Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis

Background: Although there have been case reports of hypothalamic-pituitary-adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect.

Methods: Synacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy.

Results: Twelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol <75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol <250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22-508)nmol/L v 348(41-738)nnmol/L, p=0.02), similar results were seen for peak cortisol levels (404(59-706)nmol/L v 672(432-1178)nmol/L, p<0.001) and cortisol rise (179(37-240)nmol/L v 368(210-539)nmol/L, p<0.001). The median (range) itraconazole level was 5.5(1.7-14.7)mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression.

Conclusions: In this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide.