Allergenel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALE RGENEL (ALERGENEL)

Composition:

Active substance: levocetirizine;

5 ml of solution contain 2,5 mg of levocetirizine dihydrochloride;

Excipients: maltitol liquid (E 965), glycerin, sodium methylparaben (E 218), sodium propylparaben (E 216), sodium saccharin, sodium acetate trihydrate, glacial acetic acid, apple flavor, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: colorless clear solution.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06A E09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Levocetirizine is the active, stable R-enantiomer of cetirizine, a potent and selective antagonist of peripheral H1-receptors. Studies have shown that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). The affinity of levocetirizine for H1-histamine receptors is twice that of cetirizine (Ki = 6.3 nmol/L).

Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 minutes.

After a single dose, levocetirizine demonstrates receptor occupancy of 90% at 4 hours and 57% at 24 hours.

Pharmacodynamic studies in healthy volunteers have shown that at half the dose, levocetirizine has comparable activity to cetirizine both in skin and nasal effects.

Pharmacodynamic Effects

The pharmacodynamic activity of levocetirizine has been studied in randomized, controlled trials.

In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamine-induced wheal and erythema, treatment with levocetirizine resulted in a significant reduction in wheal and erythema formation [the effect of levocetirizine was maximal within the first 12 hours and lasted for 24 hours (p < 0.001)] compared to placebo and desloratadine.

When administered at a dose of 5 mg for control of pollen-induced symptoms, onset of action occurred within 1 hour after dosing in placebo-controlled allergen challenge chamber studies.

In vitro studies (Boyd chamber and transcellular layer methods) show that levocetirizine inhibits eotaxin-induced transendothelial migration of eosinophils through skin and lung cells. An in vivo pharmacodynamic experimental study (skin chamber technique) demonstrated three main inhibitory effects of levocetirizine 5 mg during the first 6 hours of allergen-induced reaction compared to placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability, and reduction in eosinophil numbers.

Clinical Efficacy and Safety

The efficacy and safety of levocetirizine have been demonstrated in several double-blind, placebo-controlled clinical trials involving adult patients with seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. In some studies, levocetirizine was shown to significantly relieve allergic rhinitis symptoms, including nasal congestion.

A 6-month clinical trial involving 551 adult patients (including 276 patients receiving levocetirizine) with persistent allergic rhinitis (symptoms present on at least 4 days per week for at least 4 consecutive weeks) and sensitivity to house dust mites and grass pollen demonstrated that levocetirizine 5 mg was clinically and statistically significantly more effective than placebo in improving overall allergic rhinitis symptom scores throughout the study period, with no evidence of tachyphylaxis. Levocetirizine significantly improved patients' quality of life throughout the study.

In a placebo-controlled clinical trial involving 166 patients with chronic idiopathic urticaria, 85 patients received placebo and 81 patients received levocetirizine 5 mg once daily for six weeks. Treatment with levocetirizine resulted in a significant reduction in pruritus severity during the first week and throughout the treatment period compared to placebo. Levocetirizine also significantly improved health-related quality of life, as assessed by the Dermatology Life Quality Index, compared to placebo.

Chronic idiopathic urticaria was studied as a model of urticaria. Since histamine release is a causative factor in urticaria, levocetirizine is expected to be effective in providing symptomatic relief in other forms of urticaria beyond chronic idiopathic urticaria.

No significant effect of levocetirizine on the QT interval was observed on ECG.

Pediatric Population

The safety and efficacy of levocetirizine tablets in children were evaluated in two placebo-controlled clinical trials involving patients aged 6 to 12 years with seasonal and perennial allergic rhinitis, respectively. In both studies, levocetirizine significantly alleviated symptoms and improved health-related quality of life.

For children under 6 years of age, clinical safety has been established in several short-term and long-term therapeutic studies:

• A clinical trial in which 29 children aged 2 to 6 years with allergic rhinitis received levocetirizine 1.25 mg twice daily for 4 weeks;
• A clinical trial in which 114 children aged 1 to 5 years with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg twice daily for 2 weeks;
• A clinical trial in which 45 children aged 6 to 11 months with allergic rhinitis or chronic idiopathic urticaria received levocetirizine 1.25 mg once daily for 2 weeks;
• A long-term (18 months) clinical trial involving 255 patients aged 12 to 24 months at enrollment with atopy who received levocetirizine.

The safety profile was similar to that observed in short-term studies conducted in children aged 1 to 5 years.

