Elizieum

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELEZIUM (ELIZIUM)

Composition:

active substance: desloratadine;

1 ml of solution contains 0.5 mg desloratadine;

excipients: edetate disodium; sodium citrate; citric acid monohydrate; sorbitol (E 420); sucralose; propylene glycol; hypromellose; plum flavoring; purified water.

Pharmaceutical form. Oral solution.

Basic physicochemical properties: clear, colorless liquid with a characteristic odor.

Pharmacotherapeutic group. Antihistamines for systemic use.

ATC code R06A X27.

Pharmacological Properties

Pharmacodynamics

Desloratadine is a non-sedating, long-acting antihistamine that exerts a selective antagonistic effect on peripheral H1 receptors. Desloratadine is the primary active metabolite of loratadine. After oral administration, desloratadine selectively blocks peripheral histamine H1 receptors, as it barely penetrates the blood-brain barrier.

In vitro studies have demonstrated desloratadine's antiallergic and anti-inflammatory properties. These include inhibition of the release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, as well as inhibition of P-selectin adhesion molecule expression on endothelial cells. The clinical significance of these observations has not yet been fully established.

The efficacy of the oral solution containing desloratadine in children has not been studied in dedicated clinical trials. However, the safety of the syrup containing desloratadine at the same concentration has been demonstrated in three trials involving children. Children aged 1 to 11 years with indications for antihistamine therapy received a daily dose of desloratadine of 1.25 mg (children aged 1 to 5 years) or 2.5 mg (children aged 6 to 11 years). The treatment was well tolerated, as documented by clinical, laboratory, vital sign, and ECG assessments (including QT interval duration).

When administered at the recommended dose, plasma concentrations of desloratadine were comparable in children and adults. Since the course of allergic rhinitis and chronic idiopathic urticaria, as well as the safety profile of desloratadine, are similar in children and adults, efficacy data from adult studies may be extrapolated to children.

In high-dose clinical trials, where desloratadine was administered daily at doses up to 20 mg for 14 days, no statistically or clinically significant cardiovascular effects were observed. In a clinical pharmacology trial using a daily dose of 45 mg (9 times the clinical dose) for 10 days, no QT interval prolongation was observed.

Desloratadine barely penetrates the blood-brain barrier. At the recommended dose of 5 mg, the incidence of somnolence did not exceed that in the placebo group. In clinical trials, a single 7.5 mg dose of desloratadine did not affect psychomotor performance.

In trials evaluating a single daily dose of 5 mg desloratadine in adults, no changes were observed in standard flight performance tests, including no increase in subjective drowsiness or other flight-related parameters. In clinical pharmacology trials assessing concomitant use with alcohol, no increase in alcohol-related behavioral changes or drowsiness was observed. No significant differences were found in psychomotor test results between groups receiving desloratadine and those receiving placebo (regardless of alcohol consumption).

In multiple-dose clinical trials assessing concomitant administration of desloratadine with ketoconazole and erythromycin, no clinically significant changes in plasma concentrations of desloratadine were observed.

In adults and adolescents with allergic rhinitis, desloratadine tablets are effective in relieving symptoms such as sneezing, nasal itching and discharge, eye itching and redness, tearing, and palate itching. Desloratadine effectively controls symptoms for 24 hours. The efficacy of desloratadine tablets has been clearly demonstrated in clinical trials involving patients aged 12 to 17 years.

In addition to the established classification of allergic rhinitis into seasonal and perennial forms based on symptom duration, allergic rhinitis can also be classified as intermittent or persistent. Intermittent allergic rhinitis is defined as symptoms occurring for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined as symptoms occurring for 4 or more days per week and for more than 4 weeks.

Desloratadine tablets are effective in relieving symptoms of seasonal allergic rhinitis, as evidenced by overall scores in the rhinoconjunctivitis quality-of-life questionnaire. The most significant improvements are observed in the domains of practical problems and daily activities limited by symptoms.

