Glimepiride-SZ, tablets 2 mg 30 pcs

Pharmacodynamics

Glimepiride reduces blood glucose concentration mainly due to stimulation of insulin release from pancreatic beta-cells. Its effect is mainly due to an improvement in the ability of pancreatic beta cells to respond to physiological glucose stimulation. Compared to glibenclamide, taking low doses of glimepiride causes the release of less insulin while achieving approximately the same decrease in blood glucose concentrations. 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 through interaction with ATP-sensitive potassium channels on beta cell membranes. Unlike other sulfonylurea derivatives, glimepiride selectively binds to a protein with a molecular weight of 65 kilodaltons (kDa) located in the membranes of pancreatic beta cells. This interaction of glimepiride with its binding protein regulates the opening or closing of ATP-sensitive potassium channels.

Glimepiride closes potassium channels. This causes depolarization of beta 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 is much faster and therefore more likely to bind to and be released from its binding protein than glibenclamide. It is assumed that this property of glimepiride’s high rate of exchange with its binding protein accounts for its pronounced glucose sensitizing effect on beta cells and its protection against desensitization and premature depletion.

The effect of increasing tissue sensitivity to insulin

Glimepiride increases the effects of insulin on glucose uptake by peripheral tissues.

Insulinomimetic effects

Glimepiride has effects similar to those of insulin on peripheral tissue glucose uptake and hepatic glucose output. Glucose uptake by peripheral tissues is by 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 appears to be due to selective inhibition of cyclooxygenase, which is responsible for the formation of thromboxane A, an important endogenous factor of platelet aggregation.

Antiatherogenic action of the drug

Glimepiride promotes normalization of lipids, decreases malonic aldehyde in blood, which leads to a significant decrease 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 endogenous α-tocopherol, catalase activity, glutathione peroxidase and superoxide dismutase.

Cardiovascular effects

With the ATP-sensitive potassium channels (see above), 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 is no significant difference in the effect depending on whether the drug was taken 30 min before a meal or immediately before a meal. In patients with diabetes mellitus, sufficient metabolic control can be achieved within 24 h with a single dose of the drug. In a clinical study, 12 of 16 patients with renal insufficiency (creatinine clearance 4 – 79 ml/min) also achieved sufficient metabolic control.

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 insulin therapy may be initiated with maximum doses of glimepiride. According to the results of two studies, this combination achieves the same improvement in metabolic control as insulin alone; however, the combination therapy requires a lower dose of insulin.

Pediatric use

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

Pharmacokinetics

Absorption

When glimepiride is taken repeatedly at a daily dose of 4 mg, the maximum plasma concentration (Cmax) is reached after approximately 2.5 hours and is 309 ng/ml. There is a linear relationship between the dose and maximum plasma concentration of glimepiride (Cmax), as well as between the dose and the area under the curve “concentration-time” (AUC). When glimepiride is taken orally, its absolute bioavailability is complete. Food intake has no significant effect on absorption, except for a slight slowing of its rate.

Distribution

Highly low volume of distribution (about
8.8 L), approximately equal to that of albumin, high plasma protein binding (more than 99%) and low clearance (about 48 ml/min) are characteristic for glimepiride. Glimepiride penetrates into breast milk and through the placental barrier.

Metabolism

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

After a single oral dose of glimepiride, 58% of the dose is excreted by the kidneys and 35% of the dose is excreted through the intestine. Unchanged glimepiride is not detected in the urine.

The average elimination half-life (T1/2), determined by serum concentrations under repeated drug administration, is approximately 5 – 8 hours. After taking high doses, a slight increase in T1/2 is noted.

The mean T1/2 of hydroxylated and carboxylated glimepiride metabolites is 3 – 5 and 5 – 6 h, respectively.

A comparison of single and multiple (once-daily) glimepiride administration showed no significant differences in pharmacokinetic parameters; there is very low variability between different patients. There is no significant accumulation of the drug.

Pharmacokinetics in special clinical cases

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

Indications

Active ingredient

Composition

excipients: Mannitol – 65.2 mg, microcrystalline cellulose (102) – 12.0 mg, sodium carboxymethyl starch – 10.0 mg, povidone K 30 (polyvinylpyrrolidone medium molecular) – 1.3 mg, crospovidone (Collidon CL) – 9.0 mg, magnesium stearate – 0.5 mg.

How to take, the dosage

As a rule, the dose of Glimepiride-SZ is determined by the target blood glucose concentration. The lowest dose sufficient to achieve the necessary glycemic control should be used.

