Safety of Inhaled Budesonide Clinical Manifestations of Systemic Corticosteroid-Related Adverse Effects

Inhaled corticosteroid (ICS) therapy is central to the long-term management of asthma and is extensively used in the management of chronic obstructive pulmonary disease (COPD). While administration via inhalation limits systemic exposure compared with oral or injected corticosteroids and, therefore, the risk of systemic corticosteroid-related adverse effects, concerns over the long-term safety of ICS persist. The assessment of the long-term effects of ICS therapy requires considerable research effort over years or even decades. Surrogate markers/predictors forclinical endpoints such as adrenal crisis, reduced final height and fractures have been identified for use in relatively short-term studies. However, the predictive value of such markers remains questionable. Inhaled budesonide has been available since the early 1980s and there is a considerable evidence base investigating the safety of this agent. To assess the long-term safety of inhaled budesonide therapy in terms of the actual incidence of the clinical endpoints adrenal crisis/insufficiency, reduced final height, fractures and pregnancy complications, we undertook a review of the scientific literature. The external databases BIOSIS, Cochrane Central Register of Controlled Trials, Current Contents, EMBASE, International Pharmaceutical Abstracts and MEDLINE were searched, in addition to AstraZeneca's internal product literature database Planet, up to 29 February 2008. Only original articles of epidemiological studies, national surveys, clinical trials and case reports concerning inhaled budesonide were included. Eight surveys of adrenal crisis were found. The only survey with specified criteria for diagnosis involved 2912 paediatricians and endocrinologists and revealed 33 patients with adrenal crisis associated with ICS therapy;, only one patient used budesonide (in co-treatment with fluticasone propionate). In addition, 14 case reports of adrenal crisis in budesonide-treated patients were found. In only two of these, budesonide was used at recommended doses and in the absence of interacting medication. Three retrospective studies and one prospective study assessing final height were found. None of them showed any reduced final height in patients receiving inhaled budesonide during childhood or adolescence. Seventeen epidemiological studies investigating the risk of fractures were found. When adjusting for confounding factors, they did not provide any unequivocal data for an increased fracture risk with budesonide. Four prospective placebo-controlled clinical trials of 2-6 years duration with inhaled budesonide in patients with asthma or COPD were found. None of the studies identified any association between inhaled budesonide and increased risk for fractures. Four studies using data from the Swedish birth and health registries showed there was no increased risk for congenital malformations, cardiovascular defects, decreased gestational age, birth weight or birth length among infants born to women using inhaled budesonide during pregnancy compared with the general population. This was confirmed by five observational studies in Australia, Canada, Hungary, Japan and the US. Similarly, one randomized clinical trial comparing pregnancy outcomes among asthma patients receiving inhaled budesonide or placebo did not demonstrate any difference in outcome of pregnancy. In summary, based on 25 years of experience with different doses and in different populations, inhaled budesonide therapy only in very rare cases appears to be associated with an increased risk of adrenal crisis. reduction in final height, increases in the number of fractures or complications during pregnancy.