can often be accompanied by neurological symptoms such as anxiety, tremors, impaired vision, coordination, drowsiness, coma, and cramps.

Treatment consists, first of all, in preventing the absorption of the drug. To do this, induce vomiting, drink water or lemonade, take activated charcoal (adsorbent) and sodium sulfate (laxative).If a large amount of glimepiride is taken, gastric lavage is indicated, followed by the use of activated carbon and sodium sulfate. In case of severe overdose, hospitalization in the intensive care unit is necessary. Glucose administration should be started as soon as possible: if necessary, first a single intravenous injection of 50 ml of 50% solution, and then an infusion of 10% solution, constantly monitoring glycemia. Further treatment is symptomatic.

In the treatment of hypoglycemia caused by the accidental administration of Amaril^®, in infants and young children, the dose of glucose must be especially carefully adjusted, given the possibility of dangerous hyperglycemia, and its control should be carried out by carefully monitoring the level of glucose in the blood.

Storage conditions

In the original packaging at a temperature not exceeding 30 ° c.

Information for healthcare professionals. Instructions for medical use of the drug AMARIL^®tablets 2 mg. Order of the Ministry of Health of Ukraine dated 10.11.2016, No. 1225. P.S. Ministry of Health of Ukraine No. UA / 7389/01/01. Instructions for medical use of the drug AMARIL^®tablets 3 mg. Order of the Ministry of Health of Ukraine dated 10.11.2016, No. 1225. P.S. Ministry of Health of Ukraine No. UA / 7389/01/02. Instructions for medical use of the drug AMARIL^®tablets 4 mg. Order of the Ministry of Health of Ukraine dated 10.11.2016, No. 1225. P.S. Ministry of Health of Ukraine No. UA / 7389/01/03.