Budesonide Inhalation Suspension (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.04 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). However, in the male Sprague- Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

In a 91-week study in mice, budesonide caused no treatment- related carcinogenicity at oral doses up to 200 mcg/kg (approximately equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis).

Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella / microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m 2 basis. However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above approximately 0.2 times than the MRHDID in adults on a mcg/m 2 basis. No such effects were noted at 5 mcg/kg (approximately 0.05 times the MRHDID in adults on a mcg/m 2 basis).

14 CLINICAL STUDIES

Three double-blind, placebo-controlled, parallel group, randomized U.S. clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. Doses of 0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to patients in the 3 U.S. controlled clinical trials. The co-primary endpoints were nighttime and daytime asthma symptom scores (0 to 3 scale). Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double- blind treatment period in nighttime and daytime asthma symptom scores (scale 0 to 3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization). The double-blind treatment period was defined as the mean over 12 week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U.S. studies.

Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25 mg to 0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at budesonide inhalation suspension doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily compared to placebo. Use of budesonide inhalation suspension resulted in statistically significant decreases in either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0.5 mg once daily (one study). Symptom reduction in response to budesonide inhalation suspension occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of budesonide inhalation suspension studied.

Improvements in lung function were associated with budesonide inhalation suspension in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV 1 [budesonide inhalation suspension 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [budesonide inhalation suspension 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo.

A numerical reduction in nighttime and daytime symptom scores (0 to 3 scale) of asthma was observed within 2 to 8 days, although maximum benefit was not achieved for 4 to 6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials.

Patients Not Receiving Inhaled Corticosteroid Therapy

The efficacy of budesonide inhalation suspension at doses of 0.25 mg, 0.5 mg, and 1 mg once daily was evaluated in 344 pediatric patients, 12 months to 8 years of age, with mild to moderate persistent asthma (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.07 to 1.34) who were not well controlled by bronchodilators alone. The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with budesonide inhalation suspension compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

Changes from baseline to the double-blind phase for the budesonide treatment groups compared to placebo were made using analysis of variance techniques. The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables. (See Figures 1 to 3).

Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline

figure-1
(click image for full-size original)

p-value – 0.25 mg: 0.001, 0.5mg: 0.010, 1.0 mg: 0.009

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy of budesonide inhalation suspension at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 8 years of age, previously maintained on inhaled corticosteroids (mean FEV 1 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between 42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day). The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with budesonide inhalation suspension compared to placebo. Similar decrease were also observed for daytime asthma symptom scores.

Statistically significant increases in FEV 1 compared to placebo were observed with budesonide inhalation suspension at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily).

Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry.

Nighttime Asthma Change from Baseline

figure-2
(click image for full-size original)

p-values: 0.25 mg: 0.022, 0.5 mg: 0.021

Patients Receiving Once-Daily or Twice-Daily Dosing

The efficacy of budesonide inhalation suspension at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.13 to 1.31). Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0 to 12 in nighttime asthma symptom scores are shown in Figure 3. Budesonide inhalation suspension at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

Budesonide inhalation suspension at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV 1 , and at doses of 0.25 mg and 0.5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF.

The evidence supports the efficacy of the same nominal dose of budesonide inhalation suspension administered on either a once- daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice- daily dosing [see Dosage and Administration (2)].

Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry.

Nighttime Asthma Change from Baseline

figure-3
(click image for full-size original)

p-values: 0.25 mg qd: 0.121, 0.25 mg bid: <0.001, 0.5 mg bid: 0.003, 1.0 mg qd: 0.005

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