INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MELPAMID (MELPAMID®)

Composition:

Active substance: glimepiride;

1 tablet contains 2 mg or 3 mg of glimepiride;

Excipients:

tablets of 2 mg: lactose monohydrate, sodium starch glycolate, microcrystalline cellulose,
povidone K 30, erythrosine lake dye, magnesium stearate;

tablets of 3 mg: lactose monohydrate, sodium starch glycolate, microcrystalline cellulose,
povidone K 30, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2 mg: round, pink-colored, biconvex tablets;

tablets of 3 mg: round, white-colored, biconvex tablets.

Pharmacotherapeutic group. Antihyperglycemic agents, excluding insulin. Sulfonamides, 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 increasing the 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 blocking the ATP-dependent potassium channel located in the membrane of pancreatic beta cells. 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, thereby triggering insulin release through exocytosis.

Glimepiride has a high rate of displacement upon binding to the protein in the beta-cell membrane associated with the ATP-dependent potassium channel; however, the binding site location differs from that of other sulfonylurea agents.

Extrapancreatic activity. Extrapancreatic effects include, for example, improved insulin sensitivity in 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 limited by the rate of glucose utilization. Glimepiride rapidly increases the number of active glucose-transporting molecules in 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., reduced insulin secretion, is preserved under the influence of glimepiride.

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

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

Combination with metformin. In one study, improved metabolic control was demonstrated with combination therapy using glimepiride compared to metformin monotherapy in patients whose diabetes was inadequately controlled with maximum doses of metformin.

Combination with insulin. Data on the use of glimepiride in combination with insulin are limited. In patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved similar improvements in metabolic control as insulin monotherapy; however, combination therapy required a lower average insulin dose.

Special patient populations.

Children and adolescents. A 24-week, active-controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) included 285 children (aged 8–17 years) with type 2 diabetes.

Both glimepiride and metformin resulted in statistically significant reductions in HbA1c from baseline [(glimepiride – 0.95 (SE 0.41); metformin – 1.39 (SE 0.40)]. However, glimepiride did not demonstrate superior efficacy compared to metformin in terms of mean change in HbA1c from baseline. The difference between the two treatments was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference exceeded the 0.3% non-inferiority margin.

Safety findings with glimepiride treatment in children revealed no new safety concerns compared to adult patients with type 2 diabetes. Long-term efficacy and safety data in children are lacking.

Pharmacokinetics.

Absorption. After oral administration, glimepiride has 100% bioavailability. Food intake does not significantly affect absorption but slightly slows the rate of absorption. Maximum plasma concentrations (Cmax) are reached approximately 2.5 hours after oral administration (mean value is 0.3 µg/mL following repeated 4 mg daily dose). A linear relationship exists 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), which is close to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and low clearance (approximately 48 mL/min).

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

Metabolism and elimination. The mean elimination half-life at plasma concentrations corresponding to multiple dosing is approximately 5–8 hours. A slight increase in half-life was observed after administration of high doses.

After a single radiolabeled dose of glimepiride, 58% of the radioactivity was recovered in urine and 35% in feces. The unchanged drug was not detected in urine. Two metabolites were identified in urine and feces, most likely formed via hepatic metabolism (primary enzyme CYP2C9): one is a hydroxylated derivative and the other a carboxylated derivative. After oral administration of glimepiride, the elimination half-lives of these metabolites were approximately 3–6 hours and 5–6 hours, respectively.

Comparison of pharmacokinetics after single and multiple once-daily doses revealed no significant differences. Inter-subject variability was very low. No clinically relevant accumulation was observed.

Special patient populations. Pharmacokinetic parameters in men and women, as well as in younger and elderly individuals (over 65 years), were similar. In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean plasma concentrations 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 five patients who underwent biliary tract surgery were similar to those in healthy volunteers.