The blood glucose concentration should be determined regularly during treatment with Glimepiride-SZ. In addition, regular monitoring of glycated hemoglobin index is recommended.

Inappropriate administration of the drug, e.g. skipping a dose, should never be made up for by taking a higher dose at a later time.

Patient responses to Glimepiride-SZ errors (such as missing the next dose or skipping meals) or situations in which it is not possible to take the medication should be discussed between the patient and the physician in advance.

The drug Glimepiride-SZ is taken orally, whole, without chewing, with plenty of fluid (about 0.5 glasses). If necessary, the tablets can be divided along the risk into two equal parts.

The starting dose and dose selection

The starting dose is 1 mg of glimepiride once daily.

If necessary, the daily dose can be gradually (at 1-2 week intervals) increased. It is recommended to increase the dose under regular control of blood glucose concentration and in accordance with the following dose increase steps: 1 mg – 2 mg – 3 mg – 4 mg – 6 mg (- 8 mg).

Dose range in patients with well-controlled diabetes

The usual daily dose in patients with well-controlled diabetes is 1 to 4 mg of glimepiride. A daily dose of more than 6 mg is more effective only in a small number of patients.

The dosing regimen

The time of taking Glimepiride-SZ and the distribution of doses during the day is determined by the doctor depending on the patient’s lifestyle at a given time (time of meals, amount of physical activity).

In general, a single dose of the drug during a day is sufficient. It is recommended that in this case the whole dose of Glimepiride-SZ should be taken immediately before a full breakfast or, if it was not taken at this time, immediately before the first main meal. It is very important not to skip meals after taking Glimepiride-SZ tablets.

Because improved glycemic control is associated with increased insulin sensitivity, the need for glimepiride may decrease during treatment. In order to avoid the development of hypoglycemia, doses should be decreased or glimepiride-SZ should be discontinued in a timely manner.

Conditions in which it may also be necessary to adjust the dose of glimepiride:

– weight loss in patients;

– changes in the patient’s lifestyle (changes in diet, meal times, amount of physical activity);

– occurrence of other factors that lead to a predisposition to develop hypoglycemia or hyperglycemia (see See section “Special Precautions”).

The duration of treatment

The treatment with glimepiride is usually long-term.

Transferring a patient from another oral hypoglycemic drug to Glimepiride-SZ

There is no exact relationship between the doses of Glimepiride-SZ and other oral hypoglycemic drugs. When another oral hypoglycemic drug is replaced with Glimepiride-SZ, it is recommended that the algorithm of its prescription should be the same as for the initial use of glimepiride, that is, treatment should begin with the initial dose of 1 mg (even if the patient is transferred to glimepiride from the maximum dose of another oral hypoglycemic drug). Any dose escalation should be done in stages, taking into account the response to glimepiride, according to the above recommendations.

The strength and duration of the effect of the preceding oral hypoglycemic drug should be considered. Treatment may need to be interrupted in order to avoid any summation of effects, which may increase the risk of hypoglycemia.

Combination with metformin

In patients with insufficiently controlled diabetes when taking maximum daily doses of glimepiride or metformin, treatment with a combination of the two drugs may
be initiated. In this case, previous treatment with either glimepiride or metformin continues at the same dose level, and additional administration of metformin or glimepiride begins with a low dose, which is then titrated depending on the target level of glycemic 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

the maximum daily doses of glimepiride may be simultaneously administered insulin. In this case, the last prescribed dose of glimepiride to the patient remains unchanged. In this case, treatment with insulin starts with low doses, which are gradually increased under control of blood glucose concentrations. Combined treatment requires close medical supervision.

The use in patients with renal impairment

There is limited information on the use of glimepiride in patients with renal impairment. Patients with impaired renal function may be more sensitive to the hypoglycemic effect of glimepiride (see sections “Pharmacokinetics”, “Contraindications”).

The use in patients with hepatic impairment

There is limited information on the use of glimepiride in hepatic impairment (see section “Contraindications”).

The use in children

There are not enough data on the use of the drug in children.

Interaction

Glimepiride is metabolized by the CYP2C9 isoenzyme of cytochrome P450 system, which should be considered when using it simultaneously 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 combined with one of the following drugs:

Insulin and other oral hypoglycemic agents, angiotensin-converting enzyme (ACE) inhibitors, anabolic steroids and male sex hormones, chloramphenicol, coumarin derivatives, cyclophosphamide, fibrates fluoxetine, ifosfamide, monoamine oxidase inhibitors (MAOIs), fluconazole, para-aminosalicylic acid, pentoxifylline (high parenteral doses), phenylbutazone, probenecid, quinolones, salicylates, clarithromycin, sulfonamides, tetracyclines.

