COMPOSITION
Each film coated tablet contains:
Levocetirizine dihydrochloride ………… 5 mg
Other ingredients:
Microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, opadry II 85G51300 green & purified water.
DESCRIPTION
Green colored, film coated, round, biconvex tablets plain on both side.

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:

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

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.

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.

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.
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.

OVERDOSE AND TREATMENT
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.
CONTRAINDICATIONS
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.
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.
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 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 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.
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 an mg/m² basis).
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.
PHARMACOKINETIC PROPERTIES
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 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%.

STORAGE CONDITION:
Store below 30°C.
Keep all medicines out of reach of children.
SHELF LIFE:
24 months
DOSAGE FORMS AND PACKAGING AVAILABLE:
Alu-Alu blister of 10 tablets, 3 or 10 blisters are packed in a carton.
NAME AND ADDRESS OF MANUFACTURER
Kusum Healthcare Pvt. Ltd.
SP 289(A), RIICO Indl. Area,
Chopanki, Bhiwadi (Rajasthan), India
DATE OF REVISION OF PACKAGE INSERT:
Not Applicable
MM Reg. No.: 1709AA 4709