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Amaryl

Amaryl
Glimepiride tablets are used as an adjunct to diet and exercise to lower blood glucose levels in patients with insulin-dependent (Type II) diabetes mellitus, in whom diet and exercise alone cannot adequately affect hyperglycemia.

Brand: Glimepiride

Availability: In Stock
Average Delivery Time: 9 Days
Exp. Date: December 2023
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Product description

Pharmacological action

Oral hypoglycemic drug - III generation sulfonylurea derivative.

Buy Amaryl tablets in Canada

Glimepiride reduces the concentration of glucose in the blood, mainly by stimulating the release of insulin from the β-cells of the pancreas. Its effect is predominantly associated with an improvement in the ability of pancreatic β-cells to respond to physiological glucose stimulation. Compared to glibenclamide, low doses of glimepiride cause the release of less insulin while achieving approximately the same reduction in blood glucose concentration. This fact supports the presence of extrapancreatic hypoglycemic effects in glimepiride (increased tissue sensitivity to insulin and insulinomimetic effect).

Insulin secretion. Like all other sulfonylurea derivatives, glimepiride regulates insulin secretion by interacting with ATP-sensitive potassium channels on β-cell membranes. Unlike other sulfonylurea derivatives, glimepiride selectively binds to a protein with a molecular weight of 65 kilodaltons, which is located in the membranes of β-cells of the pancreas. This interaction of glimepiride with a protein binding to it regulates the opening or closing of ATP-sensitive potassium channels.

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

Glimepiride much faster and, accordingly, more often enters into a bond and is released from a bond with a protein that binds to it than glibenclamide. It is assumed that this property of a high exchange rate of glimepiride with a protein binding to it determines its pronounced effect of sensitizing β-cells to glucose and protecting them from desensitization and premature depletion.

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

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

The absorption of glucose by peripheral tissues is carried out by its transport into muscle cells and adipocytes. Glimepiride directly increases the number of glucose-transporting molecules in the plasma membranes of muscle cells and adipocytes. An increase in the intake of glucose into cells leads to the activation of glycosylphosphatidylinositol-specific phospholipase C. As a result, the intracellular calcium concentration decreases, causing a decrease in the activity of protein kinase A, which in turn leads to the stimulation of glucose metabolism.

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

Influence on platelet aggregation. Glimepiride reduces platelet aggregation in vitro and in vivo. This effect appears to be related to the selective inhibition of COX, which is responsible for the formation of thromboxane A, an important endogenous factor of platelet aggregation.

Antiatherogenic action. Glimepiride contributes to the normalization of lipids, reduces the level of malonic aldehyde in the blood, which leads to a significant decrease in lipid peroxidation. In animals, glimepiride leads to a significant reduction in the formation of atherosclerotic plaques.

Reducing the severity of oxidative stress, which is constantly present in patients with type 2 diabetes. Glimepiride increases the level of endogenous α-tocopherol, catalase, glutathione peroxidase and superoxide dismutase activity.

Cardiovascular Effects. Sulfonylurea derivatives also act on the cardiovascular system through ATP-sensitive potassium channels. Compared with traditional sulfonylurea derivatives, glimepiride has a significantly lower effect on the cardiovascular system, which can be explained by the specific nature of its interaction with the protein ATP-sensitive potassium channels that binds to it.

In healthy volunteers, the minimum effective dose of glimepiride is 0.6 mg. The effect of glimepiride is dose dependent and reproducible. The physiological response to exercise (decreased insulin secretion) persists when glimepiride is taken.

There are no significant differences in the effect depending on whether the drug was taken 30 minutes before meals or immediately before meals. In patients with diabetes mellitus, sufficient metabolic control can be achieved within 24 hours with a single dose of the drug. Moreover, in a clinical study, 12 out of 16 patients with renal insufficiency (CC 4-79 ml / min) also achieved sufficient metabolic control.

Combination therapy with metformin. In patients with insufficient metabolic control, when using the maximum dose of glimepiride, combination therapy with glimepiride and metformin may be initiated. In two studies, combination therapy has shown improved metabolic control compared to that with each of these drugs alone.

Combination therapy with insulin. In patients with insufficient metabolic control, while taking glimepiride at maximum doses, concomitant insulin therapy may be initiated. In two studies, this combination achieves the same improvement in metabolic control as insulin alone. However, combination therapy requires a lower dose of insulin.

Pharmacokinetics

Diabetes treatment with Amaryl

When comparing the data obtained with single and multiple (1 time / day) administration of glimepiride, no significant differences in pharmacokinetic parameters were found, and their variability between different patients was very low. There is no significant accumulation of the drug.

