Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature

Abstract

ObjectiveThe purpose of this article is to provide a systematic overview of the literature on adrenal suppression and Cushing's syndrome secondary to an interaction between inhaled/intranasal fluticasone and ritonavir. The clinical presentation, diagnosis and management will be discussed. MethodsA literature search using Medline and EMBASE and a search of abstracts of the three previous years of major HIV-related conferences were carried out. ResultsThere were 25 cases (15 adult and 10 paediatric) of significant adrenal suppression secondary to an interaction between ritonavir and inhaled fluticasone, and three cases involving ritonavir and intranasal fluticasone. Cases with other steroids were not reported; however, there were cases of adrenal suppression with itraconazole [also a potent cytochrome p (CYP) 3A4 inhibitor] and inhaled budesonide. Clinicians need to differentiate between antiretroviral-induced lipodystrophy syndrome and iatrogenic Cushing's syndrome secondary to glucocorticoid use. Long-term fluticasone and ritonavir should be avoided. If ritonavir is required, another inhaled steroid such as low-dose budesonide or beclomethasone can be used cautiously. Upon discontinuation of inhaled corticosteroids, close monitoring for symptoms of adrenal insufficiency is warranted. The need for steroid replacement therapy at physiological doses should be assessed. ConclusionsThe combination of ritonavir and fluticasone should be avoided. Budesonide, beclomethasone, triamcinolone and flunisolide appear to be safer options.

Inhaled Corticosteroids in Lung Diseases

“…They are all extensively metabolized by intestinal and hepatic CYP 3A4, which affects their systemic availability and clearance. Adrenal suppression, Cushing syndrome, and death have been reported with coadministration of these agents (64,74).…”

Secondary Adrenal Insufficiency Due to the Co-Administration of Ritonavir and Inhaled Fluticasone Propionate: Case report

“…7 Another review showed that it took between two weeks and 12 months for patients to experience a complete resolution of symptoms after either drug was discontinued. 8 In the current case, the patient had low ACTH and morning cortisol levels and a subnormal response to synthetic ACTH. This confirmed the diagnosis of secondary adrenal insufficiency.…”

“…[7][8][9][10][11][12][13][14] In a recent literature review, Epperla et al reported a total of 37 cases of iatrogenic Cushing's syndrome and adrenal suppression as a result of concomitant use of fluticasone and ritonavir in which the time between co-administration and the development of symptoms ranged from two weeks to two years. 7 Another review showed that it took between two weeks and 12 months for patients to experience a complete resolution of symptoms after either drug was discontinued.…”

Drug interactions between inhaled corticosteroids and enzymatic inhibitors

“…An interaction is also suspected in children [13,14,16]. However, in our series, too few children were included to be conclusive; doses were very variable and sometimes very important.…”

“…A case of Cushing's syndrome attributed to an interaction between budesonide and clarithromycin has also been reported [13]. In a recent review, 25 cases of adrenal suppression or Cushing's syndrome due to an interaction between ritonavir and inhaled or intranasal fluticasone were described [16]. In 2004, a Canadian press release was issued on the risk of adrenal insufficiency or Cushing's syndrome when ritonavir and fluticasone were administered together.…”