Amaril, tablets 2 mg 30 pcs

Pharmacodynamics

The oral hypoglycemic drug is a sulfonylurea derivative of III generation.

Glimepiride reduces blood glucose concentration, mainly due to stimulation of insulin release from the pancreatic β-cells. Its effect is mainly due to an improvement in the ability of pancreatic β-cells to respond to physiological glucose stimulation. Compared to glibenclamide, glimepiride at low doses causes the release of less insulin while achieving approximately the same decrease in blood glucose concentration. This fact is evidence in favor of the presence of extrapancreatic hypoglycemic effects of glimepiride (increased tissue sensitivity to insulin and insulinomimetic effect).

Insulin secretion. Like all other sulfonylurea derivatives, glimepiride regulates insulin secretion by interaction 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 located in the membranes of pancreatic β-cells. This interaction of glimepiride with the protein that binds to it regulates the opening or closing of ATP-sensitive potassium channels.

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

Glimepiride binds to and is released from its binding protein much faster and correspondingly more frequently than glibenclamide. It is assumed that this property of glimepiride’s high rate of exchange with its binding protein accounts for its pronounced effect in sensitizing β-cells to glucose and protecting them from desensitization and premature depletion.

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

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

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

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

The effect on platelet aggregation. Glimepiride reduces platelet aggregation in vitro and in vivo. This effect seems to be connected with selective inhibition of COX, which is responsible for formation of thromboxane A, an important endogenous factor of platelet aggregation. Antiatherogenic action. Glimepiride promotes normalization of lipids, reduces the level of malonic aldehyde in blood, which leads to a significant reduction in lipid peroxidation. In animals glimepiride leads to a significant reduction of atherosclerotic plaque formation.

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

Cardiovascular effects. Through ATP-sensitive potassium channels, sulfonylurea derivatives also have effects on the cardiovascular system. Compared with traditional sulfonylurea derivatives, glimepiride has significantly less effect on the cardiovascular system, which may be explained by the specific nature of its interaction with the ATP-sensitive potassium channel protein 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. Physiological response to physical activity (decreased insulin secretion) is maintained while taking glimepiride.

There are no significant differences in the effect depending on whether the drug was taken 30 minutes before a meal or immediately before a meal. In patients with diabetes mellitus it is possible to achieve sufficient metabolic control within 24 h with a single dose of the drug. Moreover, in a clinical trial, sufficient metabolic control was also achieved in 12 of 16 patients with renal impairment (KC 4-79 ml/min).

Combination therapy with metformin. In patients with insufficient metabolic control at the maximum dose of glimepiride, combination therapy with glimepiride and metformin may be initiated. Two studies have shown an improvement in metabolic control with combination therapy compared with treatment with each of these drugs alone.

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

Pharmacokinetics

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

Intake

When repeated oral administration of the drug at a daily dose of 4 mg, serum Cmax is reached after approximately 2.5 hours and is 309 ng/ml. There is a linear relationship between the dose and Cmax of glimepiride in blood plasma, as well as between the dose and AUC. The bioavailability of glimepiride is 100% when administered orally. Food intake has no significant effect on absorption, except for a slight delay in its rate.

Distribution

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

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

Metabolism

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

The T1/2 at plasma concentrations of the drug in the serum, corresponding to the multiple dosing regimen, is approximately 5-8 hours. After glimepiride administration in high doses, the T1/2 is slightly increased. After a single oral dose, 58% of glimepiride is excreted by the kidneys and 35% by the intestine. The unchanged active substance is not detected in the urine.

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

Pharmacokinetics in special clinical cases

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

In patients with impaired renal function (with low CK), there is a tendency for glimepiride clearance to increase and for its average serum concentrations to decrease, which is likely due to the faster excretion of the drug due to its lower protein binding. Thus, there is no additional risk of glimepiride cumulation in this category of patients.

Indications

Type 2 diabetes mellitus (as monotherapy or in combination therapy with metformin or insulin).

Active ingredient

Composition

Active substances:

Glimepiride 2 mg.

Auxiliary substances:

Lactose monohydrate,

sodium carboxymethyl starch (type A),

povidone 25,000,

microcrystalline cellulose,

magnesium stearate,

iron oxide yellow dye (E172),

indigo carmine (E132).

How to take, the dosage

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

During treatment with Amaril® blood glucose levels should be determined regularly. In addition, regular monitoring of glycosylated hemoglobin levels is recommended.

Disorders such as skipping a dose should not be made up for by taking a subsequent higher dose of the drug.

