Included as part of the PRECAUTIONS section.

Activities Requiring Mental Alertness

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with XYZAL. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of XYZAL. Concurrent use of XYZAL with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

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 XYZAL 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).

Use In Specific Populations

Pregnancy

Teratogenic Effects: Pregnancy Category B

In rats and rabbits, levocetirizine was not teratogenic at oral doses up to 200 and 120 mg/kg, respectively (approximately 320 and 390 times the maximum recommended daily oral dose in adults on a mg/m² basis). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, XYZAL should be used during pregnancy only if clearly needed.

Nursing Mothers

No peri- and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis). Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of XYZAL in nursing mothers is not recommended.

Pediatric Use

The safety and effectiveness of XYZAL in pediatric patients under 6 years of age have not been established.

The recommended dose of XYZAL for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 12 to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older [see Clinical Studies].

The recommended dose of XYZAL in patients 6 to 11 years of age for the treatment of the symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria is based on cross-study comparison of the systemic exposure of XYZAL in adults and pediatric patients and on the safety profile of XYZAL in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 to 11 years of age.

The safety of XYZAL 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo- controlled clinical trials lasting 4 and 6 weeks [see ADVERSE REACTIONS]. The effectiveness of XYZAL 2.5 mg once daily for the treatment of the symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria in children 6 to 11 years of age is supported by the extrapolation of demonstrated efficacy of XYZAL 5 mg once daily in patients 12 years of age and older and by the pharmacokinetic comparison in adults and children.

Cross-study comparisons indicate that administration of a 5 mg dose of XYZAL to 6 - 12 year old pediatric seasonal allergic rhinitis patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of XYZAL was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded [see DOSAGE AND ADMINISTRATION; Clinical Studies; and CLINICAL PHARMACOLOGY].

Geriatric Use

Clinical studies of XYZAL for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Renal Impairment

XYZAL is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment [see CLINICAL PHARMACOLOGY].

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