Oltar® 2 mg

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLTA® 2 mg / OLTA® 3 mg (OLTAR® 2 mg / OLTAR® 3 mg)

Composition:

Active substance: glimepiride;

One tablet contains 2 mg or 3 mg of glimepiride;

Excipients: lactose monohydrate, maize starch, sodium starch glycolate (type A), povidone, polysorbate 80, talc, magnesium stearate; OLTAR® 3 mg tablets additionally contain yellow iron oxide (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

OLTAR® 2 mg: white, capsule-shaped tablets with beveled edges and a score line on one side;

OLTAR® 3 mg: yellow, capsule-shaped tablets with beveled edges and a score line on one side.

Pharmacotherapeutic group. Antidiabetic agents, excluding insulin. Sulfonylureas. ATC code A10BB12.

Pharmacological properties.

Pharmacodynamics.

Glimipiride is an effective hypoglycemic agent belonging to the sulfonylurea group. Glimipiride is used in the treatment of patients with non-insulin-dependent diabetes mellitus.

Mechanism of action. The effect of glimepiride is primarily mediated through stimulation of insulin release from pancreatic beta cells. As with other sulfonylurea drugs, this effect is based on increasing the sensitivity of pancreatic beta cells to physiological glucose stimulation. In addition, glimepiride also has extrapancreatic effects, which are also characteristic of other sulfonylurea derivatives.

Insulin release.

Sulfonylurea drugs regulate insulin secretion by blocking ATP-dependent potassium channels located in the beta-cell membrane. Closure of potassium channels induces depolarization of beta cells and, via opening of calcium channels, increases calcium influx into the cell. This leads to insulin release through exocytosis.

Glimipiride has a high rate of displacement upon binding to the protein in the beta-cell membrane associated with the ATP-dependent potassium channel; however, its binding site location differs from the conventional sulfonylurea drug binding site.

Extrapancreatic activity.

Improved insulin sensitivity of peripheral tissues and reduced hepatic insulin uptake are examples of extrapancreatic effects.

Glucose uptake from blood by peripheral muscle and adipose tissue occurs via specific transport proteins located in cell membranes. Glucose transport in these tissues is limited by the rate of glucose uptake step. Glimipiride rapidly increases the number of active glucose-transporting molecules in the plasma membranes of muscle and adipose cells, thereby stimulating glucose uptake.

In isolated muscle and adipose cells, glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, which may correlate with drug-induced lipogenesis and glycogenesis. Glimipiride inhibits hepatic glucose synthesis by increasing intracellular fructose-2,6-bisphosphate concentration, which in turn suppresses gluconeogenesis.

Pharmacodynamic effects.

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 during glimepiride administration.

No significant difference in glimepiride's effect 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 can be achieved with once-daily administration.

Although the hydroxylated metabolite causes a small but significant reduction in plasma glucose levels in healthy individuals, this represents only a minor portion of the total drug effect.

Combination with metformin.

One study demonstrated improved metabolic control with combination therapy using glimepiride compared to metformin monotherapy in patients whose diabetes was not adequately controlled with maximum doses of metformin.

Combination with insulin.

Data on the use of glimepiride in combination with insulin are limited. In patients 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, with combination therapy, a lower average insulin dose was required.

Pediatric population.

A randomized, active-controlled clinical trial (glimipiride up to 8 mg daily or metformin up to 2000 mg daily) lasting 24 weeks was conducted in 285 children (aged 8–17 years) with type 2 diabetes. Both glimepiride and metformin significantly reduced HbA1c compared to baseline (glimipiride: −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 treatment difference was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not below the 0.3% non-inferiority margin. No new safety findings were observed with glimepiride treatment in children compared to adult patients with type 2 diabetes. Data on long-term efficacy and safety in children are lacking.

Pharmacokinetics.

Absorption. After oral administration, glimepiride has complete bioavailability. Food intake does not significantly affect absorption, although the rate of absorption is slightly reduced. Maximum serum concentration (Cmax) after oral administration is reached approximately 2.5 hours post-dose (mean Cmax ~0.3 µg/mL with repeated 4 mg daily dosing). A linear relationship exists between dose and both Cmax and area under the concentration-time curve (AUC).

Distribution. Glimipiride has a relatively small volume of distribution (approximately 8.8 L), roughly equivalent to the volume of distribution of albumin, a high degree of protein binding (>99%), and low clearance (approximately 48 mL/min).

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

Biotransformation. 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 higher doses.