Absorption

With repeated oral administration of the drug 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 the dose and Cmax of glimepiride in plasma, as well as between the dose and the AUC. When taken orally, the bioavailability of glimepiride is 100%. Food intake has no significant effect on absorption, with the exception of a slight slowdown in its speed.

Distribution

Glimepiride is characterized by a very low Vd (about 8.8 L), approximately equal to the Vd of albumin, a high degree of binding to plasma proteins (more than 99%) and a low clearance (about 48 ml / min).

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

Metabolism

Glimepiride is metabolized in the liver (mainly with the participation of the isoenzyme CYP2C9) with the formation of 2 metabolites - hydroxylated and carboxylated derivatives, which are found in urine and feces.

The elimination of

T1/2 at plasma concentrations of the drug in serum corresponding to a multiple dosage regimen is approximately 5-8 hours. After taking glimepiride in high doses, T1/2 increases slightly.

After a single oral administration, 58% of glimepiride is excreted by the kidneys and 35% through the intestines. The unchanged active substance is not detected in the urine.

T1/2 of hydroxylated and carboxylated metabolites of glimepiride were about 3-5 hours and 5-6 hours, respectively.

Pharmacokinetics in special clinical cases

Pharmacokinetic parameters are similar in patients of different sexes and different age groups.

In patients with impaired renal function (with low CC), there is a tendency to an increase in the clearance of glimepiride and to a decrease in its average concentrations in the blood serum, which is most likely due to a more rapid excretion of the drug due to its lower binding to proteins. Thus, in this category of patients there is no additional risk of glimepiride cumulation.

Indications for Amaryl®

  • type 2 diabetes mellitus (as monotherapy or as part of a combination therapy with metformin or insulin).

Dosage regimen

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As a rule, the dose of Amaryl® is determined by the target blood glucose concentration. The drug should be used in the minimum dose sufficient to achieve the required metabolic control.

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

Violation of the drug intake, for example, skipping the next dose, should not be replenished by taking the drug at a higher dose.

The physician should instruct the patient in advance of the action to be taken if an error occurs in receiving the drug Amaryl® (especially when skipping receiving the next dose or skip a meal), or in situations where there is no possibility to take the drug.

The tablets of Amaryl® should be taken whole, without chewing, with a sufficient amount of liquid (about 1/2 glass). If necessary, the tablets of Amaryllines® can be divided along theinto two equal parts.

The initial dose of Amaryl® is 1 mg 1 time / day. If necessary, the daily dose can be gradually increased (at intervals of 1-2 weeks) under regular monitoring of blood glucose and in the following order: 1 mg-2 mg-3 mg-4 mg-6 mg (-8 mg) per day ...

In patients with well-controlled type 2 diabetes, the daily dose of the drug is usually 1-4 mg. A daily dose of more than 6 mg is more effective in only a small number of patients.

Thetime of taking Amaryl® doctor determines theand the distribution of doses during the day, taking into account the patient's lifestyle (time of eating, the amount of physical activity). The daily dose is prescribed in 1 reception, as a rule, immediately before a full breakfast or, if the daily dose has not been taken, immediately before the first main meal. It is very importantafter taking the tablets of Amaryl® not to skip meals.

Because improvement in metabolic control is associated with an increase in insulin sensitivity, during treatment, it is possible to reduce the need for glimepiride. In order to avoid the development of hypoglycemia, it is necessary to promptly reduce the dose or stop taking Amaryl®.

Conditions in which glimepiride dose adjustment may also be required:

  • weight loss;

  • lifestyle changes (change in diet, meal time, amount of physical activity);

  • the occurrence of other factors that lead to a predisposition to the development of hypoglycemia or hyperglycemia.

Treatment with glimepiride is usually long-term.

Transfer of a patient from taking another oral hypoglycemic drug to taking Amaryl®

There is no exact relationship between the doses of Amaryl® and other oral hypoglycemic drugs. When translated from such preparations Amaryl® recommended initial daily dose of 1 mg of the latter (even if the patient is transferred to Amaryl® with a maximum dose of another oral hypoglycemic drug). Any dose escalation should be carried out in stages, taking into account the response to glimepiride in accordance with the recommendations above. It is necessary to take into account the intensity and duration of the effect of the previous hypoglycemic agent. Interruption of treatment may be required to avoid an additive effect that increases the risk of hypoglycemia.

Use in combination with metformin

In patients with insufficiently controlled diabetes mellitus, when taking glimepiride or metformin at the maximum daily doses, treatment with a combination of these two drugs can be started. In this case, the previous treatment with either glimepiride or metformin continues at the same doses, and the additional intake of metformin or glimepiride begins 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 be started under close medical supervision.