Pharmacokinetics

The pharmacokinetic parameters of levocetirizine are linear, dose- and time-independent, and show low inter-patient variability. The pharmacokinetic profile after administration of the enantiomer alone is the same as that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption

After oral administration, levocetirizine is rapidly and extensively absorbed. In adults, peak plasma concentration (Cmax) is reached within 50 minutes after a single oral therapeutic dose. Steady-state plasma concentration is achieved after 2 days of dosing.

Peak concentrations typically reach 270 ng/mL after a single dose and 308 ng/mL after repeated administration of 5 mg once daily.

The extent of absorption is independent of dose and is not altered by food intake; however, the maximum concentration (Cmax) of levocetirizine is reduced and its attainment is delayed.

Distribution

Data on tissue distribution of levocetirizine in humans are lacking, as are data on its penetration across the blood-brain barrier. In rats and dogs, the highest tissue levels are found in the liver and kidneys, and the lowest in the central nervous system (CNS).

In humans, levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg.

Metabolism

In humans, less than 14% of the dose undergoes metabolism; therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be minimal. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by cytochrome CYP3A4, while aromatic oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding peak levels after oral administration of a 5 mg dose. Due to its low extent of metabolism and lack of inhibitory potential on metabolic pathways, drug interactions with levocetirizine are unlikely.

Excretion

The elimination half-life (T1/2) in plasma in adults is 7.9 ± 1.9 hours. T1/2 is shorter in younger children. The mean apparent total clearance in adults is 0.63 mL/min/kg. The primary route of elimination of levocetirizine and its metabolites is via urine, accounting for an average of 85.4% of the dose. Only 12.9% of the dose is excreted in feces. Levocetirizine is eliminated by both glomerular filtration and active tubular secretion.

Special Populations

Renal Impairment

The apparent clearance of levocetirizine correlates with creatinine clearance. Therefore, dosing intervals for levocetirizine should be adjusted in patients with moderate and severe renal impairment based on creatinine clearance. In anuric patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to healthy subjects. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is less than 10%.

Pediatric Population

In a pediatric pharmacokinetic study, after a single oral dose of 5 mg levocetirizine administered to 14 children aged 6 to 11 years (body weight 20–40 kg), Cmax and AUC values were approximately twice as high as those in healthy adults, based on cross-study comparisons. Mean Cmax was 450 ng/mL, reached at a median of 1.2 hours (normalized for body weight), total clearance was 30% higher, and elimination half-life was 24% shorter in this pediatric population compared to adults. No specific pharmacokinetic studies have been conducted in children under 6 years of age. A retrospective population pharmacokinetic analysis was performed in 323 patients (181 children aged 1 to 5 years, 18 children aged 6 to 11 years, and 124 adults aged 18 to 55 years) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. The analysis showed that after administration of 1.25 mg once daily to children aged 6 months to 5 years, plasma concentrations were similar to those in adults receiving 5 mg once daily.

Elderly

Pharmacokinetic data in elderly patients are limited. After repeated oral administration of 30 mg levocetirizine once daily for 6 days in 9 elderly patients (65–74 years), total clearance was approximately 33% lower than in younger adults. It has been shown that the disposition of racemic cetirizine depends on renal function rather than age. This conclusion also applies to levocetirizine, as both levocetirizine and cetirizine are primarily excreted in urine. Therefore, levocetirizine dosage in elderly patients should be adjusted according to renal function.

Gender

Pharmacokinetic results in 77 patients (40 males, 37 females) were evaluated for potential gender effects. Elimination half-life was slightly shorter in females (7.08 ± 1.72 hours) than in males (8.62 ± 1.84 hours); however, oral clearance normalized for body weight was comparable between females (0.67 ± 0.16 mL/min/kg) and males (0.59 ± 0.12 mL/min/kg). For males and females with normal renal function, the same daily doses and dosing intervals are appropriate.

Race

The effect of race on levocetirizine has not been studied. Since levocetirizine is primarily renally excreted and there are no significant racial differences in creatinine clearance, differences in the pharmacokinetic characteristics of levocetirizine based on race are not expected. No race-related differences in the pharmacokinetics of racemic cetirizine have been observed.

Hepatic Impairment

The pharmacokinetics of levocetirizine in patients with hepatic impairment has not been studied. In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) receiving a single dose of 10 or 20 mg of racemic cetirizine, a 50% increase in elimination half-life and a 40% reduction in clearance were observed compared to healthy subjects.

