The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.

Improvement in the control of asthma symptoms following inhalation of PULMICORT RESPULES can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 weeks. 

Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain. 

Pre-treatment with budesonide administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge.

HPA Axis Effects

The effects of PULMICORT RESPULES on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with PULMICORT RESPULES treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMICORT RESPULES equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMICORT RESPULES or placebo once daily. A total of 28, 17, and 31 patients in the PULMICORT RESPULES 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with PULMICORT RESPULES versus placebo. However, 7 patients in this study (4 of whom received PULMICORT RESPULES 0.5 mg, 2 of whom received PULMICORT RESPULES 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (≥500 nmol/L) to a subnormal level (<500 nmol/L) at Week 12. In 4 of these patients receiving PULMICORT RESPULES, the cortisol values were near the cutoff value of 500 nmol/L.

The effects of PULMICORT RESPULES at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of PULMICORT RESPULES (1 and 2 mg twice daily) showed statistically significantly reduced (43-52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of PULMICORT RESPULES, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period. 

PULMICORT RESPULES, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see Warnings and Precautions (5.5)].