Chronic idiopathic urticaria has been studied as a clinical model for urticarial conditions, as the pathophysiological mechanisms are similar regardless of etiology, and including chronically affected patients in prospective trials is more feasible. Since histamine release is the causative factor in all urticarial conditions, desloratadine is expected to be effective in relieving symptoms and other urticaria-related conditions beyond chronic idiopathic urticaria, as recommended in clinical guidelines.

In two placebo-controlled, 6-week trials in patients with chronic idiopathic urticaria, desloratadine was effective in relieving itching and reducing the size and number of wheals as early as the end of the first dosing interval. In both trials, the effect was maintained throughout the entire 24-hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, a smaller number of patients identified as non-responders to antihistamine therapy were excluded. Relief of itching by more than 50% was observed in 55% of patients treated with desloratadine, compared to 19% of patients receiving placebo. Treatment with desloratadine significantly reduced sleep disturbance and insomnia, measured using a four-point scale used to assess these variables.

Pharmacokinetics

Absorption. Desloratadine plasma concentrations can be detected within 30 minutes after administration. Desloratadine is well absorbed, with peak plasma concentration (Cmax) reached approximately 3 hours after intake; the elimination half-life (T½) is approximately 27 hours. The extent of desloratadine accumulation corresponds to its T½ (~27 hours) and once-daily dosing regimen. Desloratadine bioavailability was dose-proportional in the range of 5 to 20 mg.

In pharmacokinetic and clinical trials, 6% of patients achieved higher plasma concentrations of desloratadine. The percentage of patients with a poor metabolizer phenotype was comparable in adults (6%) and children aged 2 to 11 years (6%), although a higher percentage was observed in individuals of African descent (18% in adults and 16% in children) compared to those of Caucasian descent (2% in adults and 3% in children).

In a multiple-dose pharmacokinetic trial of desloratadine tablets in healthy adult volunteers, four participants were identified as poor metabolizers. In these individuals, Cmax was 3 times higher at 7 hours, and terminal-phase T½ was approximately 89 hours.

Similar pharmacokinetic parameters were observed in a multiple-dose pharmacokinetic trial with syrup in poor metabolizer children aged 2 to 11 years with allergic rhinitis. The area under the plasma concentration-time curve (AUC) of desloratadine was approximately 6 times higher, and Cmax was 3–4 times higher at 3–6 hours, with a T½ of approximately 120 hours. AUC was similar between poor metabolizer adults and children when age-appropriate doses were administered. The overall safety profile in these individuals did not differ from that in the general population. The effects of desloratadine in poor metabolizers under 2 years of age have not been studied.

In separate single-dose trials of desloratadine at the recommended dose in children, AUC and Cmax values were comparable to those in adults receiving a 5 mg dose of desloratadine (syrup).

Distribution. Desloratadine is moderately bound to plasma proteins (83–87%). No evidence of clinically significant accumulation of the active substance was observed after administration of desloratadine doses (5 to 20 mg) once daily for 14 days.

Metabolism. The enzyme responsible for desloratadine metabolism has not yet been identified; therefore, some drug interactions cannot be completely ruled out. Desloratadine does not inhibit CYP3A4 in vivo. In vitro studies have shown that the drug does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.

Elimination. In a single-dose trial of 7.5 mg desloratadine, food intake (a high-fat, high-calorie meal) did not affect the pharmacokinetics of desloratadine. Grapefruit juice was also found not to affect desloratadine pharmacokinetics.

Patients with Renal Impairment.

Desloratadine pharmacokinetics were compared in patients with chronic renal impairment (CRI) and healthy volunteers in one single-dose and one multiple-dose trial. In the single-dose trial, plasma desloratadine levels were approximately 2 times higher in patients with mild and 2.5 times higher in patients with moderate to severe CRI compared to healthy volunteers. In the multiple-dose trial, steady-state concentration was reached by day 11, and plasma desloratadine levels in patients with mild and moderate CRI were ~1.5 times higher, and in patients with severe CRI ~2.5 times higher than in healthy volunteers. In both trials, changes in plasma levels (AUC and Cmax) of desloratadine and 3-hydroxydesloratadine were not clinically significant.

