Oltar® 4 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLTA® 4 MG/OLTA® 6 MG (OLTAR® 4 MG/OLTAR® 6 MG)

Composition:

Active substance: glimepiride;

1 tablet contains 4 mg or 6 mg of glimepiride;

Excipients: lactose monohydrate, maize starch, sodium starch glycolate (type A), povidone, polysorbate 80, yellow iron oxide (E 172), talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: yellow, capsule-shaped tablets with a flat bevelled edge and a score line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group.

Oral hypoglycaemic agents. Sulfonylureas.

ATC code A10BB12.

Pharmacological properties.

Pharmacodynamics.

Glimepiride is an oral hypoglycemic agent belonging to the sulfonylurea group. It is indicated for the treatment of non-insulin-dependent (type 2) diabetes mellitus.

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

Like other sulfonylurea derivatives, this effect is associated with increased sensitivity of pancreatic beta cells to physiological glucose stimulation. In addition, glimepiride likely exerts pronounced extrapancreatic effects, theoretically shared by other sulfonylurea derivatives.

Insulin release. Sulfonylurea agents regulate insulin secretion by closing ATP-dependent potassium channels in the beta cell membrane. Closure of potassium channels induces depolarization of the beta cell and, via opening of calcium channels, leads to increased intracellular calcium influx. This triggers insulin release through exocytosis.

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

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

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

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

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 glimepiride's effect was observed whether the drug was administered 30 minutes before or immediately before a meal. In patients with diabetes, good metabolic control over 24 hours can be achieved with once-daily dosing.

Although the hydroxy metabolite of glimepiride causes a slight but statistically significant reduction in serum glucose levels in healthy individuals, this contributes only minimally to the overall drug effect.

Combination therapy with metformin. One study demonstrated improved metabolic control with combination therapy using glimepiride compared to metformin monotherapy in patients with inadequate glycemic control on the maximum daily dose of metformin.

Combination therapy with insulin. Data on combination therapy with insulin are limited. In patients with inadequate glycemic control on the maximum dose of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved similar improvements in metabolic control as insulin monotherapy; however, lower mean insulin doses were required with combination therapy.

Children. A 24-week active-controlled clinical study was conducted in 285 children aged 8 to 17 years with type 2 diabetes (glimepiride up to 8 mg daily or metformin up to 2000 mg daily).

Both glimepiride and metformin significantly reduced HbA1c compared to 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 treatment difference was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for the difference exceeded the 0.3% non-inferiority margin.

After treatment with glimepiride, no new safety concerns were identified in children compared to adult patients with type 2 diabetes. Long-term efficacy and safety data in children are lacking.

Pharmacokinetics.

Absorption. Oral bioavailability of glimepiride is complete. Food intake does not significantly affect absorption, although it slightly reduces the rate of absorption. Peak serum concentration (Cmax) is reached approximately 2.5 hours after oral administration (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. Glimepiride has a low volume of distribution (approximately 8.8 L), corresponding roughly to the distribution volume of albumin, a high degree of protein binding (>99%), and low clearance (approximately 48 mL/min).

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

Biotransformation and elimination. The mean terminal elimination half-life at serum concentrations corresponding to repeated dosing is approximately 5–8 hours. After high doses, a slight increase in half-life has been observed.

Following a single dose of radiolabeled glimepiride, radioactivity was recovered in urine (58%) and feces (35%). Unchanged drug was not detected in urine. Two metabolites were identified in both urine and feces, most likely formed via hepatic metabolism (primary enzyme CYP2C9): the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively. Comparison of single and repeated once-daily dosing revealed no significant differences in pharmacokinetics, and inter-individual variability was very low. No significant accumulation was observed.

Special patient groups. Pharmacokinetics are similar in men and women, as well as in younger individuals and elderly patients (aged 65 years and older). In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean serum concentration was observed, likely due to faster elimination resulting from reduced protein binding. Renal excretion of the two metabolites was impaired. However, cumulative risk is not considered increased for these patients.

Pharmacokinetics in five non-diabetic patients after biliary surgery were similar to those in healthy individuals.

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

Preclinical safety data.

Effects observed during preclinical studies occurred only at exposure levels substantially exceeding the maximum human exposure, indicating limited relevance to clinical practice, or were attributable to the pharmacodynamic action of the drug (hypoglycemia). These findings are based on standard studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity. Adverse effects observed in developmental studies (including embryotoxicity, teratogenicity, and developmental toxicity) were considered consequences of drug-induced hypoglycemia in dams and offspring.

Clinical characteristics.

Indications.

Treatment of type 2 diabetes mellitus in adults when diet, physical exercise, and weight reduction alone are insufficient to maintain blood glucose levels.

Contraindications.

Hypersensitivity to glimepiride, to any of the excipients, or to other sulfonylurea derivatives or sulfonamides. Insulin-dependent diabetes. Diabetic coma. Diabetic ketoacidosis. Severe impairment of renal or hepatic function. In cases of severe renal or hepatic dysfunction, switching to insulin therapy is required.

Interaction with other medicinal products and other forms of interactions.

