Establishing a therapeutic index for the inhaled corticosteroids: part II. Comparisons of systemic activity and safety among different inhaled corticosteroids.

The systemic activity and safety of inhaled corticosteroids are best studied in randomized, controlled, long-term trials with clinically relevant doses in subjects. These studies require large numbers of enrolled subjects and are difficult to conduct. Potential confounders to safety analyses must be controlled. The occurrence and magnitude of adrenal suppression has been the most extensively evaluated systemic effect of inhaled corticosteroids. The significance of these findings in relation to relevant clinical outcomes must be evaluated. At low to medium inhaled corticosteroid dosages, the hypothalamic-pituitary-adrenal axis is minimally and only partially suppressed. Statistically significant changes occur at high inhaled corticosteroid dosages; the magnitude of this effect is less than with prednisone, > or = 10 mg/day. Standards for the design of growth studies in children with asthma have been recommended and recently implemented. Four randomized, controlled, clinical trials have reported reductions in growth rates of > 1 cm/yr with beclomethasone < or = 400 microg/day. By comparison, 2 randomized controlled clinical trials with fluticasone, 50 to 100 microg twice daily via dry powder inhaler, could not detect differences in height velocity in prepubertal children treated with cromolyn sodium or placebo. Trials with low to medium doses of beclomethasone, fluticasone, and budesonide document little to no effect on bone mineral density and bone metabolism. Population-based and limited randomized controlled trials suggest that low to medium doses of inhaled corticosteroids do not cause cataracts or glaucoma. Patients requiring high-dose inhaled corticosteroids should be monitored for adverse effects, with appropriate lifestyle changes and pharmacologic strategies implemented.