Pharmacokinetic/Pharmacodynamic Relationship

The effect on histamine-induced skin responses does not correlate with plasma concentrations.

Preclinical Safety Data

Preclinical data from conventional studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity, and developmental toxicity did not reveal any special hazard for humans.

Clinical Characteristics

Indications. For symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria in adults and children aged 2 years and older.

Contraindications. Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, any other piperazine derivatives, or to any of the excipients of the medicinal product.

End-stage renal disease (creatinine clearance less than 15 ml/min) requiring dialysis treatment.

Interaction with other medicinal products and other forms of interaction. Interaction studies with levocetirizine have not been conducted (including studies with CYP3A4 inducers). Interaction studies with the cetirizine racemate showed no clinically significant adverse interactions with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine.

In a multiple-dose study of theophylline (400 mg once daily), a slight reduction (by 16%) in cetirizine clearance was observed, while theophylline distribution remained unchanged upon co-administration with cetirizine.

In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir distribution was slightly altered (−11%).

Food intake does not affect the extent of levocetirizine absorption, but concomitant food intake reduces the rate of its absorption.

Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants in sensitive patients may cause additional reduction in attention and worsening of performance ability.

Special precautions for use

Caution should be exercised when using the medicinal product concomitantly with alcohol (see section "Interaction with other medicinal products and other forms of interaction").

Use with caution in patients with epilepsy and in those at risk of seizures, as levocetirizine may lead to an increased frequency of seizures.

Caution is advised when administering the medicinal product to patients with factors predisposing to urinary retention (e.g. spinal cord lesions, benign prostatic hyperplasia), since levocetirizine may increase the risk of urinary retention.

Antihistamines suppress the response to skin allergy tests; therefore, administration of the medicinal product should be discontinued 3 days prior to testing (elimination period).

Pruritus may occur after discontinuation of levocetirizine, even if this symptom was absent prior to the start of treatment. The pruritus may resolve spontaneously. In some cases, it may be intense and may require re-initiation of treatment. Pruritus should resolve after restarting treatment.

Pediatric population

Available clinical data on the use of levocetirizine in children aged 6 months to 12 years are insufficient to support its use in infants and children under 2 years of age.

Excipients

The medicinal product contains methylparaben and propylparaben, which may cause allergic reactions (possibly delayed).

The medicinal product contains liquid maltitol. Patients with intolerance to certain sugars should consult their physician before taking this medicinal product.

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of levocetirizine during pregnancy are limited (fewer than 300 cases of favorable pregnancy outcomes). However, more data are available regarding the use of cetirizine—the racemate of levocetirizine—during pregnancy (over 1000 cases of favorable pregnancy outcomes), and these data indicate no teratogenic or fetal/neonatal toxicity.

Animal studies have not revealed any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

The use of this medicinal product during pregnancy should only be considered after careful assessment of the benefit-risk ratio.

Breastfeeding

Excretion of cetirizine—the racemate of levocetirizine—into human milk has been demonstrated. Therefore, excretion of levocetirizine into breast milk is likely. Adverse reactions to levocetirizine may occur in breastfed infants. The medicinal product should be used with caution in breastfeeding women.

Reproductive function

There are no clinical data on the effect of levocetirizine on reproductive function.

Ability to affect reaction speed when driving or operating machinery

Comparative clinical studies have not shown any evidence that levocetirizine, at the recommended dose, impairs mental performance, reaction ability, or the ability to drive a vehicle or operate machinery.

However, some patients may experience somnolence, fatigue, or asthenia during treatment with levocetirizine. Therefore, patients intending to drive or operate machinery or engage in potentially hazardous activities should take into account their individual response to the medicinal product.

Dosage and Administration

The medicinal product is intended for use in adults and children aged 2 years and older.

Administration

The medicinal product is for oral use. The appropriate amount of solution should be measured using the dosing cap provided in the package. If necessary, the medicinal product may be diluted with water—the solution should be taken immediately after dilution. The medicinal product may be taken regardless of food intake.

Dosage

Adults and children aged 12 years and older

The recommended daily dose is 5 mg (10 ml of solution).

Elderly patients

Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see below).

Patients with renal impairment

Dose calculation in patients with renal impairment should be based on the degree of renal function impairment (GFR—glomerular filtration rate) according to the table below.

Dose adjustment of levocetirizine in patients with renal impairment

For children with impaired renal function, the dose of levocetirizine should be individually adjusted based on the patient's renal clearance and body weight.

There are no specific data available on the use of levocetirizine in children with impaired renal function.

