Glimax

INSTRUCTIONS for medical use of the medicinal product GLIMAX®

Composition:

Active substance: glimepiride;

One tablet contains 2 mg, or 3 mg, or 4 mg of glimepiride;

Excipients (tablets of 2 mg): lactose monohydrate, sodium starch glycolate (type A), povidone K-30, microcrystalline cellulose, magnesium stearate, iron oxide yellow (E 172);

Excipients (tablets of 3 mg): lactose monohydrate, sodium starch glycolate (type A), povidone K-30, microcrystalline cellulose, magnesium stearate;

Excipients (tablets of 4 mg): lactose monohydrate, sodium starch glycolate (type A), povidone K-30, microcrystalline cellulose, magnesium stearate, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets of 2 mg: light yellow, round, flat tablets with a break line on one side and smooth on the other;

Tablets of 3 mg: white, round, flat tablets with a break line on one side and smooth on the other;

Tablets of 4 mg: pale pink, round, flat tablets with a break line on one side and smooth on the other.

Pharmacotherapeutic group.

Hypoglycemic agents, excluding insulins. Sulfonylureas, urea derivatives.

ATC code A10B B12.

Pharmacological properties.

Pharmacodynamics.

Glimepiride is an orally active hypoglycemic agent belonging to the sulfonylurea group. It can be used in the treatment of type 2 diabetes mellitus.

Glimepiride acts primarily by stimulating insulin release from pancreatic beta cells.

As with other sulfonylurea agents, this effect is based on increased sensitivity of pancreatic cells to physiological glucose stimulation. In addition, glimepiride exerts a pronounced extrapancreatic effect, which is also characteristic of other sulfonylurea agents.

Insulin release. Sulfonylurea agents regulate insulin secretion by closing ATP-dependent potassium channels located in the beta-cell membrane of the pancreas. Closure of the potassium channel leads to depolarization of the beta cell and, via opening of calcium channels, results in increased calcium influx into the cell, which in turn triggers insulin release by exocytosis.

Glimepiride binds rapidly and specifically to a protein in the beta-cell membrane associated with the ATP-dependent potassium channel, although its binding site differs from the conventional sulfonylurea binding site.

Extrapancreatic activity. Extrapancreatic effects include, for example, improved insulin sensitivity of peripheral tissues and reduced hepatic insulin clearance.

Glucose utilization by peripheral tissues (muscle and adipose tissue) occurs via specific transport proteins located in the cell membrane. Glucose transport into these tissues is the rate-limiting step in glucose utilization. Glimepiride rapidly increases the number of active glucose-transporting molecules on the plasma membranes of muscle and adipose cells, thereby stimulating glucose uptake.

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

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

General characteristics. In healthy individuals, the minimal effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical stress, i.e., decreased insulin secretion, is preserved under the influence of glimepiride.

No significant difference in the effect of glimepiride was observed when the drug was administered 30 minutes before or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours was achieved with once-daily administration.

Although the hydroxylated metabolite causes a slight but significant reduction in blood glucose levels in healthy individuals, this represents only a minor component of the overall drug effect.

Use in combination with metformin. One study demonstrated improved metabolic control with combination therapy of glimepiride compared to monotherapy with metformin in patients whose diabetes was 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. For patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved the same degree of metabolic control as insulin monotherapy; however, with combination therapy, a lower average insulin dose was required.

Pharmacokinetics.

Absorption. After oral administration, glimepiride has 100% bioavailability. Food intake does not significantly affect absorption but slightly slows its rate. Maximum drug concentrations in plasma (Cmax) are reached approximately 2.5 hours after oral administration (mean value is 0.3 μg/mL following repeated daily dose of 4 mg). There is a linear relationship between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve).

Distribution. Glimepiride has a very low volume of distribution (approximately 8.8 L), roughly equivalent to the distribution volume of albumin, a high degree of plasma protein binding (over 99%), and low clearance (approximately 48 mL/min).

In animals, glimepiride crosses into breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.

Metabolism and elimination. The mean terminal half-life at plasma concentrations corresponding to multiple dosing regimens is approximately 5 to 8 hours. After administration of high doses, a slight increase in half-life was observed.

After a single radiolabeled dose of glimepiride, 58% of the radioactivity was recovered in urine and 35% in feces. The unchanged substance was not detected in urine. Two metabolites were identified in urine and feces, most likely formed via hepatic metabolism (main enzyme CYP2C9), one being a hydroxy derivative and the other a carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3 to 6 hours and 5 to 6 hours, respectively.

