General Information

The active component of Xyzal, Levocetirizine dihydrochloride, is an antihistamine. It is an orally active and selective H1-receptor antagonist. Histamines act on H1 receptors, causing the symptoms commonly seen in allergic reactions. Xyzal inhibits these H1 receptors.

Xyzal is specifically indicated for the relief of symptoms associated with allergic rhinitis (seasonal and perennial) in adults and children 6 years of age and older. Xyzal is also indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older.

Mechanism of Action

The active component of Xyzal, Levocetirizine dihydrochloride, is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. It is an orally active and selective H1-receptor antagonist. Histamines act on H1 receptors, causing the symptoms commonly seen in allergic reactions. Xyzal inhibits these H1 receptors.

Side Effects

Adverse events associated with the use of Xyzal in adult and pediatric subjects ages 12 years and older may include, but are not limited to, the following:

• Somnolence
• Nasopharyngitis
• Fatigue
• Dry mouth
• Pharyngitis

Adverse events associated with the use of Xyzal in pediatric subjects ages 6 to 12 years may include, but are not limited to, the following:

• Pyrexia
• Cough
• Somnolence
• Epistaxis

Dosing/Administration

Xyzal is supplied as a 5-mg tablet designed for oral administration. The recommended initial dose of Xyzal in adults and children ages 12 years and older is 5 mg once daily in the evening. Some patients may be adequately controlled by 2.5 mg once daily in the evening. The recommended initial dose of Xyzal in children 6 to 11 years old is 2.5 mg (1/2 tablet) once daily in the evening. The 2.5-mg dose should not be exceeded because the systemic exposure with 5 mg is approximately twice that of adults.

Clinical Trial Results

FDA Approval
FDA approval of Xyzal was based on the results of several clinical trials.

Seasonal and Perennial Allergic Rhinitis
Adults and Adolescents 12 Years of Age and Older
FDA approval was based on the results of six randomized, placebo-controlled, double-blind clinical trials in adult and adolescent patients 12 years and older with symptoms of seasonal allergic rhinitis or perennial allergic rhinitis. Three of these were dose-ranging trials of two to four weeks duration, one was a two-week efficacy trial in patients with seasonal allergic rhinitis and two were efficacy trials (one six-week and one six-month) in patients with perennial allergic rhinitis. The trials enrolled a total of 2,412 subjects. Efficacy was assessed using a total symptom score from patient recording of four symptoms (sneezing, rhinorrhea, nasal pruritus and ocular pruritus) in five studies and five symptoms (sneezing, rhinorrhea, nasal pruritus, ocular pruritus and nasal congestion) in one study. Symptoms were recorded using a 0 (absent) to 3 (severe) categorical scale once daily in the evening, reflective of the 24-hour treatment period. The primary end point was the mean total symptom score averaged over the first week and over two weeks for seasonal allergic rhinitis trials, and four weeks for perennial allergic rhinitis trials.

The three dose ranging trials were conducted to evaluate the efficacy of Xyzal 2.5, 5, and 10 mg once daily in the evening. The seasonal allergic rhinitis trial was two weeks in duration and two trials were for perennial allergic rhinitis and were four weeks in duration. In these trials, each of the three doses of Xyzal demonstrated greater decrease in the reflective total symptom score than placebo and the difference was statistically significant for all three doses in two of the studies (p=<0.001).

The two-week efficacy trial was designed to evaluate the efficacy of Xyzal 5 mg once daily in the evening compared with placebo in subjects with seasonal allergic rhinitis. Xyzal demonstrated a greater decrease from baseline in the reflective and instantaneous total symptom score than placebo, and the difference was statistically significant (p=0.011).

The six-week trial was designed to compare the efficacy of Xyzal 5 mg once daily in the evening compared to placebo in patients with perennial allergic rhinitis. The six-month trial was designed to compare efficacy over a six-month treatment duration. Xyzal 5 mg demonstrated a greater decrease from baseline in the reflective total symptom score than placebo and the difference from placebo was statistically significant.

Pediatric Patients Ages 6 to 11 Years
No clinical trials were conducted with Xyzal 2.5 mg once daily in pediatric subjects 6 to 11 years of age. Recommended dose was based on cross-study comparison of the systemic exposure of Xyzal in adults and pediatric subjects and on the safety profile of Xyzal in both adult and pediatric subjects at doses equal to or higher than the recommended dose for subjects 6 to 11 years. The safety of Xyzal 5 mg once daily was evaluated in 243 pediatric subjects 6 to 12 years of age in two placebo-controlled clinical trials lasting four and six weeks. 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 pediatrics 6 to 11 years of age is supported by the extrapolation of demonstrated efficacy of Xyzal 5 mg once daily in subjects 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– to 12-year-old pediatric seasonal allergic rhinitis subjects resulted in about twofold the systemic exposure (AUC) observed when 5 mg of XYZAL was administered to healthy adult subjects.

Chronic Idiopathic Urticaria
Adult Patients 18 Years of Age and Older
FDA approval for Xyzal in the treatment of urticaria was based on the results of two multicenter, randomized, placebo-controlled, double-blind clinical trials. The two trials enrolled 423 subjects ages 18 to 85 years. The trials included one four-week dose ranging trial and one four-week single-dose level trial. Of the 423 subjects, 146 received Xyzal 5 mg once daily in the evening. Efficacy was based on the recording of pruritus severity on a severity score of 0 (absent) to 3 (severe). The primary efficacy end point was the mean reflective pruritus severity score over the first week and over the entire treatment period. Additional efficacy end points included instantaneous pruritus severity score, the number and size of wheals and duration of pruritus.

The dose-ranging trial was conducted to evaluate Xyzal 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of Xyzal demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (p=<0.001).

The single-dose trial evaluated the efficacy of Xyzal 5 mg once daily in the evening compared to placebo in subjects with chronic idiopathic urticaria over a four-week treatment period. Xyzal 5 mg demonstrated a greater decrease from baseline in the reflective pruritus severity score than placebo and the difference from placebo was statistically significant (p=<0.001). The secondary end points also showed significant improvement over placebo.

Pediatric Patients
No clinical trials were conducted in pediatric subjects with chronic idiopathic urticaria. However, as stated above, safety and efficacy data were extrapolated from cross-comparison studies.

Ongoing Study Commitments

• UCB has agreed to a deferred pediatric study under PREA for the treatment of symptoms of perennial allergic rhinitis in pediatric patients ages 0 to <6 years of age.
  Final report submission: May 31, 2009
• UCB has agreed to a deferred pediatric study under PREA for the treatment of symptoms of seasonal allergic rhinitis in pediatric patients ages 2 to <6 years of age.
  Final report submission: May 31, 2009
• UCB has agreed to a deferred pediatric study under PREA for the treatment of chronic idiopathic urticaria in pediatric patients ages 0 to <6 years of age.
  Final report submission: May 31, 2009