Levocetil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOSETIL (LEVOSETIL)

Composition:

Active substance: levocetirizine;

1 ml of solution contains levocetirizine dihydrochloride 5 mg;

Excipients: propylene glycol; glycerin; methylparaben (E 218); propylparaben (E 216); sodium acetate trihydrate; sodium saccharin; glacial acetic acid; purified water.

Medicinal form. Oral drops, solution.

Main physicochemical properties: colorless clear solution.

Pharmacotherapeutic group

Antihistamines for systemic use. Piperazine derivatives. Levocetirizine.

ATC code R06AE09.

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 for H1-histamine receptors is 2 times higher for levocetirizine than for cetirizine (Ki = 6.3 nmol/L).

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

After single administration, levocetirizine demonstrates 90% receptor occupancy 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 5 mg levocetirizine, 5 mg desloratadine, 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 levocetirizine was administered at a dose of 5 mg to control allergen-induced symptoms, onset of action was observed within 1 hour after drug intake in placebo-controlled allergen challenge chamber studies.

In vitro studies (Boyden chambers 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 administered at 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 count.

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 reduce 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 for at least 4 days per week for at least 4 consecutive weeks) and sensitivity to house dust mites and grass pollen demonstrated that levocetirizine at a dose of 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. Throughout the study, levocetirizine significantly improved patients' quality of life.

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 entire 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 urticarial conditions beyond chronic idiopathic urticaria.

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

Paediatric Population

The safety and efficacy of levocetirizine in tablet form were studied in two placebo-controlled clinical trials involving children 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 was 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 involving children aged 1 to 5 years.

Pharmacokinetics

The pharmacokinetics of levocetirizine are linear, dose- and time-independent, and show low variability across different patients. The pharmacokinetic profile after administration of the enantiomer alone is identical to that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption

After oral administration, levocetirizine is rapidly and extensively absorbed. In adults, Cmax in plasma 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 dosing of 5 mg once daily.

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

Distribution

Data on tissue distribution of levocetirizine in humans and on its penetration across the blood-brain barrier are lacking. 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. 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, so 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 occurs primarily via cytochrome CYP3A4, while aromatic oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 at concentrations significantly exceeding peak levels after oral administration of a 5 mg dose. Due to low metabolism and lack of inhibitory effect on metabolism, drug interactions with levocetirizine are unlikely.

Elimination

The elimination half-life (T1/2) from 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 in patients with moderate to severe renal impairment should be adjusted based on creatinine clearance. In anuric patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to healthy subjects. Less than 10% of levocetirizine is removed during a standard 4-hour hemodialysis session.

Paediatric Population

In a paediatric pharmacokinetic study, after a single oral dose of 5 mg levocetirizine administered to 14 children aged 6 to 11 years with body weights between 20 and 40 kg, Cmax and AUC values were approximately twice as high as in healthy adults in cross-study comparisons. The mean Cmax was 450 ng/mL, reached on average at 1.2 hours (normalized for body weight), total clearance was 30% higher, and elimination half-life was 24% shorter in this paediatric population compared to adults. No specific pharmacokinetic studies were 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 patient age. This conclusion also applies to levocetirizine, as both levocetirizine and cetirizine are predominantly 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. The 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 apply.

Race

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

Hepatic Impairment

The pharmacokinetics of levocetirizine in patients with hepatic impairment have not been studied. In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis) who received 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 reactions is independent of plasma concentration of levocetirizine.

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

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, to any other piperazine derivatives and/or to any of the excipients of the medicinal product.

End-stage renal disease (glomerular filtration rate (GFR) < 15 mL/min) requiring dialysis.

Interaction with other medicinal products and other forms of interaction

Studies on levocetirizine interactions (including with CYP3A4 inducers) have not been conducted. Studies on cetirizine (the racemate compound) interactions have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse effects.

Concomitant administration with theophylline (400 mg daily) in a multiple-dose study showed a slight decrease (by 16%) in cetirizine clearance (theophylline distribution was not altered).

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

There are no data regarding potentiation of sedative effects when used with other sedatives at therapeutic doses; however, concomitant use of sedatives should be avoided during levocetirizine treatment.

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

Concomitant administration of cetirizine or levocetirizine with alcohol or other CNS depressants in sensitive patients may result in additional reduction in attention and ability to perform tasks.

Special precautions for use

During the use of the medicinal product, caution should be exercised in case of alcohol consumption (see section "Interaction with other medicinal products and other forms of interaction").

When using the medicinal product in patients with factors predisposing to urinary retention (e.g. spinal cord injury, benign prostatic hyperplasia), it should be borne in mind that levocetirizine may increase the risk of urinary retention.

The medicinal product should be used with caution in patients with epilepsy or those at risk of seizures, as its use may lead to exacerbation of seizures.

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 not present before the start of treatment. Pruritus may resolve spontaneously. In some cases, it may be intense and may necessitate re-treatment. Pruritus should resolve after re-initiation of treatment.

Available clinical data on the use of levocetirizine in children aged 6 months to 12 years (see sections "Pharmacodynamics", "Pharmacokinetics", "Side effects") are insufficient to support its use in infants and children under 2 years of age.

The medicinal product contains methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions that may not manifest immediately.

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

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of levocetirizine in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). However, extensive data on cetirizine, the racemate of levocetirizine (more than 1000 pregnancy outcomes), indicate no teratogenic or toxic effects on the fetus/newborn. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, delivery, or postnatal development. If necessary, the use of the medicinal product during pregnancy may be considered.

