Use of XYZAL has been associated with somnolence, fatigue, and asthenia [see WARNINGS and PRECAUTIONS].

Clinical Trials Experience

The safety data described below reflect exposure to XYZAL in 2549 patients with seasonal or perennial allergic rhinitis and chronic idiopathic urticaria in 12 controlled clinical trials of 1 week to 6 months duration. The short-term (exposure up to 6 weeks) safety data for adults and adolescents are based upon eight clinical trials in which 1896 patients (825 males and 1071 females aged 12 years and older) were treated with XYZAL 2.5, 5, or 10 mg once daily in the evening. The short- term safety data from pediatric patients are based upon two clinical trials in which 243 children with seasonal or perennial allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with XYZAL 5 mg once daily for 4 to 6 weeks. The long-term (exposure of 4 or 6 months) safety data are based upon two clinical trials in adults and adolescents in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with XYZAL 5 mg once daily. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Adults and Adolescents 12 years of Age and Older

In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian.

In these trials 43% and 42% of the subjects in the XYZAL 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.

In placebo-controlled trials of 1-6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with XYZAL showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).

Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to XYZAL 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with XYZAL than placebo.

Table 1: Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to XYZAL 2.5 mg or 5 mg in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration

Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to XYZAL are syncope (0.2%) and weight increased (0.5%).

Pediatric Patients 6 to 12 Years of Age

A total of 243 pediatric patients 6 to 12 years of age received XYZAL 5 mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were between 6-8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6-12 years exposed to XYZAL 5 mg in placebo-controlled clinical trials and that were more common with XYZAL than placebo.

The safety of XYZAL in children under 6 years of age has not been established [see Use in Specific Populations].

Table 2: Adverse Reactions in Subjects Aged 6-12 Years Reported in ≥2%* for XYZAL 5 mg in Placebo- Controlled Clinical Trials 4 and 6 Weeks in Duration

Long-Term Clinical Trials Experience

In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with XYZAL 5 mg once daily for 4 or 6 months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with XYZAL discontinued because of somnolence, fatigue or asthenia compared to 2 (<1%) in the placebo group.

Laboratory Test Abnormalities

Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, adverse events have also been identified during post-approval use of XYZAL in other countries. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse events of hypersensitivity and anaphylaxis, angioneurotic edema, fixed drug eruption, pruritus, rash, and urticaria, convulsion, aggression and agitation, visual disturbances, palpitations, dyspnea, nausea, hepatitis, and myalgia have been reported.

Besides these events reported under treatment with XYZAL, other potentially severe adverse events have been reported from the post-marketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with XYZAL: hallucinations, suicidal ideation, orofacial dyskinesia, severe hypotension, cholestasis, glomerulonephritis, and still birth.

In vitro data indicate that levocetirizine is unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in vivo drug- drug interaction studies have been performed with levocetirizine. 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.

Ritonavir

Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

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