Children, including adolescents. A study evaluating pharmacokinetics, safety, and tolerability after a single 1 mg dose of glimepiride administered under fed conditions in 30 children (4 children aged 10–12 years and 26 children aged 12–17 years) with type 2 diabetes demonstrated that mean AUC(0-last), Cmax, and T1/2 values were similar to those 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 low clinical relevance or that they were caused by the pharmacodynamic action of the drug (hypoglycemia). These findings were obtained within traditional safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, carcinogenic potential assessments, and reproductive toxicity studies. Adverse effects identified in later studies (including embryotoxicity, teratogenicity, and developmental toxicity assessments) were considered consequences of hypoglycemic effects induced by the drug in female animals and their 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.

type 1 diabetes mellitus;
diabetic ketoacidosis;
diabetic coma;
severe impairment of renal or hepatic function. In cases of severe renal or hepatic dysfunction, patients must be switched to insulin therapy;
hypersensitivity to glimepiride or to any excipient contained in the medicinal product, to sulfonylurea derivatives or other sulfonamide drugs (risk of developing hypersensitivity reactions).

Interaction with other medicinal products and other forms of interactions.

Concomitant administration of glimepiride with certain other medicinal products may either reduce or enhance its hypoglycemic effect. Therefore, other drugs should be taken only as prescribed by 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. In vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, increases the AUC of glimepiride by approximately two-fold. Clinical experience with glimepiride and other sulfonylurea derivatives supports the existence of such interactions.

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

Reduction of glucose-lowering effect may occur when patients are concomitantly taking estrogens and progestogens; thiazide diuretics and saluretics; thyroid-stimulating agents; glucocorticoids; phenothiazine derivatives, chlorpromazine; adrenaline 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.

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

Alcohol intake 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 administration.

Special precautions for use.

The medicinal product 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 case of irregular eating habits or missed meals, treatment with this drug may cause hypoglycaemia. Possible symptoms of hypoglycaemia include headache, intense feeling of hunger, nausea, vomiting, fatigue, apathy, drowsiness, sleep disturbances, increased motor activity, aggression, impaired concentration, anxiety, delayed reaction time, depressive state, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, signs 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 intake of carbohydrates (sugar). Artificial sweeteners are ineffective.

Based on experience with other sulfonylurea derivatives, it is known that despite initial effectiveness of measures to correct hypoglycaemia, it may recur.

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

Factors predisposing to the development of hypoglycaemia include:

unwillingness or inability (especially in elderly patients) of the patient to cooperate with the physician;
inadequate food intake, irregular eating, skipping meals or periods of fasting;
dietary disturbances;
mismatch between physical exertion and carbohydrate intake;
alcohol consumption, especially in combination with skipped meals;
impaired renal function;
severe impairment of liver function;
drug overdose;
certain decompensated endocrine disorders affecting carbohydrate metabolism or hypoglycaemia counter-regulation (e.g. certain thyroid disorders, hypopituitarism or adrenal insufficiency);
concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with this drug requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycated haemoglobin is recommended.

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

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

Experience with the use of this drug in patients with severe hepatic impairment 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 sulfonylurea drugs may lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea drugs, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Alternative non-sulfonylurea agents should be considered for such patients.

The drug contains lactose monohydrate. This medicinal product should not be used in patients with rare hereditary intolerance to galactose, Lapp lactase deficiency or glucose-galactose malabsorption. As the medicinal product contains sodium starch glycolate, caution should be exercised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Risk associated with diabetes. Abnormal blood glucose levels during pregnancy increase the risk of congenital malformations and perinatal mortality. Therefore, careful monitoring of blood glucose levels 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. Animal studies indicate reproductive toxicity of the drug, likely related to the pharmacological effect of glimepiride (hypoglycaemia). Therefore, glimepiride is contraindicated throughout pregnancy. If a patient taking glimepiride plans pregnancy or becomes pregnant, she should be switched to insulin therapy as soon as possible.

Breastfeeding period.

To avoid transfer of glimepiride into breast milk and potential harmful effects on the infant, this drug should not be used by women during breastfeeding. If necessary, the patient should switch to insulin therapy or discontinue breastfeeding completely.

Fertility.

There are no available data on the effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies evaluating 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 reduced due to hypoglycaemia or hyperglycaemia, or, for example, due to impaired vision. This creates 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 vehicles. This is especially important for individuals who poorly or not at all recognize early warning symptoms of hypoglycaemia, and for those who experience frequent hypoglycaemic episodes. Serious consideration should be given to whether it is appropriate to drive or operate machinery under such circumstances.

