Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria

Precaution is recommended with intake of alcohol (see Interactions).

The presence of methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

Xyzal contains maltitol: Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Even if some clinical data are available in children aged 6 months to 12 years (see section 4.8, 5.1 and 5.2), these data are not sufficient to support the administration of levocetirizine to infants and toddlers aged less than 2 years

No interaction studies have been performed with Levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide and diazepam). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration.

In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.

The extent of absorption of Levocetirizine is not reduced with food, although the rate of absorption is decreased.

In sensitive patients the simultaneous administration of cetirizine or Levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system, although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol

For Levocetirizine no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant or lactating women.

Comparative clinical trials have revealed no evidence that Levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive.

Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with Levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account

To reports any side effect (s):

a) Symptoms

Symptoms of overdose may include drowsiness in adults and initially agitation and restlessness, followed by drowsiness in children.

b) Management of overdoses

There is no known specific antidote to Levocetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following short-term ingestion. Levocetirizine is not effectively removed by haemodialysis

Pharmacotherapeutic group: antihistamine for systemic use, piperazine derivative.

ATC code: R06A E09.

Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.

Binding studies revealed that Levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 min.

After single administration, Levocetirizine shows a receptor occupancy of 90% at 4 hours and 57% at 24 hours.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, Levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.

The pharmacodynamic activity of Levocetirizine has been studied in randomised, controlled trials:

In a study comparing the effects of Levocetirizine 5mg, desloratadine 5mg, and placebo on histamine-induced wheal and flare, Levocetirizine treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.

The onset of action of Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that Levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed three main inhibitory effects of Levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in eosinophil recruitment.

The efficacy and safety of Levocetirizine has been demonstrated in several double-blind, placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic rhinitis, perennial allergic rhinitis, or persistent allergic rhinitis. Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis, including nasal obstruction in some studies.

A 6-month clinical study in 551 adult patients (including 276 Levocetirizine-treated patients) suffering from persistent allergic rhinitis (symptoms present 4 days a week for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen demonstrated that Levocetirizine 5 mg was clinically and statistically significantly more potent than placebo on the relief from the total symptom score of allergic rhinitis throughout the whole duration of the study, without any tachyphylaxis. During the whole duration of the study, Levocetirizine significantly improved the quality of life of the patients.

The paediatric safety and efficacy of Levocetirizine tablets has been studied in two placebo controlled clinical trials including patients aged 6 to 12 years and suffering from seasonal and perennial allergic rhinitis, respectively. In both trials, Levocetirizine significantly improved symptoms and increased health-related quality of life.

In children below the age of 6 years, clinical safety has been established from several short- or long -term therapeutic studies:

- one clinical trial in which 29 children 2 to 6 years of age with allergic rhinitis were treated with Levocetirizine 1.25 mg twice daily for 4 weeks

- one clinical trial in which 114 children 1 to 5 years of age with allergic rhinitis or chronic idiopathic urticaria were treated with Levocetirizine 1.25 mg twice daily for 2 weeks

- one clinical trial in which 45 children 6 to 11 months of age with allergic rhinitis or chronic idiopathic urticaria were treated with Levocetirizine 1.25 mg once daily for 2 weeks

- one long-term (18 months) clinical trial in 255 Levocetirizine - treated atopic subjects aged 12 to 24 months at inclusion.

The safety profile was similar to that seen in the short-term studies conducted in children 1 to 5 years of age.

In a placebo-controlled clinical trial including 166 patients suffering from chronic idiopathic urticaria, 85 patients were treated with placebo and 81 patients with Levocetirizine 5mg once daily over six weeks. Treatment with Levocetirizine resulted in significant decrease in pruritus severity over the first week and over the total treatment period as compared to placebo. Levocetirizine also resulted in a larger improvement of health-related quality of life as assessed by the Dermatology Life Quality Index as compared to placebo.

Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, Levocetirizine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria.

Pharmacokinetic / pharmacodynamic relationship:

The action on histamine-induced skin reactions is out of phase with the plasma concentrations.

ECGs did not show relevant effects of Levocetirizine on QT interval

The pharmacokinetics of Levocetirizine are linear with dose- and time-independent with low inter-subject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption:

Levocetirizine is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution:

No tissue distribution data are available in humans, neither concerning the passage of Levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment.

In humans, Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.

Biotransformation:

The extent of metabolism of Levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.

Due to its low metabolism and absence of metabolic inhibition potential, the interaction of Levocetirizine with other substances, or vice-versa, is unlikely.

Elimination:

The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children.

The mean apparent total body clearance in adults is 0.63 ml/min/kg. The major route of excretion of Levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

Renal impairment:

The apparent body clearance of Levocetirizine is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of Levocetirizine, based on creatinine clearance in patients with moderate and severe renal impairment. In anuric end stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects. The amount of Levocetirizine removed during a standard 4-hour hemodialysis procedure was < 10%.

Paediatric population:

Data from a paediatric pharmacokinetic study with oral administration of a single dose of 5 mg Levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this paediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in paediatric patients younger than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years of age is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.

Geriatric Patients:

Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg Levocetirizine for 6 days in 9 elderly subjects (65–74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for Levocetirizine, as Levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the Levocetirizine dose should be adjusted in accordance with renal function in elderly patients.

Gender:

Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

Race:

The effect of race on Levocetirizine has not been studied. As Levocetirizine is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of Levocetirizine are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Hepatic impairment:

The pharmacokinetics of Levocetirizine in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in half life along with a 40% decrease in clearance compared to healthy subjects

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity

Sorbitol liquid 70 %, Glycerol, Propylene Glycol, Methyl Paraben, Propyl Paraben, Sodium Acetate, Peach Flavor, water.

Not applicable

Store below 30°C

Do not use Layal after the bottle has been opened for more than 1 month.

Amber glass bottle with screw cap each packed in A printed carton with a folded pack insert

No special requirements.

Do not use if cap seal is broken