Comparison of pharmacokinetics after single-dose administration and repeated once-daily dosing revealed no significant differences. Interindividual variability was very low. No clinically significant accumulation was observed.

Special patient populations.

Pharmacokinetic parameters in men and women, as well as in younger and elderly individuals (aged 65 years and older), were similar. In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean plasma concentration was observed, most likely due to faster elimination resulting from reduced protein binding. Renal excretion of both metabolites was impaired. Overall, no additional risk of drug accumulation is expected in these patients.

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

Children, including adolescents. A study investigating the pharmacokinetics, safety, and tolerability of a single 1 mg dose of glimepiride administered in the fed state in 30 children (4 children aged 10–12 years and 26 children aged 12–17 years) with type 2 diabetes demonstrated that mean values of AUC(0-last), Cmax, and t1/2 were similar to those previously observed in adults.

Preclinical safety data. Effects observed during preclinical studies occurred at exposure levels substantially exceeding the maximum exposure levels in humans, indicating their limited relevance to clinical practice, or were due to the pharmacodynamic action of the drug (hypoglycemia). These findings were obtained within traditional safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, carcinogenic potential, and reproductive toxicity studies. Adverse effects identified in the latter (including studies on embryotoxicity, teratogenicity, and developmental toxicity) were considered consequences of the hypoglycemic effects induced by the drug in pregnant females and offspring.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus in adults when blood glucose levels cannot be controlled by diet, physical exercise, and weight reduction alone.

Contraindications.

The drug is not intended for the treatment of insulin-dependent type 1 diabetes mellitus, diabetic ketoacidosis, or diabetic coma. The use of the drug is contraindicated in patients with severe renal or hepatic impairment. In cases of severe renal or hepatic dysfunction, patients should be switched to insulin therapy.

The drug must not be administered to patients with hypersensitivity to glimepiride or to any excipient contained in the formulation, to sulfonylurea derivatives or other sulfonamide drugs (risk of hypersensitivity reactions).

Pregnancy or breastfeeding period (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Concomitant administration of Glimax® with certain medicinal products may either reduce or enhance the hypoglycemic effect of glimepiride. Therefore, other medications should be taken only with the consent (or prescription) of a physician. Glimepiride is metabolized via cytochrome P450 2C9 (CYP2C9). It is known that co-administration of inducers (e.g., rifampicin) or inhibitors of CYP2C9 (e.g., fluconazole) may alter this metabolism. Results of in vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, approximately doubles the AUC of glimepiride.

The following types of interactions are documented based on clinical experience with glimepiride and other sulfonylurea derivatives.

Potentiation of glucose-lowering effect, and thus, in some cases, hypoglycemia, may occur when glimepiride is used concomitantly with the following drugs: phenylbutazone, azapropazone, and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents (such as metformin), certain long-acting sulfonamides, tetracyclines, salicylates and p-aminosalicylic acid, MAO inhibitors, anabolic steroids and androgens, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high parenteral doses), fibrates, troglitazone, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclophosphamide, ifosfamide, and trofosfamide.

Reduced glucose-lowering effect and, consequently, increased blood glucose levels may be observed when the patient is concurrently taking the following drugs: estrogens and progestogens; thiazide diuretics and saluretics; thyroid-stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; epinephrine and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (prolonged use); phenytoin, diazoxide; glucagon, barbiturates, and rifampicin; acetazolamide.

H2-receptor antagonists, beta-blockers, clonidine, and reserpine may either potentiate or reduce the glucose-lowering effect.

Under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the symptoms of adrenergic counter-regulation of hypoglycemia may be diminished or absent.

Alcohol consumption may unpredictably enhance or reduce the hypoglycemic effect of glimepiride.

Glimepiride may either increase or decrease the effect of coumarin derivatives.

Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was administered at least 4 hours prior to colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam.

Special precautions for use.

Glimeks® should be taken shortly before or during meals.

During the first weeks of treatment, there is an increased risk of developing hypoglycaemia; therefore, particularly careful monitoring is required.

In cases of irregular eating or missed meals, treatment with Glimeks® may cause hypoglycaemia. Possible symptoms of hypoglycaemia include headache, intense hunger, nausea, vomiting, fatigue, apathy, drowsiness, sleep disturbances, increased motor activity, aggression, difficulty concentrating, anxiety, slowed reaction time, depressive mood, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, epileptic seizures, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, symptoms of adrenergic counter-regulation may occur, such as sweating, cold and clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms of hypoglycaemia can almost always be rapidly relieved by immediate ingestion of carbohydrates (sugar). Artificial sweeteners are ineffective.

