Composition:

Each film-coated tablet contains 5 mg of Levocetirizine Dihydrochloride.

Additional ingredients:

Microcrystalline cellulose, Croscarmellose sodium,Colloidal

anhydrous silica, Magnesium Stearate, Purified water.

Tablet coating:

Opadry II 85G51300 Green

Indications:

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

Administration & Dosage:

The film-coated tablet must be taken orally, swallowed whole with liquid and may be taken

with or without food. It is recommended to take the daily dose in one single intake.

Adults and adolescents 12 years and above:

The daily recommended dose is 5 mg (1 film-coated tablet).

Elderly:

Adjustment of the dose is recommended in elderly patients with moderate to severe renal

impairment (see Patients with renal impairment below).

Children aged 6 to 12 years:

The daily recommended dose is 5 mg (1 film-coated tablet).

For children aged 2 to 6 years no adjusted dosage is possible with the film-coated tablet

formulation. It is recommended to use a paediatric formulation of levocetirizine.

Patients with renal impairment:

The dosing intervals must be individualized 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:

Group Creatinine clearance (ml/min) Dosage and frequency

table

table

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%).

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.

> Immune system disorders:

Hypersensitivity including anaphylaxis

> Psychiatric disorders:

Aggression, agitation

> Nervous system disorders:

Convulsion

> Eyes disorders:

Visual disturbances

> Cardiac disorders:

Palpitations

> Respiratory, thoracic, and mediastinal disorders:

Dyspnoea

> Gastrointestinal disorders:

Nausea

> Hepatobiliary disorders:

Hepatitis

> Skin and subcutaneous tissue disorders:

Angioneurotic oedema, fixed drug eruption,

pruritus, rash, urticaria

> Musculoskeletal, connective tissues, and bone disorders:

Myalgia

> Investigations:

Weight increased, abnormal liver function tests

Adverse Drug Reaction

“Inform doctors about unexpected reactions after using drug.”

Drug Interactions:

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 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.

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.

Precautions in use:

The use of the film-coated tablet formulation is not recommended in children aged less than 6

years since this formulation does not allow for appropriate dose adaptation. It is

recommended to use a paediatric formulation of levocetirizine.

The administration of levocetirizine to infants and toddlers aged less than 2 years is not

recommended.

Precaution is recommended with intake of alcohol.

Contraindication:

Hypersensitivity to levocetirizine, to other piperazine derivatives, or to any of the excipients.

Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

Overdosage:

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.

Pharmaceutical Form: Film-coated tablet.

Pharmacotherapeutic group: Antihistamine for systemic use.

Pharmacological properties:

Pharmacodynamic: 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 dura

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:

Mechanism of Action: Levocetirizine, the active enantiomer of cetirizine, is an antihistamine;

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 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%.

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.

Storage

Store below 30°C.

Shelf life

2 years

Packing

Levocetrizine dihydrochloride film coated tablets are supplied in PVC/PVDC Blister pack of

10’s and 3 such blisters (3 x 10 Tablets) are packed in a carton along with pack insert.

Manufacturer

Kusum Healthcare Private Limited

Address

SP 289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, India