Clinical characteristics.

Indications.

Relief of symptoms associated with:

• allergic rhinitis (sneezing, nasal discharge, nasal itching, nasal swelling and congestion, eye redness and itching, tearing, itching of the palate, and cough);
• urticaria (itching, rash).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product or to loratadine.

Interaction with other medicinal products and other forms of interaction.

No clinically significant changes in plasma concentrations of desloratadine were observed with repeated administration together with ketoconazole, erythromycin, azithromycin, fluoxetine, or cimetidine. Since the enzyme responsible for desloratadine metabolism has not been identified, interactions with other medicinal products cannot be completely excluded.

Food (high-fat, high-calorie meal) or grapefruit juice do not affect desloratadine distribution.

Effect on laboratory test results.

The use of the medicinal product should be discontinued approximately 48 hours before performing skin tests, as antihistamines may prevent or reduce the appearance of positive dermatological reactions to allergens.

Special precautions for use.

Elzium should be administered under medical supervision in patients with severe renal impairment.

Desloratadine should be prescribed with caution to patients who have a history of seizures. Children may be more susceptible to developing a new seizure during desloratadine treatment. The physician must decide whether to discontinue desloratadine in patients who experience a seizure while taking the drug.

Since it may be difficult to differentiate allergic rhinitis from other forms of rhinitis in children under 2 years of age, medical history, physical examination findings, skin and laboratory tests should be considered, along with the absence of upper respiratory tract infections or structural abnormalities.

Approximately 6% of adults and children aged 2–11 years have a slow metabolism of desloratadine, resulting in increased drug exposure. The safety profile of desloratadine in children aged 2–11 years is similar between slow and normal metabolizers. The effects of desloratadine in children under 2 years of age who are slow metabolizers have not been studied.

Elzium contains sorbitol; therefore, if a patient has known sugar intolerance, medical advice should be sought before taking this medication. The cumulative effect of simultaneously ingested products containing sorbitol (or fructose), as well as dietary intake of sorbitol (or fructose), should be taken into account. The sorbitol content in orally administered medicinal products may affect the bioavailability of other orally administered drugs taken concomitantly.

Use during pregnancy or breastfeeding.

Pregnancy. A large amount of data on the use of the drug in pregnant women (over 1000 completed pregnancies) shows no evidence of malformative or fetal/neonatal toxicity of desloratadine. Animal studies have not revealed any direct or indirect effects related to reproductive toxicity. As a precautionary measure, desloratadine should not be used during pregnancy.

Breastfeeding. Desloratadine has been detected in the bodies of newborns/infants breastfed by women taking this medication. The effects of desloratadine on newborns/infants are unknown. Women who are breastfeeding should decide whether to discontinue breastfeeding or avoid using the drug, taking into account the benefits of breastfeeding for the child and the therapeutic benefits of the drug for the mother.

Fertility. There are no data available on the effect of the drug on fertility in men or women.

Ability to affect reaction speed when driving or operating machinery.

According to clinical trials, desloratadine has no effect or only a negligible effect on the ability to drive vehicles or operate machinery. Patients should be informed that somnolence may occur very rarely. Due to individual responses to medications, it is recommended to advise patients not to engage in activities requiring mental alertness, such as driving vehicles or operating machinery, until they know how they react to the medication.

Dosage and Administration.

To relieve symptoms associated with allergic rhinitis (including both intermittent and persistent forms) and urticaria, the medicinal product Elizium should be administered orally, regardless of food intake, in the following doses:

Adults and children aged 12 years and older: 10 mL of solution (5 mg of desloratadine) once daily.