Based on experience with other sulphonylurea derivatives, although initial measures to correct hypoglycaemia may be effective, recurrence may occur.

Severe or prolonged hypoglycaemia, which is only temporarily corrected by usual amounts of sugar, requires immediate treatment and sometimes hospitalization.

Factors predisposing to the development of hypoglycaemia include:

• unwillingness or (especially in elderly patients) inability of the patient to cooperate with the physician;
• undernutrition, irregular eating or skipped meals or periods of fasting;
• dietary irregularities;
• imbalance between physical exertion and carbohydrate intake;
• alcohol consumption, especially in combination with skipped meals;
• impaired renal function;
• severe impairment of liver function;
• overdose of Glimeks®;
• certain decompensated endocrine disorders affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (e.g. certain thyroid gland disorders or deficiency of the anterior pituitary or adrenal cortex);
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with Glimeks® requires regular monitoring of blood and urine glucose levels. In addition, determination of glycated haemoglobin levels is recommended.

During treatment with Glimeks®, liver function parameters and haematological parameters (especially white blood cell and platelet counts) should be monitored regularly.

In stressful situations (e.g. trauma, unplanned surgery, infections accompanied by fever), temporary switching of the patient to insulin may be indicated.

Experience with the use of Glimeks® in patients with severe liver dysfunction or in patients undergoing dialysis is lacking. Patients with severe renal or hepatic impairment should be switched to insulin therapy.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulphonylurea drugs may lead to the development of haemolytic anaemia. Since glimepiride belongs to the sulphonylurea class of drugs, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Alternative non-sulphonylurea agents should be considered for such patients.

Glimeks® contains lactose monohydrate. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, careful monitoring of blood glucose in pregnant women is essential to avoid teratogenic risk.

Pregnant women with diabetes should be switched to insulin therapy. Women with diabetes should inform their physician about planned pregnancy for timely adjustment of treatment and transition to insulin.

Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. Preclinical studies have shown that the drug has reproductive toxicity, likely related to the pharmacological action of glimepiride (hypoglycaemia). Therefore, glimepiride must not be used throughout pregnancy (see section "Contraindications").

If a patient taking glimepiride plans a pregnancy or becomes pregnant, she should be switched to insulin therapy as soon as possible.

Breastfeeding period.

It is unknown whether the drug is excreted in human breast milk. In rats, glimepiride is excreted in breast milk. Since other sulphonylurea derivatives are excreted in breast milk and considering the risk of hypoglycaemia in breastfed infants, breastfeeding is not recommended during treatment with glimepiride.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the drug on the ability to drive vehicles or operate machinery have not been conducted.

The ability to concentrate and reaction speed may be impaired due to hypoglycaemia or hyperglycaemia or, for example, due to visual disturbances. This may pose a risk in situations where such abilities are particularly important (e.g. driving a car or operating machinery).

Patients should be warned not to allow hypoglycaemia to develop while driving. This is especially important for individuals who poorly or not at all recognize early warning signs of hypoglycaemia and for those who experience frequent hypoglycaemic episodes. Serious consideration should be given to whether driving or operating machinery is appropriate under such circumstances.

Method of Administration and Dosage

Successful treatment of diabetes mellitus depends on the patient adhering to an appropriate diet, regular physical activity, and consistent monitoring of blood and urine glucose levels. Failure by the patient to follow a proper diet cannot be compensated by taking tablets or insulin.

Dosage is determined based on blood and urine glucose test results.

Monotherapy

The initial dose is 1 mg (½ of a 2 mg tablet) of glimepiride per day. If this dose achieves adequate disease control, it should be used for maintenance therapy.

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

Doses exceeding 4 mg per day provide better efficacy only in individual cases. The maximum recommended dose is 6 mg of Glimax® per day.

Combination with Metformin

If the maximum daily dose of metformin does not provide adequate glycemic control, concomitant therapy with glimepiride may be initiated.

Without changing the previous metformin dosage, glimepiride therapy should be started at a low dose, which can then be gradually increased up to the maximum daily dose, guided by the desired level of metabolic control. Combination therapy must be conducted under close medical supervision.

Combination with Insulin

If the maximum daily dose of Glimax® does not provide adequate glycemic control, concomitant insulin therapy may be initiated when necessary. Without changing the previous glimepiride dosage, insulin treatment should begin with a low dose, which can then be increased based on the desired level of metabolic control.

Combination therapy should be conducted under close medical supervision.