Two metabolites, most likely formed via hepatic metabolism (main enzyme CYP2C9), have been identified in feces and urine: hydroxy derivative and carboxy derivative of glimepiride. After oral administration of glimepiride, elimination half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively.

Excretion.

After a single dose of radiolabeled glimepiride, 58% of radioactivity was recovered in urine and 35% in feces. The unchanged active substance was not detected in urine. Comparison of single-dose and repeated once-daily administration showed no significant pharmacokinetic differences, and inter-subject variability was very low. No significant accumulation was observed.

Special patient populations.

Renal impairment. In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased plasma concentrations was observed, likely due to faster elimination resulting from reduced protein binding. Renal excretion of both metabolites was impaired. However, no additional risk of increased accumulation is considered to exist for these patients.

Hepatic impairment. Pharmacokinetics in 5 non-diabetic patients after surgery was similar to that in healthy volunteers.

Elderly patients. Pharmacokinetic parameters in men and women, as well as in young and elderly individuals (over 65 years), were similar.

Pediatric population. A study investigating pharmacokinetics, safety, and tolerability after 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 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 exposures substantially exceeding maximum human exposure and thus have limited clinical relevance, or were due to the pharmacodynamic (hypoglycemic) action of the active substance. These results were obtained within traditional safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, oncogenic potential, and reproductive toxicity studies. Adverse effects observed in later studies (including embryotoxicity, teratogenicity, and developmental toxicity assessments) were considered consequences of hypoglycemic effects induced by the drug in pregnant females and their offspring.

Clinical characteristics.

Indications.

Type 2 diabetes mellitus, when diet, physical exercise, and weight reduction are insufficient. Amaryl is indicated for adult patients.

Contraindications.

Amaryl is contraindicated in patients with the following conditions:

• hypersensitivity to the active substance, to any of the excipients, or to other sulfonylurea or sulfonamide drugs;
• insulin-dependent diabetes mellitus;
• diabetic coma;
• ketoacidosis;
• severe renal or hepatic impairment. Patients with severe renal or hepatic dysfunction should be switched to insulin therapy.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of glimepiride and certain other medicinal products may lead to undesirable enhancement or reduction of its hypoglycemic effect. Therefore, other medicinal products should be used only with a physician's approval (or by prescription). Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). This metabolism is affected by concomitant use of CYP2C9 inducers (e.g., rifampicin) or inhibitors of cytochrome CYP2C9 (e.g., fluconazole). Results of in vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, increases the AUC of glimepiride approximately twofold.

Experience with glimepiride and other sulfonylurea derivatives indicates that these types of interactions exist.

Enhancement of glucose-lowering effect, and thus, in some cases, development of hypoglycemia, may occur when glimepiride is used concomitantly with the following substances: phenylbutazone, azapropazone, oxyphenbutazone; insulin and oral antidiabetic agents, e.g., metformin; salicylates and para-aminosalicylic acid; anabolic steroid agents and male sex hormones; chloramphenicol, certain long-acting sulfonamides, tetracyclines, antibacterial quinolone derivatives and clarithromycin; coumarin anticoagulants; fenfluramine; disopyramide; fibrates; angiotensin-converting enzyme (ACE) inhibitors; fluoxetine, monoamine oxidase (MAO) inhibitors; allopurinol, probenecid, sulfinpyrazone; sympatholytic agents; cyclophosphamide, trophosphamide, ifosfamide; miconazole, fluconazole; pentoxifylline (administered parenterally in high doses); troxiquetamine.

Possible reduction of glucose-lowering effect and, consequently, increased blood glucose levels when used concomitantly with the following substances: estrogens and progestogens; saluretics, thiazide diuretics; thyroid-stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; epinephrine and sympathomimetic agents; nicotinic acid (in high doses) and its derivatives; mild laxatives (with prolonged use); phenytoin, diazoxide; glucagon, barbiturates and rifampicin; acetazolamide.

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

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

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

Glimepiride may enhance or reduce 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.

Oltar should be taken immediately before or during a meal.

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

If meals are taken irregularly or a meal is missed, glimepiride may cause hypoglycemia. Possible symptoms of hypoglycemia include: headache, intense hunger, nausea, vomiting, increased fatigue, drowsiness, sleep disturbances, agitation, aggression, impaired concentration, slowed reaction time, depression, confusion, disturbances of consciousness, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, convulsions, drowsiness, and loss of consciousness progressing to precoma and coma, shallow breathing, bradycardia.

In addition, symptoms of adrenergic counter-regulation may occur, such as sweating, clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina pectoris, and cardiac arrhythmias. The clinical picture of severe hypoglycemia may resemble that of stroke.