The physician should instruct the patient in advance about the steps to be taken when there are errors in taking Amaryl® (such as skipping the next dose or skipping meals) or in situations where it is not possible to take the medication.

The tablets of Amaril® should be taken whole without chewing, with enough fluid (about 1/2 cup). If necessary, Amaril® tablets can be divided into two equal parts.

The initial dose of Amaril® is 1 mg 1 time per day. If necessary, the daily dose may be gradually increased (at intervals of 1-2 weeks) under regular blood glucose monitoring 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 mellitus, the daily dose of the drug is usually 1-4 mg. A daily dose of more than 6 mg is more effective only in a small number of patients.

The time of Amaril® administration and the distribution of doses during the day is determined by the physician with regard to the patient’s lifestyle (time of meals, amount of physical exertion). The daily dose is prescribed at 1 meal, usually immediately before a full breakfast or, if the daily dose was not taken, immediately before the first main meal. It is very important not to skip meals after taking Amaril® tablets.

Because improvement in metabolic control is associated with increased insulin sensitivity, it is possible to decrease the need for glimepiride during treatment. In order to avoid the development of hypoglycemia it is necessary to decrease the dose or discontinue Amaril® in a timely manner.

Conditions in which glimepiride dose adjustment may also be required:

Treatment with glimepiride is usually long-term.

Transferring a patient from another oral hypoglycemic drug to Amaril®

There is no exact relationship between doses of Amaril® and other oral hypoglycemic drugs. When switching from these drugs to Amaril® , the recommended initial daily dose of Amaril® is 1 mg (even if the patient is switched to Amaril® from the maximum dose of another oral hypoglycemic drug). Any dose increase should be done in stages, taking into account the response to glimepiride in accordance with the above recommendations. The intensity and duration of the effect of the preceding hypoglycemic drug should be taken into account. Treatment may need to be interrupted to avoid additive effect, which increases the risk of hypoglycemia.

Use in combination with metformin

In patients with insufficiently controlled diabetes when taking glimepiride or metformin at maximum daily doses, treatment with a combination of the two drugs may be initiated. In this case, previous treatment with either glimepiride or metformin is continued at the same dose, and additional administration of metformin or glimepiride is started 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.

The use in combination with insulin

Patients with insufficiently controlled diabetes when taking glimepiride in 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, treatment with insulin begins with low doses, which are gradually increased under the control of blood glucose concentrations. Combined treatment is carried out under close medical supervision.

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

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

Interaction

Glimepiride is metabolized with participation of CYP2C9 isoenzyme, which should be considered when concomitant use of the drug with inducers (e.g., rifampicin) or inhibitors (e.g., fluconazole) of CYP2C9.

Potentiation of hypoglycemic action and in some cases the associated possible development of hypoglycemia may be observed when Amaryl® is combined with one of the following drugs: insulin, other oral hypoglycemic agents, ACE inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, pheniramidol, fibrates, fluoxetine, guanethidine ifosfamide, MAO inhibitors, fluconazole, PASC, pentoxifylline (high parenteral doses), phenylbutazone, azapropazon, oxyphenbutazone, probenecid, quinolones, salicylates, sulfinpyrazone, clarithromycin, sulfonamides, tetracyclines, tritoqualine, trophosphamide.

Decrease of hypoglycemic action and related increase of blood glucose concentration is possible when combined with one of the following drugs: acetazolamide, barbiturates, GCS, diazoxide, diuretics, sympathomimetic agents (incl.epinephrine), glucagon, laxatives (with prolonged use), nicotinic acid (in high doses), estrogens and progestagens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones.

Histamine H2-receptor blockers, beta-adrenoblockers, clonidine and reserpine can both increase and decrease the hypoglycemic effects of glimepiride.

The signs of adrenergic counter-regulation in response to hypoglycemia may be reduced or absent under the influence of sympatholytic agents such as beta-adrenoblockers, clonidine, guanethidine and reserpine.

In the background of glimepiride administration, the effect of coumarin derivatives may be enhanced or weakened.

Onetime or chronic alcohol consumption may both enhance or weaken the hypoglycemic effect of glimepiride.

Bile acid sequestrants: Coelcevelam binds to glimepiride and reduces the absorption of glimepiride from the gastrointestinal tract. In the case of glimepiride at least 4 h before ingestion of coleselam no interaction is observed. Therefore, glimepiride should be taken at least 4 h before taking coloselam.