Worsening of hypoglycemic action and associated increase in blood glucose concentration may be observed when combined with one of the following drugs:

Acetazolamide, barbiturates, glucocorticosteroids, diuretics, epinephrine and other sympathomimetic agents, glucagon, laxatives (with long-term use), nicotinic acid (in high doses), estrogens and progestogens, phenothiazines, phenytoin, rifampicin, iodine-containing thyroid hormones.

H2-histamine receptor blockers, beta-adrenoblockers, clonidine and reserpine can both increase and decrease the hypoglycemic effect 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 and reserpine.

The effect of coumarin derivatives may be increased or decreased with glimepiride administration.

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

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

Special Instructions

In special clinical stress conditions, such as trauma, surgical interventions, infections with febrile fever, glycemic control in diabetic patients may worsen, and they may require temporary transfer to insulin therapy to maintain adequate glycemic control.

In the first weeks of treatment, the risk of hypoglycemia may increase, and therefore particularly close monitoring of blood glucose concentrations is required at this time.

Factors contributing to the risk of hypoglycemia include:

– the patient’s unwillingness or inability (most commonly seen in elderly patients) to cooperate with the physician;

– malnutrition, irregular meals, or skipping meals;

– An imbalance between exercise and carbohydrate intake;

– Dietary changes;

– Alcohol, especially when combined with skipping meals;

– Serious renal failure;

– severe hepatic impairment (in patients with severe hepatic impairment, transfer to insulin therapy is indicated, at least until glycemic control is achieved);

– glimepiride overdose;

– Certain decompensated endocrine disorders that impair carbohydrate metabolism or adrenergic counter-regulation in response to hypoglycemia (e.g., some thyroid and anterior pituitary gland dysfunction, insufficiency of the adrenal cortex);

– concurrent administration of certain medications (see

– concomitant use of some drugs (see section “Interaction with other medicinal products”);

– taking glimepiride in the absence of indications for its use.

The treatment with sulfonylurea derivatives, which includes glimepiride, may lead to hemolytic anemia; therefore, in patients with glucose-6-phosphate dehydrogenase deficiency, special caution should be exercised when prescribing glimepiride and hypoglycemic agents that are not sulfonylurea derivatives are better used.

If the above risk factors for hypoglycemia are present, the dose of glimepiride or all therapy may need to be adjusted. This also applies to the occurrence of intercurrent illnesses during treatment or changes in patients’ lifestyle.

The symptoms of hypoglycemia, which reflect the body’s adrenergic counter-regulation in response to hypoglycemia (see section “Side effects”), may be mild or absent with gradual development of hypoglycemia, in elderly patients, patients with autonomic nervous system neuropathy or patients receiving beta-adrenoblockers, clonidine, reserpine and other sympatholytic agents.

Hypoglycemia can be quickly resolved with immediate administration of rapidly digestible carbohydrates (glucose or sucrose).

As with other sulfonylurea derivatives, hypoglycemia may recur despite initial successful resolution of hypoglycemia. Therefore, patients should remain under continuous monitoring.

In severe hypoglycemia, additional immediate treatment and physician monitoring are required, and in some cases, the patient must be hospitalized.

During treatment with glimepiride, regular monitoring of liver function and peripheral blood count (especially leukocyte and platelet counts) is required.

As some adverse reactions, such as severe hypoglycemia, serious changes in blood count, severe allergic reactions, and liver failure, can be life-threatening under certain circumstances, if adverse reactions develop, especially severe, the patient should inform the treating physician immediately and under no circumstances continue the drug without their recommendation.

Contraindications

Diabetes mellitus type 1;

Diabetic ketoacidosis, diabetic precoma, and coma;

Hypersensitivity to glimepiride or to any excipient of the drug, to other sulfonylurea derivatives, or to other sulfonamides (risk of hypersensitivity reactions);

Severe hepatic impairment (no history of clinical use);

Severe renal impairment, including in patients on glycoprotein.

Prenatal and breastfeeding conditions;

in children and adolescents

under 18 years of age (lack of clinical experience).

In the first weeks of treatment (increased risk of hypoglycemia).

If risk factors for hypoglycemia are present (see Special Precautions, adjustments to glimepiride dose or all therapy may be required).