Hypoglycemic condition can almost always be rapidly corrected by ingestion of carbohydrates (sugar). Artificial sugar substitutes are not suitable for this purpose.

From experience with other sulfonylurea drugs, it is known that hypoglycemia may recur despite successful initial treatment. Severe or prolonged hypoglycemia, even if temporarily controlled by sugar intake, requires immediate medical treatment and possibly hospitalization.

Factors predisposing to hypoglycemia include: unwillingness or inability of the patient to cooperate with the physician (especially in elderly patients); inadequate, irregular nutrition or skipped meals, or fasting; imbalance between physical exertion and carbohydrate intake; dietary changes; alcohol consumption, especially in combination with skipped meals; impaired renal function; severe hepatic impairment; glimepiride overdose; certain uncompensated endocrine disorders affecting carbohydrate metabolism or acting as counter-regulators of hypoglycemia (e.g., certain thyroid disorders, hypopituitarism, or adrenal insufficiency); concomitant use of other medicinal products.

Treatment with glimepiride requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycosylated hemoglobin (HbA1c) is recommended.

During glimepiride therapy, liver function tests and blood parameters (especially leukocyte and platelet counts) should be monitored regularly.

In stressful situations (e.g., trauma, emergency surgery, infections with fever, etc.), temporary switch to insulin therapy may be indicated.

There is no experience with the use of glimepiride in patients with severe hepatic impairment or in patients undergoing hemodialysis. Insulin therapy is recommended for patients with severe hepatic or renal impairment. Sulfonylurea drugs may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency; therefore, glimepiride should be used with caution, and alternative treatment options should be considered.

This medicinal product contains lactose monohydrate. It should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

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 blood glucose control in pregnant women is essential to avoid teratogenic risk. In such cases, insulin therapy is required. Female patients with diabetes should inform their physician if they are planning pregnancy.

Risk associated with glimepiride.

There are no or limited data on the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity, likely related to the pharmacological effect (hypoglycemia) of glimepiride. Therefore, glimepiride should not be used throughout pregnancy. If a patient on glimepiride plans to become pregnant or pregnancy is diagnosed, insulin therapy should be initiated as soon as possible.

Breastfeeding period.

It is unknown whether glimepiride or its metabolites pass into human breast milk. Glimepiride passes into the milk of rats. Since other sulfonylurea drugs are known to pass into human breast milk, there is a risk of hypoglycemia in the nursing infant; therefore, breastfeeding is not recommended during glimepiride therapy.

Fertility.

There are no data on the effect of glimepiride on fertility in humans.

Ability to affect reaction speed when driving or operating machinery.

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

In patients with diabetes, the ability to concentrate may be reduced due to possible episodes of hypoglycemia or hyperglycemia, as well as due to possible visual disturbances. This may pose a risk in situations where such ability is particularly important (e.g., driving a car or operating machinery).

Patients should be warned to take precautions to avoid hypoglycemic episodes while driving. This is especially important for patients who frequently experience hypoglycemic episodes or have reduced or absent awareness of hypoglycemia symptoms. In such cases, the appropriateness of driving should be carefully considered.

Method of administration and dosage.

The foundation of successful diabetes treatment is an adequate diet, regular physical activity, and regular monitoring of blood and urine glucose levels. Oral antidiabetic agents or insulin cannot compensate for poor metabolic control if the patient does not adhere to the recommended diet.

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

The initial dose is 1 mg of glimepiride per day. If good glycemic control is achieved, this dose should be maintained as a maintenance dose. Different dosage forms of the drug are available for various dosage regimens. If blood glucose correction is insufficient, the dose should be gradually increased to 2 mg, 3 mg, or 4 mg of glimepiride per day at intervals of 1–2 weeks under blood glucose monitoring. A dose higher than 4 mg of glimepiride per day increases the drug's effectiveness only in isolated cases. The recommended maximum dose is 6 mg of glimepiride per day.

Combined therapy with glimepiride and metformin.

If the maximum daily dose of metformin does not provide adequate glycemic control, concomitant therapy with glimepiride may be initiated. While maintaining the current metformin dosage, glimepiride therapy should begin with a low dose, which can then be gradually increased up to the maximum daily dose, depending on the desired level of metabolic control. Combined therapy should be initiated under medical supervision.

Combined therapy with glimepiride and insulin.

