LEVOCETIRIZINE DIHYDROCHLORIDE: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies is 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 40, 40, 25, and 10 times the MRHDs in adults, children 6 to 11 years of age, children 2-5 years, and children 6 months to 2 years of age, respectively, 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 15, 15, 9, and 5 times the MRHDs in adults, children 6 to 11 years of age, children 2-5 years, and children 6 months to 2 years of age, respectively, on a mg/m2 basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 4, 4, 2, and 1 times the MRHDs in adults, children 6 to 11 years of age, children 2-5 years, and children 6 months to 2 years of age, respectively on a mg/m2 basis). The clinical significance of these findings during long-term use of levocetirizine 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.

Fertility and reproductive performance were unaffected in male and female mice and rats that received cetirizine at oral doses up to 64 and 200 mg/kg/day, respectively (approximately 60 and 390 times the MRHD in adults on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Perennial Allergic Rhinitis

Adults and Adolescents 12 Years of Age and Older
The efficacy of levocetirizine dihydrochloride tablet was evaluated in four randomized, placebo-controlled, double-blind clinical trials in adult and adolescent patients 12 years and older with symptoms of perennial allergic rhinitis. The four clinical trials include two dose-ranging trials of 4 weeks duration and two efficacy trials (one 6-week and one 6-month) in patients with perennial allergic rhinitis.

These trials included a total of 1729 patients (752 males and 977 females) of whom 227 were adolescents 12 to 17 years of age. Efficacy was assessed using a total symptom score from patient recording of 4 symptoms (sneezing, rhinorrhea, nasal pruritus, and ocular pruritus) in three studies and 5 symptoms (sneezing, rhinorrhea, nasal pruritus, ocular pruritus, and nasal congestion) in one study. Patients recorded symptoms using a 0-3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) once daily in the evening reflective of the 24 hour treatment period. The primary endpoint was the mean total symptom score averaged over the first week and over 4 weeks for perennial allergic rhinitis trials.

The two dose-ranging trials were conducted to evaluate the efficacy of levocetirizine dihydrochloride tablet 2.5, 5, and 10 mg once daily in the evening. These trials were 4 weeks in duration and included patients with perennial allergic rhinitis. In these trials, each of the three doses of levocetirizine dihydrochloride tablet demonstrated greater decrease in the reflective total symptom score than placebo and the difference was statistically significant for all three doses in the two studies. Results for one of these trials are shown in Table 4.Table 4: Mean Reflective Total Symptom Score* in Allergic Rhinitis Dose-Ranging Trials

Treatment

N

Base- line

On Treatment Adjusted Mean

Difference from Placebo

Esti- mate

95% CI

p-value

Perennial Allergic Rhinitis Trial – Reflective total symptom score

Levocetirizine Dihydrochloride 2.5 mg

133

7.14

4.12

1.17

(0.71, 1.63)

<0.001

Levocetirizine Dihydrochloride 5 mg

127

7.18

4.07

1.22

(0.76, 1.69)

<0.001

Levocetirizine Dihydrochloride 10 mg

129

7.58

4.19

1.10

(0.64, 1.57)

<0.001

Placebo

128

7.22

5.29

*Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0-3 categorical severity scale.
One clinical trial evaluated the efficacy of levocetirizine dihydrochloride 5 mg once daily in the evening compared to placebo in patients with perennial allergic rhinitis over a 6-week treatment period. Another trial conducted over a 6-month treatment period assessed efficacy at 4 weeks. Levocetirizine dihydrochloride 5 mg demonstrated a greater decrease from baseline in the reflective total symptom score than placebo and the difference from placebo was statistically significant. Results of the former are shown in Table 5.Table 5: Mean Reflective Total Symptom Score* in Allergic Rhinitis Trial

Treatment

N

Baseline

On Treatment Adjusted Mean

Difference from Placebo

Estimate

95% CI

p-value

Perennial Allergic Rhinitis Trial – Reflective total symptom score

Levocetirizine Dihydrochloride 5 mg

150

7.69

3.93

1.17

(0.70, 1.64)

