Full Prescribing Info
Contents
Levocetirizine diHCl.
Action
Pharmacotherapeutic Group: Antiallergic Agent.
Pharmacology: Pharmacodynamics: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective peripheral H1-receptor antagonist.
Binding studies revealed that levocetirizine has high affinity for human H1-receptors (Ki=3.2 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 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 3 main inhibitory effects of levocetirizine 5 mg in the 1st 6 hrs of pollen-induced reaction, compared with placebo in 14 adult patients: Inhibition of vascular cell adhesion molecule-1 (VCAM-1) release, modulation of vascular permeability and a decrease in eosinophil recruitment.
Pharmacokinetic/Pharmacodynamic Relationship: Levocetirizine 5 mg provide a similar pattern of inhibition of histamine-induced wheal and flare than cetirizine 10 mg. As for cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations.
Electrocardiograms (ECGs) did not show relevant effects of levocetirizine on QT interval.
Pharmacokinetics: The pharmacokinetics of levocetirizine is 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. Peak plasma concentrations are achieved 0.9 hr after dosing. Steady state is achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5-mg once daily 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. 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 <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 CYP3A4 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 hrs. The mean apparent total body clearance 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-hr hemodialysis procedure was <10%.
Indications/Uses
Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and chronic idiopathic urticaria.
Dosage/Direction for Use
Adults and Children ≥6 years: Recommended Daily Dose: 5 mg (1 FC tab). Children <6 years: No adjusted dosage is yet possible.
Elderly: Adjustment of the dose is recommended in elderly patients with moderate to severe renal impairment (see text on Renal Impairment as follows).
Renal Impairment: The dosing intervals must be individualized according to renal function. Refer to Table 1 and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CrCl) in mL/min is needed. The CrCl (mL/min) may be estimated from serum creatinine (mg/dL) determination using the following formula:


Click on icon to see table/diagram/image




Click on icon to see table/diagram/image


Hepatic Impairment: No dose adjustment is needed in patients with solely hepatic impairment. In patients with hepatic and renal impairment, adjustment of the dose is recommended (see previously mentioned text on Renal Impairment).
Duration of Use: The duration of use depends on the type, duration and course of the complaints. For hay fever 3-6 weeks, and in case of short-term pollen exposure as little as 1 week, is generally sufficient.
Clinical experience with levocetirizine 5 mg as a FC tablet formulation is currently available for a 6-month treatment period. For chronic urticaria and chronic allergic rhinitis, up to 1 year's clinical experience is available for the racemate, and up to 18 months in patients with pruritus associated with atopic dermatitis.
Administration: Xyzal 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 1 single intake.
Overdosage
Symptoms: Adults: Drowsiness.
Children: Initially, agitation and restlessness followed by drowsiness.
Treatment: 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
History of hypersensitivity to levocetirizine or to any of the other components of Xyzal, or to any piperazine derivatives.
Patients with severe renal impairment at CrCl <10 mL/min creatinine clearance.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Xyzal.
Special Precautions
The use of Xyzal is not recommended in children <6 years since the currently available FC tablets does not allow dose adaption yet.
Precaution is recommended with intake of alcohol (see Interactions).
Effects on the Ability to Drive or Operate Machinery: 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 Xyzal. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to Xyzal into account.
Use in pregnancy & 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.
Use In Pregnancy & 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.
Adverse Reactions
Therapeutic studies in women and men 12-71 years showed that 15.1% of the patients in the levocetirizine 5 mg group had at least 1 adverse drug reaction compared to 11.3% in the placebo group; 91.6% of these adverse drug reaction were mild to moderate. In therapeutic trials, the drop-out rate due to adverse events was 1% (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 daily dose of 5 mg.
From this pooling, the following incidence of adverse drug reactions were reported at rates of ≥1% (Common: >1/100, <1/10) under levocetirizine 5 mg or placebo: (See Table 2.)


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Further uncommon incidence of adverse reaction (Uncommon >1/1000, <1/100) eg, asthenia or abdominal pain were observed. The incidence of sedating adverse drug reactions eg, somnolence, fatigue and asthenia was altogether more common (8.1%) under levocetirizine 5 mg than after 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.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea.
Gastrointestinal Disorders: Nausea.
Skin and Subcutaneous Tissue Disorders: Angioneurotic oedema, pruritus, rash, urticaria.
Investigations: Increased weight.
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 daily), while the disposition of theophylline was not altered by concomitant cetirizine administration.
The extent of levocetirizine absorption 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.
Incompatibilities: None known.
Storage
Do not store above 30°C.
ATC Classification
R06AE09 - levocetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.
Presentation/Packing
FC tab 5 mg x 5 x 10's.
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