Typically, a single daily dose of glimepiride is sufficient. It is recommended to take it shortly before or during a substantial breakfast, or—if breakfast is not consumed—shortly before or during the first main meal of the day. Errors in drug administration, such as missing a dose, must never be corrected by taking a higher dose at the next scheduled time. The tablet should be swallowed whole, without chewing, with liquid.

If a hypoglycemic reaction occurs in a patient taking 1 mg of glimepiride per day, this indicates that diabetes may be controlled by diet alone.

Improved diabetes control is associated with increased insulin sensitivity; therefore, during the course of treatment, the need for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or therapy discontinued altogether. Re-evaluation of dosage may also be necessary if the patient experiences changes in body weight or lifestyle, or if other factors that increase the risk of hypo- or hyperglycemia are present.

Switching from Oral Hypoglycemic Agents to Glimax®

Patients can usually be switched from other oral hypoglycemic agents to Glimax®. When making this transition, the efficacy and half-life of the previous agent should be considered. In some cases, especially when the antidiabetic agent has a long half-life (e.g., chlorpropamide), it is recommended to wait several days before starting Glimax®. This helps reduce the risk of hypoglycemic reactions due to additive effects of the two drugs.

The recommended initial dose is 1 mg of glimepiride per day. As noted above, the dose may be gradually increased according to the patient's response.

Switching from Insulin to Glimax®

In exceptional cases, patients with type 2 diabetes mellitus who are receiving insulin may be candidates for switching to Glimax**®**. This transition must be conducted under close medical supervision.

Children

There is insufficient data on the safety and efficacy of the drug in children; therefore, it is not recommended for use in this patient population.

Overdose

Overdose may lead to hypoglycemia lasting from 12 to 72 hours, which may recur even after initial improvement. Symptoms may appear up to 24 hours after drug absorption. Affected patients should generally be monitored in a clinical setting. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia is often accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures.

Treatment of Overdose. Treatment primarily involves preventing drug absorption. To achieve this, vomiting should be induced, followed by ingestion of water or soda containing activated charcoal (an adsorbent) and sodium sulfate (a laxative). If a large amount of glimepiride has been ingested, gastric lavage is indicated, followed by administration of activated charcoal and sodium sulfate. In cases of severe overdose, hospitalization in an intensive care unit is necessary. Glucose administration should be initiated as soon as possible: if necessary, initially a single intravenous injection of 50 mL of a 50% glucose solution, followed by infusion of a 10% glucose solution, with continuous monitoring of blood glucose levels. Further treatment is symptomatic.

When treating hypoglycemia caused by accidental ingestion of Glimax® in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, and blood glucose levels must be closely monitored.

Adverse Reactions

Based on the experience with Glimax**®** and other sulfonylurea derivatives, the following adverse reactions have been observed during clinical trials, listed by organ system classes in decreasing order of frequency: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders.

Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia, and pancytopenia, which are usually reversible upon discontinuation of the drug.
Frequency not known: severe thrombocytopenia with platelet count below 10,000/µL and thrombocytopenic purpura.

Immune system disorders.

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions, which may progress to severe forms accompanied by dyspnea, hypotension, and sometimes shock.
Frequency not known: possible cross-sensitivity with sulfonylurea drugs, sulfonamides, or related compounds.

Metabolism and nutrition disorders.

Rare: hypoglycemia.

Such hypoglycemic reactions usually occur immediately, may be severe, and are not always easily corrected. The occurrence of such reactions, as with other hypoglycemic agents, depends on individual factors such as dietary habits and dosage (see section "Special precautions for use" for details).

Eye disorders.

Frequency not known: transient visual disturbances may occur, particularly at the beginning of treatment, due to changes in blood glucose levels.

Gastrointestinal disorders.

Very rare: nausea, vomiting, diarrhea, abdominal distension, abdominal discomfort, abdominal pain, which rarely necessitate discontinuation of treatment.

Hepatobiliary disorders.

Frequency not known: increased levels of liver enzymes.
Very rare: liver function abnormalities (e.g., with cholestasis or jaundice), hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders.

Frequency not known: hypersensitivity reactions may occur, including pruritus, rash, urticaria, and photosensitivity.

Laboratory findings:

Very rare: decreased serum sodium levels.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.

Packaging.

10 tablets in a blister; 3, 6, or 10 blisters in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its business site.

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine

or

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's location and address of its business site.

54 Davydovskoho Hryhorii Street, Sumy, Sumy Oblast, 40020, Ukraine