Special Instructions

In special clinical stress conditions, such as trauma, surgical interventions, infections with febrile fever, deterioration of metabolic control in patients with diabetes mellitus is possible; therefore, temporary transfer to insulin therapy may be required to maintain adequate metabolic control.

In the first weeks of treatment, there may be an increased risk of hypoglycemia, which requires particularly close monitoring of blood glucose concentrations.

Factors contributing to the risk of hypoglycemia include:

Contraindications

With caution: should use the drug in the first weeks of treatment (increased risk of hypoglycemia); if there are risk factors for hypoglycemia (may require adjustment of the dose of glimepiride or all therapy); in case of intercurrent diseases during treatment or changes in patients’ lifestyle (change of diet and meal time, increase or decrease of physical activity); in glucose-6-phosphate dehydrogenase deficiency; in disorders of absorption of food and drugs from gastrointestinal tract (intestinal obstruction, intestinal paresis).

Side effects

Metabolism disorders: hypoglycemia may occur, which, as with the use of other sulfonylurea derivatives, may be prolonged. Symptoms of hypoglycemia – headache, hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, restlessness, aggressiveness, violation of concentration, vigilance and reaction rate, depression, confusion, speech disorders, aphasia, visual disturbances, tremor, paresis, sensory disturbances, dizziness, loss of self-control, delirium, cerebral convulsions, drowsiness or loss of consciousness up to coma, shallow breathing, bradycardia. In addition, there may be manifestations of adrenergic counter-regulation in response to hypoglycemia, such as cold clammy sweat, anxiety, tachycardia, arterial hypertension, angina, palpitations and heart rhythm disturbances. The clinical picture of severe hypoglycemia may resemble a stroke. Symptoms of hypoglycemia almost always disappear after its elimination.

With the visual organ: transient visual disturbances due to changes in blood glucose concentration are possible (especially at the beginning of treatment). This is caused by a temporary change in lens swelling, which depends on the blood glucose concentration, and due to this a change in the refractive index of the lenses.

The digestive system: rarely – nausea, vomiting, a feeling of heaviness or overflow in the epigastrium, abdominal pain, diarrhea; in individual cases – hepatitis, increased liver enzyme activity and/or cholestasis and jaundice, which may progress to life-threatening liver failure, but may undergo reversal when withdrawing the drug.

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

Allergic reactions: rare – allergic and pseudoallergic reactions such as itching, urticaria, skin rash. These reactions are almost always mild, but may progress to severe reactions with dyspnea, a sharp decrease in BP, which sometimes progress to anaphylactic shock; in some cases – allergic vasculitis.

Others: in some cases – hyponatremia, photosensitization.

In case of symptoms of urticaria should immediately consult a physician.

Overdose

Symptoms: in acute overdose, as well as long-term treatment with glimepiride in excessively high doses, development of severe life-threatening hypoglycemia is possible.

Treatment: hypoglycemia can almost always be quickly stopped by immediate intake of carbohydrates (glucose or a piece of sugar, sweet fruit juice or tea). The patient should therefore always carry at least 20 g of glucose (4 lumps of sugar). Sugar substitutes are ineffective in the treatment of hypoglycemia.

Till such time as the physician decides that the patient is out of danger, the patient needs close medical observation. Keep in mind that hypoglycemia may recur after the initial recovery of blood glucose concentrations.

If a patient with diabetes is treated by different doctors (e.g., during a hospital stay after an accident, during a weekend illness), they should be sure to tell them about their illness and previous treatment.

Sometimes a patient may need to be hospitalized, even if only as a precaution. Significant overdose and severe reactions 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, concentrated dextrose (glucose) solution (for adults, starting with 40 ml of 20% solution) should be administered intravenously. Alternatively, adults may be given intravenous, p/c or intramural glucagon, e.g. at a dose of 0.5-1 mg.

When treating hypoglycemia due to accidental administration of Amaryl® in infants or young children, the dose of dextrose should be carefully adjusted to avoid the possibility of dangerous hyperglycemia; dextrose should be administered under continuous monitoring of blood glucose concentrations.

In case of overdose, Amaryl® may require gastric lavage and administration of activated charcoal.

After rapid recovery of blood glucose concentrations, it is necessary to perform an intravenous infusion of dextrose solution at a lower concentration to prevent recurrence of hypoglycemia. Blood glucose concentration in such patients should be constantly monitored for 24 hours. In severe cases with prolonged hypoglycemia, the risk of low blood glucose levels may persist for several days.

As soon as an overdose is detected, the physician should be informed promptly.

Similarities