Use in combination with insulin

Patients with insufficiently controlled diabetes mellitus while taking glimepiride at the maximum daily dose may be simultaneously prescribed insulin. In this case, the last dose of glimepiride prescribed to the patient remains unchanged. In this case, insulin treatment begins with low doses, which are gradually increased under the control of the concentration of glucose in the blood. The combined treatment is carried out under close medical supervision.

Patients with impaired renal function may be more sensitive to the hypoglycemic effect of glimepiride. Data on the use of Amaryl® in patients with renal insufficiency are limited.

The data on the use of Amaryl® in patients with hepatic impairment are limited.


Contraindications to the use of

  • type 1 diabetes mellitus;

  • diabetic ketoacidosis, diabetic precoma and coma;

  • severe liver dysfunction (lack of clinical experience of use);

  • severe renal dysfunction, incl. patients on hemodialysis (lack of clinical experience of use);

  • pregnancy;

  • lactation (breastfeeding);

  • childhood (lack of clinical experience of use);

  • rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption;

  • hypersensitivity to drug components;

  • hypersensitivity to other sulfonylurea derivatives and sulfonamide drugs (risk of developing hypersensitivity reactions).

Thewith caution drug should be usedin the first weeks of treatment (increased risk of hypoglycemia); in the presence of risk factors for the development of hypoglycemia (a dose adjustment of glimepiride or all therapy may be required); with intercurrent diseases during treatment or with a change in the patient's lifestyle (change in diet and meal time, increase or decrease in physical activity); with deficiency of glucose-6-phosphate dehydrogenase; with violations of absorption of food and drugs from the gastrointestinal tract (intestinal obstruction, intestinal paresis).

Application during pregnancy and lactation

Amaryl® is contraindicated for use during pregnancy. In the event of a planned pregnancy or pregnancy, a woman should be transferred to insulin therapy.

It has been established that glimepiride is excreted in breast milk. During lactation, the woman should be transferred to insulin or breastfeeding should be stopped.

Application for violations of liver function

Use is contraindicated in severe violations of liver function.

Application for impaired renal function

Use is contraindicated in severe impaired renal function (including patients on hemodialysis);

Use in children

Contraindicated in childhood.

Special instructions

In special clinical stressful conditions, such as trauma, surgery, infections occurring with febrile temperature, metabolic control may deteriorate in patients with diabetes mellitus, therefore, temporary transfer to insulin therapy may be required to maintain adequate metabolic control.

In the first weeks of treatment, the risk of hypoglycemia may increase, which requires particularly careful monitoring of the blood glucose concentration.

Factors contributing to the risk of developing hypoglycemia include:

  • unwillingness or inability of the patient (more often observed in elderly patients) to cooperate with a doctor;

  • malnutrition, irregular meals, or skipping meals;

  • imbalance between exercise and carbohydrate intake;

  • diet change;

  • drinking alcohol, especially in combination with skipping meals;

  • severe renal dysfunction;

  • severe hepatic dysfunction (in patients with severe hepatic dysfunction, transfer to insulin therapy is indicated, at least until metabolic control is achieved);

  • overdose of glimepiride;

  • some decompensated endocrine disorders that disrupt carbohydrate metabolism or adrenergic counter-regulation in response to hypoglycemia (for example, some disorders of the thyroid gland and anterior pituitary gland, adrenal insufficiency);

  • concomitant use of certain medications;

  • taking glimepiride in the absence of indications for taking it.

Treatment with sulfonylurea derivatives, which include glimepiride, can lead to the development of hemolytic anemia, therefore, in patients with glucose-6-phosphate dehydrogenase deficiency, special care should be taken when prescribing glimepiride, it is preferable to use hypoglycemic agents that are not sulfonylurea derivatives.

In case of the presence of the above risk factors for the development of hypoglycemia, as well as the occurrence of intercurrent diseases during treatment or changes in the patient's lifestyle, it may be necessary to adjust the dose of glimepiride or the entire therapy.

Symptoms of hypoglycemia resulting from adrenergic counterregulation of the body in response to hypoglycemia may be mild or absent with the gradual development of hypoglycemia, in elderly patients, in patients with disorders of the autonomic nervous system, or in patients receiving beta-blockers, clonidine, reserpine , guanethidine and other sympatholytic agents.

Hypoglycemia can be quickly resolved by immediate intake of rapidly absorbing carbohydrates (glucose or sucrose). As with other sulfonylurea derivatives, despite the initial successful relief of hypoglycemia, hypoglycemia may recur. Therefore, patients must remain under constant supervision. In severe hypoglycemia, immediate treatment and medical supervision are additionally required, and in some cases, hospitalization of the patient.

During treatment with glimepiride, regular monitoring of liver function and peripheral blood counts (especially the number of leukocytes and platelets) is required.