Children aged 6 to 11 years: 5 mL of solution (2.5 mg of desloratadine) once daily.

Children aged 1 to 5 years: 2.5 mL of solution (1.25 mg of desloratadine) once daily.

Treatment of intermittent allergic rhinitis (symptoms present less than 4 days per week or for less than 4 weeks) should be based on patient history: treatment should be discontinued after symptoms resolve and resumed upon their recurrence. For persistent allergic rhinitis (symptoms present more than 4 days per week or for more than 4 weeks), treatment should continue throughout the entire period of allergen exposure.

Children.

Most cases of rhinitis in children under 2 years of age are infectious, and there is no evidence supporting the use of desloratadine for treating infectious rhinitis.

The efficacy and safety of Elizium oral solution in children under 1 year of age have not been established.

Overdose.

In case of overdose, adverse reactions are similar to those observed at therapeutic doses, but symptoms may be more pronounced.

In the event of overdose, standard measures should be taken to remove any unabsorbed active substance, and symptomatic treatment should be administered.

During clinical trials, administration of desloratadine at doses up to 45 mg (9 times higher than the recommended dose) in adults and adolescents did not result in clinically significant effects.

Desloratadine is not removed by hemodialysis; its elimination via peritoneal dialysis has not been established.

Adverse Reactions.

Summary of safety profile.

Pediatric population. In clinical trials in the pediatric population, desloratadine syrup was administered to 246 children aged 6 months to 11 years. The overall incidence of adverse reactions in children aged 2 to 11 years was similar in the desloratadine and placebo groups. In infants and younger children (aged 6 to 23 months), the most commonly reported adverse reactions with higher frequency compared to placebo were: diarrhea (3.7%), fever (2.3%), and insomnia (2.3%). In a subsequent trial following a single 2.5 mg oral solution dose of desloratadine in children aged 6 to 11 years, no adverse reactions were observed.

In a clinical trial involving 578 adolescent patients aged 12 to 17 years, the most commonly reported adverse reaction was headache. It occurred in 5.9% of patients receiving desloratadine and in 6.9% of patients receiving placebo.

Adults and adolescents. In clinical trials for the approved indications, including allergic rhinitis and chronic idiopathic urticaria, adverse reactions were reported 3% more frequently in patients receiving desloratadine than in those receiving placebo. The most commonly reported adverse reactions more frequently than with placebo were fatigue (1.2%), dry mouth (0.8%), and headache (0.6%).

Tabulated list of adverse reactions.

The frequency of adverse reactions observed in clinical trials more frequently than with placebo, and other adverse reactions reported during the post-marketing period, are listed in the table below. Frequency categories are defined as 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), and frequency not known (cannot be estimated from available data).

Pediatric population. Other adverse reactions reported during the post-marketing period with unknown frequency include: QT interval prolongation, arrhythmia, bradycardia, behavioral disturbances, and aggression.

A retrospective observational safety study revealed an increased incidence of seizures occurring in patients aged 0 to 19 years during desloratadine use compared to periods when desloratadine was not used. Among children aged 0–4 years, the adjusted absolute increase was 37.5 (95% confidence interval [CI] 10.5–64.5) per 100,000 person-years with a background incidence of 80.3 seizures per 100,000 person-years. Among patients aged 5–19 years, the adjusted absolute increase was 11.3 (95% CI 2.3–20.2) per 100,000 person-years with a background incidence of 36.4 per 100,000 person-years.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

After opening the container, use within 6 months.

Storage conditions.

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

Packaging.

60 ml or 120 ml in a polyethylene terephthalate container closed with a tamper-evident cap, supplied with a dosing spoon and dosing syringe, in a carton.

Availability.

Over-the-counter (without prescription).

Manufacturer.

Ukrainian-Spanish joint enterprise "Sperko Ukraine".

Manufacturer's address and location of operations.

25, 600-Richchya Street, Vinnytsia, 21027, Ukraine.