In case of intercurrent illnesses during treatment or when patients change their lifestyle (changes in diet and meal times, increased or decreased physical activity).

In glucose-6-phosphate dehydrogenase deficiency.

In disorders of absorption of food and drugs in the gastrointestinal tract (GIT) (intestinal obstruction, intestinal paresis).

Side effects

Adverse reactions during glimepiride administration are presented according to the World Health Organization (WHO) classification: Very common (≥10%), common (≥1%, < 10%), infrequent (≥0.1%, < 1%), rare (≥0.01%, < 0.1%), very rare, including individual reports
(< 0.01%), frequency unknown (the frequency cannot be determined from available data).

Metabolic disorders

Hypoglycemia

Hypoglycemia may occur as a result of the hypoglycemic action of Glimepiride-SZ, which, as with other sulfonylurea derivatives, may be prolonged.

The symptoms of hypoglycemia are: headache, acute feeling of hunger, nausea, vomiting, feeling of fatigue, drowsiness, sleep disturbances, restlessness, aggressiveness, impaired concentration and speed of psychomotor reactions, depression, confusion, speech disorders, aphasia, visual disturbances, tremor, paresis, sensory disturbances, dizziness, loss of self-control, helplessness, delirium, cerebral convulsions, somnolence or loss of consciousness up to coma, shallow breathing, bradycardia.

In addition, there may be manifestations of adrenergic counter-regulation in response to the development of hypoglycemia, such as: increased sweating, cold and wet skin, increased anxiety, tachycardia, increased blood pressure, angina, “palpitations” and heart rhythm disturbances.

The clinical picture of severe hypoglycemia can be similar to a stroke.

The symptoms of hypoglycemia almost always disappear after it is resolved.

Body weight gain

Body weight gain (frequency unknown) may occur when taking glimepiride, as well as other sulfonylurea derivatives.

Visual disturbances

Transient visual disturbances due to changes in blood glucose concentrations may be observed during treatment (especially at the beginning of treatment). This is caused by a temporary change in lens swelling depending on the blood glucose concentration and, as a result, a change in the refractive index of the lens.

Gastrointestinal disorders

Rarely: nausea, vomiting, a feeling of heaviness or congestion in the epigastrium, abdominal pain, diarrhea.

Prevalence unknown: dysgeusia (taste disorders).

Liver and biliary tract disorders

In isolated cases: Hepatitis, increased activity of “hepatic” enzymes and/or cholestasis and jaundice, which may progress to life-threatening liver failure, but may undergo reversal when the drug is withdrawn

Blood and lymphatic system disorders

Rarely: thrombocytopenia.

In isolated cases: leukopenia, hemolytic anemia, erythrocytopenia,

granulocytopenia, agranulocytosis and pancytopenia.

Prevalence unknown: Cases of severe thrombocytopenia with platelet counts less than 10000/μL and thrombocytopenic purpura have been reported during post-registration use of the drug.

Immune system disorders

Rarely: 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 blood pressure, which sometimes progress to anaphylactic shock. If symptoms of urticaria occur, you should consult a doctor immediately. Cross-allergy with other sulfonylurea derivatives, sulfonamides or similar substances is possible.

In isolated cases: allergic vasculitis.

Skin and subcutaneous tissue disorders

In isolated cases: photosensitization.

Prevalence unknown: alopecia.

Laboratory and instrumental findings

In isolated cases: hyponatremia.

Overdose

Symptoms of overdose

An acute overdose, as well as long-term treatment with too high doses of glimepiride may lead to severe life-threatening hypoglycemia.

The treatment of an overdose

As soon as an overdose is detected, a physician should be informed immediately. Hypoglycemia can almost always be quickly controlled with 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, close medical observation of the patient is necessary. 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 condition 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,

If the patient is unconscious, intravenous (IV) infusion of concentrated dextrose (glucose) solution (starting with 40 ml of a 20% solution in adults) is necessary. Alternatively, subcutaneous or intramuscular administration of glucagon in adults at a dose of 0.5 to 1 mg is possible.

In the treatment of hypoglycemia due to accidental administration in infants or young children, the dose of dextrose administered should be carefully adjusted to the possibility of dangerous hyperglycemia, and dextrose administration should be performed under continuous monitoring of blood glucose concentrations.

In case of glimepiride overdose, gastric lavage and administration of activated charcoal may be necessary.

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

Pregnancy use

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

Glimepiride penetrates into breast milk, so it should not be taken during breastfeeding. In this case, it is necessary to switch to insulin therapy or stop breastfeeding.

Similarities