Method of Administration and Dosage

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

The dosage is determined based on blood and urine glucose test results.

The initial dose is 1 mg (1/2 tablet of 2 mg) 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 increased stepwise to 2, 3, or 4 mg of glimepiride per day, with intervals of 1–2 weeks between dose adjustments.

Doses exceeding 4 mg per day provide better results only in individual cases. The maximum recommended dose is 6 mg of the drug per day.

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

Maintaining the previous metformin dosage, glimepiride therapy should be initiated at a low dose, which can then be gradually increased up to the maximum daily dose, depending on the desired level of metabolic control. Combination therapy must be conducted under close medical supervision.

If the maximum daily dose of the drug does not provide adequate glycemic control, concomitant insulin therapy may be initiated if necessary. Maintaining 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 must 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, should never be corrected by taking a higher dose at the next administration. The tablet should be swallowed whole, without chewing, with water.

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

Improved diabetes control is associated with increased insulin sensitivity; therefore, during treatment, the requirement for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or treatment discontinued altogether. A dosage review may also be necessary if the patient experiences changes in body weight or lifestyle, or if other factors affecting the risk of hypo- or hyperglycemia arise.

Switching from other oral hypoglycemic agents to glimepiride.

Switching from other oral hypoglycemic agents to glimepiride is generally possible. When making such a switch, the potency and half-life of the previous agent should be considered. In some cases, especially if the antidiabetic agent has a long half-life (e.g., chlorpropamide), a break of several days is recommended before starting glimepiride to reduce the risk of hypoglycemic reactions due to additive effects of both agents.

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

Switching from insulin to glimepiride.

In exceptional cases, switching from insulin to glimepiride may be indicated in patients with type 2 diabetes mellitus. This transition must be performed under close medical supervision.

Children. Not recommended.

Overdose.

Overdose may lead to hypoglycemia, which can last from 12 to 72 hours and may recur even after initial improvement. Symptoms may appear within 24 hours after drug administration. In such cases, hospital observation is generally recommended. 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 lemonade containing activated charcoal (adsorbent) and sodium sulfate (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 needed, initially a single intravenous bolus injection of 50 mL of 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 the drug in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, with close monitoring of blood glucose levels.

Adverse reactions.

During clinical trials, the following adverse reactions were observed with the use of glimepiride and other sulfonylurea derivatives:

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: cases of severe thrombocytopenia with platelet count less than 10,000/μL and thrombocytopenic purpura have been reported.

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-allergy with sulfonamides, sulfonamide-containing drugs, or similar substances.

Metabolism and nutrition disorders.

Rare: hypoglycemia.

Hypoglycemic reactions usually occur suddenly, may be severe, and are not always easily corrected. The occurrence of such reactions, as with treatment using other hypoglycemic agents, depends on individual factors such as dietary habits and dosage (see section "Special precautions for use" for details). The clinical presentation of severe hypoglycemia may resemble that of stroke.

Eye disorders.

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

Gastrointestinal disorders.

Very rare: nausea, vomiting, diarrhea, sensation of fullness and discomfort in the abdomen, abdominal pain. These symptoms are not intense and rarely necessitate discontinuation of treatment.

Rare: dysgeusia.

Hepatobiliary disorders.

Frequency not known: increased levels of liver enzymes.

Very rare: liver function abnormalities (e.g., cholestasis or jaundice), hepatitis, and hepatic failure.

Skin and subcutaneous tissue disorders.

Frequency not known: allergic and pseudoallergic reactions, including pruritus, rash, urticaria, and photosensitivity.

Rare: alopecia.

Investigations.

Very rare: decreased serum sodium levels.

Rare: weight gain.

Healthcare professionals, patients, and pharmacists are requested to report any suspicion of adverse reactions or lack of therapeutic effect to the e-mail address of Bosnaliek d.d.: [email protected].

Shelf life. 3 years.

Storage conditions.

Keep out of reach and sight of children. Store at a temperature not exceeding 25 °C.

Packaging.

No. 30 (15×2): 15 tablets in a blister, 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Bosnaliek d.d.

Address of manufacturer's premises.

Yukicheva 53, 71 000 Sarajevo, Bosnia and Herzegovina

Address of applicant.