FORMULATION:

Each film-coated tablet contains;

Levocetirizine hydrochloride ………… 5 mg

INDICATIONS

Allergic Rhinitis

Levocetirizine is indicated for the relief of symptoms associated with allergic rhinitis (seasonal and perennial) in adults

and children 6 years of age and older.

Chronic Idiopathic Urticaria

Levocetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in

adults and children 6 years of age and older.

DOSAGE AND ADMINISTRATION

Adults and Children 12 Years of Age and Older

The recommended dose of Levocetirizine is 5 mg once daily in the evening. Some patients may be adequately

controlled by 2.5 mg once daily in the evening.

Children 6 to 11 Years of Age

The recommended dose of Levocetirizine is 2.5 mg (1/2 tablet) once daily in the evening. The 2.5 mg dose should not be

exceeded because the systemic exposure with 5 mg is approximately twice that of adults.

Dose Adjustment for Renal and Hepatic Impairment

In adults and children 12 years of age and older with:

 Mild renal impairment (creatinine clearance [CLcr] = 50-80 mL/min): a dose of 2.5 mg once daily is recommended;

 Moderate renal impairment (CLcr = 30-50 mL/min): a dose of 2.5 mg once every other day is recommended;

 Severe renal impairment (CLcr = 10-30 mL/min): a dose of 2.5 mg twice weekly (administered once every 3-4

days) is recommended;

 End-stage renal disease patients (CLcr < 10 mL/min) and patients undergoing hemodialysis should not receive

Levocetirizine.

No dose adjustment is needed in patients with solely hepatic impairment. In patients with both hepatic impairment and

renal impairment, adjustment of the dose is recommended.

Elderly

Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see Patients with

renal impairment below).

Adult patients with 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 (CLcr) in ml/min is needed.

The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing Adjustments for Patients with Impaired Renal Function:

In pediatric 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.

Patients with 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.

UNDESIRABLE EFFECTS

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.

In therapeutic trials, the drop out 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 drug 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, <1/10) under levocetirizine 5 mg or placebo:

Dosing Adjustments for Patients with Impaired Renal Function:

Further uncommon incidences of adverse reactions (uncommon >1/1000, <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%).

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

In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following

adverse drug reactions have been reported in post-marketing experience.

Cardiac disorders:

Palpitations

Eyes disorders:

Visual disturbances

Hepatobiliary disorders:

Hepatitis

Immune system disorders:

Hypersensitivity including anaphylaxis

Respiratory, thoracic and mediastinal disorders:

Dyspnoea

Gastrointestinal disorders:

Nausea

Skin and subcutaneous tissue disorders:

Angioneurotic oedema, pruritus, rash, urticaria

Investigations:

Weight increased, abnormal liver function tests

DRUG INTERACTIONS

Drug interaction studies have been performed with racemic cetirizine.

Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline and Pseudoephedrine

Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with

antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole, and cimetidine. There was a small decrease

(~16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline

doses could have a greater effect.

Pregnancy and lactation:

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.

WARNINGS AND PRECAUTIONS

Precaution is recommended with intake of alcohol. Due to the lack of data in this population, the administration of the product to infants and toddlers aged less than 2 years is not recommended.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

INTERACTIONS WITH OTHER MEDICAMENTS

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 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.

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.

Overdosage Symptoms

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

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.

CONTRAINDICATION

The use of Levocetirizine tablet is not recommended in children aged less than 6 years.

Precaution is recommended with intake of alcohol .

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hypersensitivity to levocetirizine, to any piperazine derivative, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or any of the other excipients.

Severe renal impairment at less than 10 ml/min creatinine clearance.

PHARMACODYNAMIC PROPERTIES:

Pharmacotherapeutic group:

antihistamine for systemic use, piperazine derivative.

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.

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.

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 polleninduced

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 have been demonstrated in several double-blind, placebo controlled, clinical

trials performed in patients suffering from seasonal allergic rhinitis or perennial allergic rhinitis. Clinical experience

with 5 mg levocetirizine as a – tablet formulation is currently available for a 6-month treatment period. For chronic

urticaria and chronic allergic rhinitis, up to one year’s clinical experience is available for the racemate, and up to 18

months in patients with pruritus associated with atopic dermatitis.

A 6-month clinical study in 551 patients (incl. 276 levocetirizine-treated patients) suffering from PAR (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.

Pharmacokinetic / pharmacodynamic relationship:

5 mg levocetirizine provide a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg cetirizine.

As for cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations.

ECGs did not show relevant effects of levocetirizine on QT interval.

PHARMACOKINETIC PROPERTIES

Clinical Pharmacology

Mechanism of Action

Levocetirizine, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via inhibition

of H1 receptors. The antihistaminic activity of levocetirizine has been documented in a variety of animal and human

models. In vitro binding studies revealed that levocetirizine has an affinity for the human H1-receptor 2-fold higher than

that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively. The clinical relevance of this finding is unknown.

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 once a day 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 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%.

Preclinical safety data

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenesis studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity

studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study,

in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 16 times the maximum

recommended daily oral dose in adults and approximately 20 times the maximum recommended daily oral dose in

children on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign

hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 7 times the maximum recommended daily oral

dose in adults and approximately 8 times the maximum recommended daily oral dose in children on a mg/m2 basis). No

increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum

recommended daily oral dose in adults and children on a mg/m2 basis). The clinical significance of these findings during

long-term use of Levocetirizine is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse

lymphoma assay, and in vivo micronucleus test in mice.

In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64

mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m² basis).