When glimepiride is used concomitantly with certain other medicinal products, both enhancement and reduction of its glucose-lowering effect are possible; therefore, other medicinal products should be used only upon a physician's advice (or by prescription). Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). It is known that its metabolism may be affected by concomitant use of CYP2C9 inducers (e.g., rifampicin) or CYP2C9 inhibitors (e.g., fluconazole). Results of in vivo interaction studies demonstrate that fluconazole, one of the most potent CYP2C9 inhibitors, increases the AUC of glimepiride by approximately two-fold.

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

Enhancement of the glucose-lowering effect of glimepiride, and thus, in some cases, hypoglycemia, may occur when used concomitantly with the following substances:

phenylbutazone, azapropazone, oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents such as metformin, certain long-acting sulfonamides, tetracyclines, salicylates and para-aminosalicylic acid, monoamine oxidase inhibitors (MAO), anabolic steroid preparations and male sex hormones, antibacterial agents – quinolone derivatives and clarithromycin, chloramphenicol, probenecid, anticoagulants of the coumarin type, miconazole, fenfluramine, disopyramide, pentoxifylline (administered parenterally in high doses), fibrates, troxipide, angiotensin-converting enzyme (ACE) inhibitors, fluoxetine, allopurinol, sympatholytic agents, cyclophosphamide, trofosfamide, ifosfamide, fluconazole.

Reduction of the glucose-lowering effect of glimepiride, and consequently elevated blood glucose levels, may occur when used concomitantly with the following substances:

estrogens and progestogens, saluretics, thiazide diuretics, thyrotropic and glucocorticoid agents, phenothiazine derivatives, chlorpromazine, adrenaline and sympathomimetic agents, nicotinic acid (in high doses) and its derivatives, laxatives (with prolonged use), phenytoin, diazoxide, glucagon, barbiturates and rifampicin, acetazolamide.

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

Under the influence of sympatholytic medicinal products such as β-adrenoblockers, clonidine, guanethidine, and reserpine, symptoms of compensatory adrenergic regulation during hypoglycemia may be weakened or absent.

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

Glimepiride may either enhance or reduce the effects 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 administration of colesevelam.

Special precautions for use.

Amaryl® should be taken immediately before or during a meal.

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

Irregular eating patterns or skipping meals may lead to hypoglycaemia when treated with glimepiride. Possible symptoms of hypoglycaemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, restlessness, aggression, impaired concentration, anxiety, prolonged reaction time, depression, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral 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, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical presentation 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 sugar substitutes are ineffective.

With other sulphonylurea drugs, hypoglycaemia may recur despite initially successful management.

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

Factors that may predispose to hypoglycaemia include: unwillingness or inability of the patient to cooperate with the physician (most commonly in elderly patients); inadequate, irregular nutrition, skipping meals or periods of fasting; imbalance between physical exertion and carbohydrate intake; dietary changes; alcohol consumption, especially when combined with skipped meals; impaired renal function; severe hepatic impairment; glimepiride overdose; certain uncompensated endocrine disorders affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (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 glimepiride requires regular monitoring of blood glucose and urine sugar levels.

In addition, measurement of glycosylated haemoglobin levels is recommended.

During treatment with glimepiride, 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 conversion 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 dialysis. 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 induce haemolytic anaemia. Since glimepiride belongs to the sulphonylurea class of drugs, it should be used with caution in patients with glucose-6-phosphate dehydrogen enzyme deficiency, and alternative non-sulphonylurea medicinal products should be considered.

This medicinal product contains lactose monohydrate and therefore 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 mellitus. Abnormal blood glucose levels during pregnancy may lead to increased incidence of congenital malformations and perinatal mortality. Therefore, careful monitoring of blood glucose levels during pregnancy is essential to avoid teratogenic risk.

Under these circumstances, insulin therapy should be used. Female patients with diabetes who are planning pregnancy should inform their physician to adjust treatment and switch to insulin.

Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity, which was likely related to the pharmacological effect of glimepiride (hypoglycaemia).

Therefore, glimepiride should not be used throughout pregnancy.

If a patient taking 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 passes into human breast milk. In rats, glimepiride is excreted in breast milk. Since other sulphonylurea drugs are known to pass into human breast milk and there is a risk of hypoglycaemia in breastfed infants, breastfeeding is not recommended during treatment with glimepiride.

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 on reaction speed when driving or operating machinery have not been conducted.

Hypoglycaemia or hyperglycaemia, or for example visual disturbances, may reduce a patient's ability to concentrate and react. This may pose a risk in situations where such ability is of particular importance (e.g. driving a car or operating machinery). Patients should be advised to take precautionary measures to avoid hypoglycaemia while driving. This is especially important for patients who have impaired or absent awareness of the warning symptoms of hypoglycaemia, or those who experience frequent episodes of hypoglycaemia. In such circumstances, the appropriateness of driving or operating machinery should be carefully considered.

Method of Administration and Dosage.

Successful diabetes management relies on an appropriate diet, regular physical activity, and periodic monitoring of blood and urine glucose levels. Oral antidiabetic agents or insulin cannot compensate for failure to follow the prescribed diet.

The dosage is determined by the physician based on blood and urine glucose measurements.