Period of breastfeeding

It has been established that cetirizine, the racemate of levocetirizine, is excreted in human milk. Therefore, excretion of levocetirizine in breast milk is likely. Adverse reactions associated with levocetirizine may occur in breastfed infants. The medicinal product should be used with caution during breastfeeding.

Fertility

There are no clinical data on the effect of levocetirizine on fertility.

Ability to influence reaction rate while driving or operating machinery

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

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

Dosage and Administration

The medicinal product is intended for oral use.

Dosage

Adults and children aged 12 years and older

The recommended daily dose is 5 mg (20 drops) once daily.

Elderly patients

Elderly patients with normal renal function do not require dose adjustment.

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

Patients with renal impairment

Dosage must be adjusted according to the degree of renal impairment (glomerular filtration rate, GFR) as specified in the table below.

Dose adjustment of levocetirizine for patients with renal impairment

In 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 in patients with hepatic impairment. However, in 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 (20 drops) once daily.

Children aged 2 to 6 years

The recommended daily dose is 2.5 mg (10 drops) per day, divided into two doses of 1.25 ml (5 drops) each.

Duration of treatment

Patients with intermittent allergic rhinitis (duration of symptoms 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 (duration of symptoms more than 4 days per week or more than 4 weeks per year) during allergen exposure periods, continuous therapy may be considered. There is clinical experience with levocetirizine use for at least a 6-month treatment period. For chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year (data are available from clinical studies using the racemate).

Method of administration

The drops are taken orally using a spoon, independent of food intake. If necessary, the medicinal product may be diluted with water. When diluting the drops in water, especially in children, it should be ensured that the volume of water corresponds to the amount of liquid the patient can swallow. The diluted solution should be taken immediately.

Children

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

Although some clinical data are available on the use of levocetirizine in children aged 6 months to 12 years (see sections "Pharmacodynamics", "Pharmacokinetics", "Adverse reactions"), this information is insufficient to support its use in infants and children under 2 years of age (see also section "Special warnings and precautions for use").

Overdose

Symptoms

Symptoms of overdose in adults may include somnolence. In children, initial excitation and increased irritability may occur, followed by somnolence.

Treatment

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

Adverse Reactions

Clinical Studies

Adults and adolescents aged 12 years and older

In therapeutic studies involving men and women aged 12 to 71 years, 15.1% of patients in the group receiving levocetirizine 5 mg experienced at least one adverse reaction, compared with 11.3% in the placebo group. 91.6% of these adverse reactions were mild to moderate in severity.

In therapeutic studies, the rate of discontinuation due to adverse events was 1.0% (9/935) in patients receiving levocetirizine 5 mg and 1.8% (14/771) in those receiving placebo.

Clinical therapeutic studies of levocetirizine included 935 patients who received the medicinal product at the recommended dose of 5 mg once daily. The following adverse reactions were reported with an incidence of 1% or greater (common: ≥ 1/100 to < 1/10) during treatment with levocetirizine 5 mg or placebo:

Uncommon (≥ 1/1000, < 1/100): asthenia and abdominal pain have also been reported.

The frequency of sedative adverse reactions such as somnolence, fatigue, and asthenia was generally higher with levocetirizine 5 mg (8.1%) compared to placebo (3.1%).

Paediatric population

In two placebo-controlled studies involving paediatric patients aged 6 to 11 months and aged 1 to 6 years, 159 subjects received levocetirizine 1.25 mg once daily for 2 weeks and 1.25 mg twice daily, respectively. The incidence of adverse reactions with levocetirizine or placebo was 1% or higher.

Double-blind, placebo-controlled studies were conducted involving children aged 6 to 12 years, in which 243 children received 5 mg of levocetirizine daily for various durations ranging from less than 1 week to 13 weeks. The adverse reactions listed below were reported with an incidence of 1% or higher during treatment with levocetirizine or placebo.

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

During the post-marketing period, the following adverse reactions have also been reported. Adverse reactions are listed by system organ classes according to MedDRA and by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Immune system disorders:

Frequency not known – hypersensitivity, including anaphylaxis.

Metabolism and nutrition disorders:

Frequency not known – increased appetite.

Psychiatric disorders:

Frequency not known – aggression, agitation, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

Nervous system disorders:

Frequency not known – seizures, paraesthesia, dizziness, somnolence, tremor, dysgeusia.

Ear and labyrinth disorders:

Frequency not known – vertigo.

Eye disorders:

Frequency not known – visual disturbance, blurred vision, nystagmus.

Cardiac disorders:

Frequency not known – palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders:

Frequency not known – dyspnoea.

Gastrointestinal disorders:

Frequency not known – diarrhoea, vomiting, nausea.

Hepatobiliary disorders:

Frequency not known – hepatitis.

Renal and urinary disorders:

Frequency not known – dysuria, urinary retention.

Skin and subcutaneous tissue disorders:

Frequency not known – angioedema, fixed drug eruption, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders:

Frequency not known – myalgia, arthralgia.

General disorders and administration site conditions:

Frequency not known – swelling.

Investigations: frequency not known – weight increased, abnormal liver function tests.

Description of selected adverse reactions

Pruritus after discontinuation of levocetirizine has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or 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 bottle, the medicinal product can be used for up to 3 months.

Storage conditions

Store at temperatures not exceeding 25 ºC in a place inaccessible to children.

Packaging

20 ml in a bottle, 1 bottle in a cardboard box.

Pharmaceutical category

Over-the-counter.

Manufacturer

UORLД MEDICINE ILAC SAN. VE TIC. A.Ш./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of manufacturing site

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.