Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and urticaria in adults
and children aged 2 years and above.

Posology

Adults and adolescents 12 years and above:

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

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Renal impairment below).

Renal impairment

The dosing intervals must be individualised according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CL_cr) in ml/min is needed. The CL_cr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing adjustments for patients with impaired renal function:

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient and his body weight. There are no specific data for children with renal impairment.

Hepatic impairment

No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic impairment and renal impairment, adjustment of the dose is recommended (see Renal impairment above).

Paediatric population

Children aged 6 to 12 years:

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

Children aged 2 to 6 years:

The daily recommended dose is 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 ml of solution twice daily).

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 (see also section 4.4).

Method of administration

An oral syringe is included in the package. The appropriate volume of oral solution should be measured with the oral syringe, and poured in a spoon or in a glass of water. The oral solution must be taken orally immediately after dilution, and may be taken with or without food.

Duration of use:

Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less than four weeks a year) has to be treated according to the disease and its history; it can be stopped once the symptoms have disappeared and can be restarted again when symptoms reappear. In case of persistent allergic rhinitis (symptoms experienced for more than four days a week or for more than four weeks a year), continuous therapy can be proposed to the patient during the period of exposure to allergens.

There is clinical experience with the use of levocetirizine for treatment periods of at least 6 months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of use of cetirizine (racemate) for up to one year.

Precaution is recommended with concurrent intake of alcohol (see section 4.5).
Levozal contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause
allergic reactions (possibly delayed).
Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine
may cause seizure aggravation.
Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Caution should be taken in patients with predisposing factors of urinary retention (e.g. spinal cord
lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is
required before performing them.
Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before
treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be
intense and may require treatment to be restarted. The symptoms should resolve when the treatment is
restarted.
Paediatric population
Even if some clinical data are available in children aged 6 months to 12 years (see sections 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, azithromycin, cimetidine, diazepam, erythromycin,
glipizide, ketoconazole and pseudoephedrine). 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 concurrent administration of cetirizine or levocetirizine and alcohol or other
CNS depressants may cause additional reductions in alertness and impairment of performance.

Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of
levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large
amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or
feto/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to
pregnancy, embryo/fetal development, parturition or postnatal development (see section 5.3).
The use of levocetirizine may be considered during pregnancy, if necessary.
Breast-feeding
Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human. Therefore, the
excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine
may be observed in breastfed infants. Therefore, caution should be exercised when prescribing
levocetirizine to lactating women.
Fertility
For levocetirizine no clinical data are available.

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.

Clinical studies

Adults and adolescents above 12 years of age

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

In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mg and 1.8% (14/771) with placebo.

Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1% or greater (common: ≥ 1/100 to < 1/10) under levocetirizine 5 mg or placebo:

Further uncommon incidences of adverse reactions (uncommon ≥ 1/1000 to < 1/100) like asthenia or abdominal pain were observed.

The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than under placebo (3.1%).

Paediatric population

In two placebo-controlled studies in paediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for 2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5 mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo.

As stated in sections 4.2 and 4.4, please note that even if clinical data presented in this section are available in children aged 6 months to 12 years, we do not have sufficient data to support the administration of the product to infants and toddlers aged less than 2 years.

Post-marketing experience

Adverse reactions from post-marketing experience are per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

• Immune system disorders:

Not known: hypersensitivity including anaphylaxis

• Metabolism and nutrition disorders:

Not known: increased appetite

• Psychiatric disorders:

Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare

• Nervous system disorders:

Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia

• Ear and labyrinth disorders:

Not known: vertigo

• Eyes disorders:

Not known: visual disturbances, blurred vision, oculogyration

• Cardiac disorders:

Not known: palpitations, tachycardia

• Respiratory, thoracic and mediastinal disorders:

Not known: dyspnoea

• Gastrointestinal disorders:

Not known: nausea, vomiting, diarrhoea

• Hepatobiliary disorders:

Not known: hepatitis

• Renal and urinary disorders:

Not known: dysuria, urinary retention

• Skin and subcutaneous tissue disorders:

Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria

• Musculoskeletal, connective tissues, and bone disorders:

Not known: myalgia, arthralgia

• General disorders and administration site conditions:

Not known: oedema

• Investigations:

Not known: weight increased, abnormal liver function tests

Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions (possibly delayed).

Description of selected adverse reactions

After levocetirizine discontinuation, pruritus has been reported.

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

Symptoms
Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may
initially occur, followed by drowsiness.
Management of overdoses
There is no known specific antidote to levocetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage may be
considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by
haemodialysis.

Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives,
ATC code: R06A E09.
Mechanism of action
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.
Pharmacodynamic effects
The pharmacodynamic activity of levocetirizine has been studied in randomised, controlled trials:
In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, and placebo on histamineinduced
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 eotaxininduced
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.
Clinical efficacy and safety
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.
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 5 mg 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.
ECGs did not show relevant effects of levocetirizine on QT interval.
Paediatric population
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.
 

The pharmacokinetics of levocetirizine are linear with dose- and time-independent with low intersubject
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.
Special population
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, weightnormalized,
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 323 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.
Elderly
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 hours) than in men (8.62 ± 1.84
hours); 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.
Pharmacokinetic / pharmacodynamic relationship
The action on histamine-induced skin reactions is out of phase with the plasma concentrations.

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

Sodium acetate
Glycerol
Sorbitol
Methylparaben
Propylparaben
Saccharin sodium
Strawberry flavor
Glacial acetic acid
Purified water

Not applicable.

Do not store above 30°C.

Clear, amber color glass bottle type III with rounded shoulder and smooth surface
Pack sizes: 100 ml, 150 ml and 200 ml.
Not all pack sizes may be marketed.

No special requirements.