If the maximum daily dose of glimepiride does not provide adequate glycemic control, concomitant insulin therapy may be initiated when necessary. While maintaining the previous glimepiride dosage, insulin therapy should begin with a low dose, which can then be increased based on the desired level of metabolic control. Combined therapy should be initiated under medical supervision.

The daily dose of the drug should usually be taken once daily. It is recommended to take the dose immediately before or during breakfast. If the dose was not taken in the morning, it should be taken immediately before or during the main meal. If a dose is missed, do not correct it by increasing the next dose. Tablets should be swallowed whole with liquid. If a patient receiving 1 mg of glimepiride per day experiences hypoglycemia, this indicates that dietary management alone is sufficient for metabolic correction.

During treatment, the need for glimepiride may decrease as improved metabolism increases tissue sensitivity to insulin. To avoid hypoglycemia, gradual dose reduction or discontinuation of therapy should be considered. Dose adjustments may also be necessary due to changes in the patient’s body weight, lifestyle, or other factors that may increase the risk of hypo- or hyperglycemia.

Switching from other oral hypoglycemic agents to glimepiride.

Switching from another oral antidiabetic agent to glimepiride is possible. When switching, the potency and half-life of the previous drug should be taken into account. In some cases, particularly with antidiabetic agents having a longer half-life (e.g., chlorpropamide), a break of several days may be advisable to reduce the risk of hypoglycemic reactions due to drug potentiation. The recommended initial dose of glimepiride is 1 mg per day. Depending on the patient’s response, the glimepiride dose can be gradually increased as described above.

Switching from insulin to glimepiride.

In exceptional cases, when patients with type 2 diabetes are using insulin, switching to glimepiride may be indicated. Such a switch should be performed under close medical supervision.

Special populations.

For patients with impaired renal or hepatic function, see section "Contraindications".

Method of administration.

For oral use.

Children.

The safety and efficacy of the medicinal product Olta® in children under 8 years of age have not been established. Data on the use of glimepiride as monotherapy in children aged 8 to 17 years are limited (see sections "Pharmacodynamics" and "Pharmacokinetics").

Available data on safety and efficacy in children are insufficient; therefore, use in this population is not recommended.

Overdose.

Symptoms. Glimepiride overdose may lead to hypoglycemia lasting from 12 to 72 hours, which may recur after initial recovery. Symptoms may be absent for up to 24 hours after drug administration. In such cases, hospital observation is generally recommended. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia may be accompanied by neurological symptoms such as agitation, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures.

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

Management in case of overdose.

As soon as an overdose is suspected, a physician should be notified immediately. The patient should immediately ingest sugar, preferably in the form of glucose, unless the physician assumes responsibility for managing the overdose. Careful monitoring is required until the physician confirms the patient is out of danger. It should be remembered that hypoglycemia may recur after initial recovery.

In mild cases of hypoglycemia, treatment primarily involves oral glucose intake. Severe hypoglycemic reactions require immediate treatment.

Significant overdoses and severe reactions with symptoms such as loss of consciousness or other serious neurological disturbances are medical emergencies and require immediate intervention. Hospitalization in an intensive care unit is indicated.

Initial management should focus on preventing absorption by inducing vomiting, followed by ingestion of large amounts of water or soda with activated charcoal (adsorbent) and sodium sulfate (laxative). If a large amount of the drug has been ingested, gastric lavage is recommended, followed by administration of activated charcoal and sodium sulfate. In cases of severe overdose, hospitalization in an intensive care unit is indicated. Intravenous glucose should be initiated as soon as possible, if necessary, as a 50 mL injection of 50% solution, followed by infusion of a 10% solution, with careful monitoring of blood glucose concentration. Further treatment should be symptomatic.

In severe cases with prolonged hypoglycemia, the risk of recurrent hypoglycemia may persist for several days.

Pediatric population.

When treating hypoglycemia caused by accidental ingestion of the drug in infants and young children, glucose dosage must be carefully controlled to avoid dangerous hyperglycemia. Careful monitoring of blood glucose concentration is required.

Adverse reactions.

The adverse reactions listed below have been observed with the use of glimepiride and other sulfonylurea derivatives. The adverse reactions are listed in decreasing order of frequency.

Reporting of possible adverse reactions

Reporting possible adverse reactions after the medicinal product has been registered plays an important role. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any possible adverse reactions to the State Expert Center of the Ministry of Health of Ukraine.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 30 °C. Keep in the original packaging. Store the medicinal product out of the reach of children!

Packaging. Blister packs of 30 tablets; 1 or 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's address and place of business.

Via Campo di Pile, 67100 L’Aquila (AQ), Italy.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.