The initial dose of glimepiride is 1 mg* per day. Once adequate control is achieved, this dose should be used for maintenance therapy.

Tablets with appropriate strengths are available for different dosage regimens. If glycemic control is inadequate, the dosage should be gradually increased based on monitoring results, with approximately 1–2 weeks between each increment, up to 2, 3*, or 4 mg of glimepiride per day.

Doses exceeding 4 mg of glimepiride per day provide additional benefit only in exceptional cases. The maximum recommended daily dose of glimepiride is 6 mg.

In patients with inadequate control on the maximum daily dose of metformin, combination therapy with glimepiride may be initiated.

When continuing metformin therapy, glimepiride treatment should begin at a low dose, which may then be gradually increased up to the maximum daily dose, depending on the desired level of metabolic control. Combination therapy should be initiated under close medical supervision.

In patients with inadequate control on the maximum daily dose of glimepiride, insulin therapy may be initiated if necessary. When continuing glimepiride, insulin therapy should begin at a low dose, which should be gradually increased according to the desired level of metabolic control. Combination therapy should be initiated under close medical supervision.

Typically, a single daily dose of glimepiride is sufficient. It is recommended to take the dose immediately before or during a main meal, preferably breakfast, or, if breakfast is not consumed, immediately before or during the first substantial meal of the day. If a dose is missed, do not compensate by increasing the next dose. Tablets should be swallowed whole with liquid.

If a patient experiences hypoglycemic reactions at a daily dose of 1 mg* of glimepiride, this suggests that glycemic control may be achievable with diet alone.

During treatment, as improved diabetes control is associated with increased insulin sensitivity, the requirement for glimepiride may decrease. Therefore, to prevent hypoglycemia, temporary dose reduction or discontinuation of therapy should be considered. Dosage adjustments may also be necessary due to changes in body weight, lifestyle, or the emergence of other factors increasing the risk of hypo- or hyperglycemia.

Switching from other oral antidiabetic agents to glimepiride.

In general, switching from other oral antidiabetic agents to glimepiride is possible. When switching, the potency and elimination half-life of the previous agent should be considered. In some cases, particularly when switching from agents with a long half-life (e.g., chlorpropamide), a washout period of several days is recommended to minimize the risk of hypoglycemic reactions due to additive effects.

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

* Use glimepiride at the appropriate dosage strength.

Switching from insulin to glimepiride.

In exceptional cases, patients with type 2 diabetes receiving insulin therapy may be switched to glimepiride. Such transition 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.

Tablets should be swallowed whole with a small amount of liquid.

Children.

The safety and efficacy of Olta® in children under 8 years of age have not been established. Limited data are available for children aged 8 to 17 years receiving glimepiride as monotherapy (see sections "Pharmacodynamics" and "Pharmacokinetics").

Due to insufficient data on safety and efficacy in children, use in this population is not recommended.

Overdose.

Overdose may cause hypoglycemia lasting from 12 to 72 hours, which may recur after initial improvement. Symptoms may be absent for up to 24 hours after drug administration. Hospitalization and close monitoring are generally recommended. Possible symptoms include nausea, vomiting, and epigastric pain. Hypoglycemia may generally be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures.

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

Treatment of overdose.

As soon as an overdose is suspected, a physician must be notified immediately. The patient should promptly ingest sugar, preferably in the form of glucose, unless the physician assumes responsibility for managing the overdose. Close monitoring is required until the physician is certain the patient is out of danger. Recurrence of hypoglycemia after initial recovery should be anticipated.

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

Significant overdoses and severe reactions, including loss of consciousness or other serious neurological disturbances, constitute medical emergencies requiring immediate treatment. Hospitalization in an intensive care unit is indicated.

Initial treatment should focus on preventing absorption by inducing emesis, followed by administration of water or soda with activated charcoal (adsorbent) and sodium sulfate (laxative). Gastric lavage followed by activated charcoal and sodium sulfate is indicated after ingestion of large quantities of the drug. Hospitalization in an intensive care unit is indicated in cases of severe overdose. Intravenous glucose administration should be initiated as soon as possible; if necessary, a bolus injection of 50 mL of 50% glucose solution should be given, followed by infusion of 10% glucose solution, with careful monitoring of blood glucose concentration. Further treatment should be symptomatic.

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

Particularly in the treatment of hypoglycemia in infants and young children caused by accidental ingestion of Olta®, the dose of glucose must be carefully controlled to avoid the risk of dangerous hyperglycemia. Close monitoring of blood glucose levels is essential.

Adverse reactions

Based on the experience with glimepiride and other sulfonylurea derivatives, the following adverse reactions are listed below by organ system classes and in decreasing order of frequency: very common: ≥ 1/10; common: ≥ 1/100 – < 1/10; uncommon: ≥ 1/1000 – < 1/100; rare: ≥ 1/10,000 – < 1/1000; very rare: < 1/10,000; frequency not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

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. Keep out of reach and sight of children.

Packaging.

30 tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Manufacturer's address.

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

Marketing Authorization Holder.

BERLIN-CHEMIE AG.

Address of the Marketing Authorization Holder.

Glienicker Weg 125, 12489 Berlin, Germany.