Side effects such as severe hypoglycemia, serious changes in the blood picture, severe allergic reactions, liver failure can be life-threatening, therefore, if such reactions develop, the patient should immediately inform the attending physician about them, stop taking the drug and not resume taking without the doctor's recommendation ...

Pediatric Use There are no

data on the long-term efficacy and safety of the drug in children.

Influence on the ability to drive vehicles and control mechanisms

At the beginning of treatment, after changing treatment or with irregular intake of glimepiride, there may be a decrease in concentration of attention and the speed of psychomotor reactions caused by hypo- or hyperglycemia. This can adversely affect the ability to drive vehicles or operate various machines and mechanisms.

Overdose

Symptoms: in acute overdose, as well as long-term treatment with glimepiride in excessively high doses, severe life-threatening hypoglycemia may develop.

Treatment: hypoglycemia can almost always be quickly stopped by immediate intake of carbohydrates (glucose or a sugar cube, sweet fruit juice or tea). In this regard, the patient should always have at least 20 g of glucose (4 pieces of sugar) with him. Sugar substitutes are ineffective in the treatment of hypoglycemia.

Until the doctor decides that the patient is out of danger, the patient needs careful medical supervision. It should be borne in mind that hypoglycemia may resume after the initial restoration of blood glucose concentration.

If a patient with diabetes is treated by different doctors (for example, during a hospital stay after an accident, during an illness on weekends), he must inform them about his illness and previous treatment.

Sometimes hospitalization of the patient may be required, even if only as a precautionary measure. Significant overdose and severe reaction with manifestations such as loss of consciousness or other serious neurological disorders are medical emergencies and require immediate treatment and hospitalization.

In case of loss of consciousness, intravenous administration of a concentrated solution of dextrose (glucose) is necessary (for adults, starting with 40 ml of a 20% solution). As an alternative to adults, it is possible to administer IV, SC or IM glucagon, for example, at a dose of 0.5-1 mg.

In the treatment of hypoglycemia due to accidental intake of Amaryl® by infants or young children, the dose of dextrose should be carefully adjusted to avoid the possibility of dangerous hyperglycemia; the introduction of dextrose should be carried out under constant monitoring of the concentration of glucose in the blood.

In case of an overdose of Amaryl®, it may be necessary to perform gastric lavage and take activated charcoal.

After a rapid restoration of the concentration of glucose in the blood, it is imperative to carry out an intravenous infusion of a dextrose solution at a lower concentration to prevent the resumption of hypoglycemia. The concentration of glucose in the blood in such patients should be constantly monitored for 24 hours. In severe cases with a prolonged course of hypoglycemia, the danger of a decrease in blood glucose levels can persist for several days.

As soon as an overdose is detected, it is necessary to urgently inform the doctor about it.


Side effect

From the side of metabolism: hypoglycemia is possible, which, as with the use of other sulfonylurea derivatives, can be prolonged. Symptoms of hypoglycemia - headache, hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, anxiety, aggressiveness, impaired concentration, alertness and reaction speed, depression, confusion, speech disorders, aphasia, visual disturbances, tremors, paresis , sensory disturbances, dizziness, loss of self-control, delirium, cerebral cramps, drowsiness or loss of consciousness up to coma, shallow breathing, bradycardia. In addition, manifestations of adrenergic counterregulation in response to hypoglycemia may occur, such as the appearance of cold clammy sweat, anxiety, tachycardia, arterial hypertension, angina pectoris, palpitations and cardiac arrhythmias. The clinical picture of severe hypoglycemia may resemble a stroke. Symptoms of hypoglycemia almost always disappear after its elimination.

From the side of the organ of vision: possible (especially at the beginning of treatment) transient visual disturbances caused by changes in the concentration of glucose in the blood. They are caused by a temporary change in the swelling of the lens, depending on the concentration of glucose in the blood, and due to this change in the refractive index of the lens.

From the digestive system: rarely - nausea, vomiting, feeling of heaviness or fullness in the epigastrium, abdominal pain, diarrhea; in some cases - hepatitis, increased activity of liver enzymes and / or cholestasis and jaundice, which can progress to life-threatening liver failure, but may undergo a regression if the drug is discontinued.

From the hematopoietic system: rarely - thrombocytopenia; in some cases - leukopenia, hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia. With post-marketing use of the drug, cases of severe thrombocytopenia with platelet count <10,000 / μl and thrombocytopenic purpura have been reported (frequency unknown).

Allergic reactions: rarely - allergic and pseudo-allergic reactions such as itching, urticaria, skin rash. Such reactions are almost always mild, but they can turn into severe reactions with shortness of breath, a sharp decrease in blood pressure, which sometimes progress to anaphylactic shock; in some cases - allergic vasculitis.

Others: in some cases - hyponatremia, photosensitivity.

If symptoms of hives develop, see your doctor immediately.