Patients with hepatic impairment

Dose adjustment is not required for patients with hepatic impairment. However, for patients with both hepatic and renal impairment, dosage regimen should be adjusted according to the table provided above.

Paediatric population:

Children aged 6 to 12 years

The recommended daily dose is 5 mg (10 mL of solution).

Children aged 2 to 6 years

The recommended daily dose is 2.5 mg (5 mL of solution), divided into two doses of 1.25 mg (2.5 mL of solution) twice daily.

Duration of treatment

Patients with intermittent allergic rhinitis (disease symptoms lasting less than 4 days per week or less than 4 weeks per year) should be treated according to the course of the disease and medical history: treatment may be discontinued if symptoms resolve and restarted upon recurrence of symptoms.

In cases of persistent allergic rhinitis (disease symptoms lasting more than 4 days per week or more than 4 weeks per year), patients may be offered continuous therapy throughout the allergen exposure period. Clinical experience supports the use of levocetirizine for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), there is clinical experience with cetirizine (the racemate) for up to 1 year.

Children

The medicinal product can be used in children aged 2 years and older.

Available clinical data on the use of levocetirizine in children aged 6 months to 12 years are insufficient to justify its use in infants and children under 2 years of age.

Overdose

Symptoms

Symptoms of overdose in adults may include somnolence. In children, initial symptoms may include excitation and restlessness, followed by drowsiness.

Treatment

There is no specific antidote for levocetirizine. In case of overdose symptoms, symptomatic and supportive therapy is recommended. Gastric lavage may be considered shortly after drug ingestion. Hemodialysis is not effective for removing levocetirizine from the body.

Adverse Reactions

Clinical Trials

Adults and children aged 12 years and older

In studies involving male and female patients aged 12 to 71 years, at least one adverse event was observed in 15.1% of patients in the 5 mg levocetirizine group compared to 11.3% of patients in the placebo group. 91.6% of these adverse events in the 5 mg levocetirizine group were of mild to moderate severity. The rate of withdrawal from the study due to adverse events was 1.0% (9/935) in the 5 mg levocetirizine group and 1.8% (14/771) in the placebo group.

A total of 935 patients receiving levocetirizine at the recommended dose of 5 mg once daily were included in the clinical trials of levocetirizine. In these studies, adverse reactions reported at a frequency of 1% or greater (from ≥ 1/100 to < 1/10), occurring in the 5 mg levocetirizine and placebo groups, were:

The following adverse reactions were observed infrequently (≥ 1/1000, < 1/100): asthenia or abdominal pain. Sedative adverse reactions such as somnolence, fatigue, and asthenia were observed in 8.1% of patients in the 5 mg levocetirizine group and in 3.1% of patients in the placebo group.

Paediatric population

In two placebo-controlled trials involving children aged 6 to 11 months and 1 to 6 years, 159 patients received levocetirizine at a dose of 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The following adverse reactions were reported, occurring in at least 1% of children in the levocetirizine and placebo groups:

A double-blind, placebo-controlled clinical trial was conducted in 243 children aged 6 to 12 years who received 5 mg of levocetirizine daily over periods ranging from 1 week to 13 weeks. Adverse reactions reported to occur in at least 1% of children during treatment with levocetirizine and placebo were:

Post-marketing period

Adverse reactions reported during the post-marketing period are listed by system organ class according to MedDRA [Medical Dictionary for Regulatory Activities]. Frequency of adverse reactions is unknown (cannot be estimated from the available data).

Immune system disorders: hypersensitivity, including anaphylaxis.

Metabolism and nutrition disorders: increased appetite.

Psychiatric disorders: aggression, agitation, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

Nervous system disorders: seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

Ear and labyrinth disorders: vertigo.

Eye disorders: visual disturbance, blurred vision, nystagmus.

Cardiac disorders: palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: dyspnoea.

Gastrointestinal disorders: nausea, vomiting, diarrhoea.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

General disorders and administration site conditions: oedema.

Investigations: weight increased, hepatic function test abnormalities.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store below 25 °C in a place inaccessible to children.

After first opening of the bottle, store for no more than 3 months.

Packaging. 75 ml or 150 ml in a bottle, 1 bottle with a measuring cap in a cardboard box.

Supply classification. Over-the-counter (without prescription).

Manufacturer. Vivimed Labs Ltd

Manufacturer's address and site of operations. D–125 and 128, Phase-III, IDA, Jeedimetla, Medchal-Malkajgiri District - 500055, Telangana State, India