<0.001

Placebo

142

7.44

5.10

*Total symptom score is the sum of individual symptoms of sneezing, rhinorrhea, nasal pruritus, and ocular pruritus as assessed by patients on a 0-3 categorical severity scale.
Onset of action was evaluated in two environmental exposure unit studies in allergic rhinitis patients with a single dose of levocetirizine dihydrochloride 2.5 or 5 mg. Levocetirizine dihydrochloride 5 mg was found to have an onset of action 1 hour after oral intake. Onset of action was also assessed from the daily recording of symptoms in the evening before dosing in the allergic rhinitis trials. In these trials, onset of effect was seen after 1 day of dosing.
Pediatric Patients Less than 12 Years of Age
There are no clinical efficacy trials with levocetirizine dihydrochloride 2.5 mg once daily in pediatric patients under 12 years of age, and no clinical efficacy trials with levocetirizine dihydrochloride 1.25 mg once daily in pediatric patients 6 months to 5 years of age. The clinical efficacy of levocetirizine dihydrochloride in pediatric patients under 12 years of age has been extrapolated from adult clinical efficacy trials based on pharmacokinetic comparisons [see Use in Specific Populations (8.4)].

14.2 Chronic Idiopathic Urticaria

Adult Patients 18 Years of Age and Older
The efficacy of levocetirizine dihydrochloride for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria was evaluated in two multi-center, randomized, placebo-controlled, double-blind clinical trials of 4 weeks duration in adult patients 18 to 85 years of age with chronic idiopathic urticaria. The two trials included one 4-week dose-ranging trial and one 4-week single-dose level efficacy trial. These trials included 423 patients (139 males and 284 females). Most patients (>90%) were Caucasian and the mean age was 41. Of these patients, 146 received levocetirizine dihydrochloride 5 mg once daily in the evening. Efficacy was assessed based on patient recording of pruritus severity on a severity score of 0–3 (0 = none to 3 = severe). The primary efficacy endpoint was the mean reflective pruritus severity score over the first week and over the entire treatment period. Additional efficacy variables were the instantaneous pruritus severity score, the number and size of wheals, and duration of pruritus.

The dose-ranging trial was conducted to evaluate the efficacy of levocetirizine dihydrochloride 2.5, 5, and 10 mg once daily in the evening. In this trial, each of the three doses of levocetirizine dihydrochloride demonstrated greater decrease in the reflective pruritus severity score than placebo and the difference was statistically significant for all three doses (see Table 6).

The single dose level trial evaluated the efficacy of levocetirizine dihydrochloride 5 mg once daily in the evening compared to placebo in patients with chronic idiopathic urticaria over a 4-week treatment period. Levocetirizine dihydrochloride 5 mg demonstrated a greater decrease from baseline in the reflective pruritus severity score than placebo and the difference from placebo was statistically significant.

Duration of pruritus, number and size of wheals, and instantaneous pruritus severity score also showed significant improvement over placebo. The significant improvement in the instantaneous pruritus severity score over placebo confirmed end of dosing interval efficacy (see Table 6).Table 6: Mean Reflective Pruritus Severity Score in Chronic Idiopathic Urticaria Trials

Treatment

N

Baseline

On Treatment Adjusted Mean

Difference from Placebo

Estimate

95% CI

p- value

Dose-Ranging Trial – Reflective pruritus severity score

Levocetirizine Dihydrochloride2.5 mg

69

2.08

1.02

0.82

(0.58, 1.06)

<0.001

Levocetirizine dihydrochloride 5 mg

62

2.07

0.92

0.91

(0.66, 1.16)

<0.001

Levocetirizine Dihydrochloride10 mg

55

2.04

0.73

1.11

(0.85, 1.37)

<0.001

Placebo

60

2.25

1.84

Chronic Idiopathic Urticaria Trial – Reflective pruritus severity score

Levocetirizinedihydrochloride 5 mg

80

2.07

0.94

0.62

(0.38,0.86)

<0.001

Placebo

82

2.06

1.56

Pediatric Patients
There are no clinical efficacy trials in pediatric patients with chronic idiopathic urticaria [see Use in Specific Populations (8.4) ].

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