Iatrogenic Cushing's syndrome and osteoporosis due to an interaction between fluticasone and ritonavir

Abstract

The advent of highly active antiretroviral therapy for HIV infection dramatically changed the landscape of the disease. Ritonavir, a protease inhibitor (PI) frequently used in low doses to 'boost' the concentrations of other PIs, inhibits the cytochrome P450 3A4 isoenzyme, a common metabolic pathway to multiple drugs, so the potential for drug interactions is not negligible. A 39-year-old man with HIV-1 infection, treated with a ritonavir-boosted PI, was started on fluticasone/salmeterol inhaler and intranasal fluticasone, in 2009, in the setting of asthma and allergic rhinitis. In 2013, he presented with 1-year evolution of symptoms suggesting Cushing's syndrome, and was experiencing recurrent falls. A spine CT showed a vertical L3 fracture and thoracolumbar erosions; a bone density scan revealed severe osteoporosis. Hormonal assays were compatible with hypothalamic-pituitary-adrenal axis suppression, and iatrogenic Cushing's syndrome due to ritonavir-fluticasone interaction was considered. Fluticasone was suspended and oral corticosteroid replacement initiated, with a favourable outcome.

Avascular Necrosis of Both Hips From Iatrogenic Cushing ’s Syndrome due to Coadministration of Fluticasone and Ritonavir in an HIV-Infected Patient

“…Our patient presented with clinical cushingoid features in the setting of biochemical adrenal insufficiency consistent with the diagnosis of iatrogenic Cushing's syndrome leading to secondary adrenal suppression. Iatrogenic Cushing's syndrome due to inhibition of hepatic CYP3A4 metabolism of inhaled and nasal fluticasone by PI is well documented in the literature [1][2][3][4][5]. However, our case presented with non-PTH-mediated hypercalcemia and AVN of bilateral hips, most likely complications of iatrogenic Cushing's syndrome.…”

“…Inhaled (ICS) and nasal corticosteroids, such as fluticasone, are known substrates of CYP3A4. Thus, it stands to reason that coadministration of ritonavir and fluticasone can induce adverse effects of prolonged, elevated glucocorticoids, such as Cushing's syndrome, osteoporosis, or avascular necrosis (AVN), and tertiary adrenal insufficiency after withdrawal of glucocorticoids [1][2][3][4][5]. We report a case of AVN from iatrogenic Cushing's syndrome in an HIV-positive patient taking inhaled and nasal fluticasone and ritonavir.…”

Complications of combination intranasal corticosteroids and anti-retroviral therapy

“…The more than 60 cases of inhaled or intranasal corticosteroid interactions with ritonavir reported in the literature to date would suggest that greater awareness of the hazards of this prescribing decision is needed to prevent morbidity. [5][6][7][8][9][10]12 Two case reports have previously described interactions between intranasal fluticasone and ritonavir, in which one patient developed Cushing's syndrome and the other developed both Cushing's syndrome and adrenal insufficiency. 32,33 In these two patients, symptoms resolved once fluticasone was discontinued or a new protease inhibitor was initiated that did not interact with CYP3A4, respectively.…”

“…The interaction between fluticasone (inhaled and intranasal forms) and ritonavir has previously been described, [5][6][7][8][9][10][11][12] but it remains a poorly recognised entity amongst clinicians, particularly in the field of otolaryngologya field where an admittedly high proportion of intranasal steroids are administrated. We present the first case of avascular necrosis of the shoulder and Cushing's syndrome resultant from drug interaction between intranasal fluticasone spray and ritonavir.…”

Drug Interactions With Oral Inhaled Medications

“…HIV-infected patients may be receiving concurrent protease inhibitors (ritonavir, atazanavir, darunavir, fosamprenavir, saquinavir, indinavir, nelfinavir, tipranavir), which are potent inhibitors of 3A4. 42 Another population with increased risk for toxicity is patients taking prolonged, concurrent azole antifungal therapy. 43 The most common azole-implicated antifungals (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) all demonstrate an ability to inhibit CYP 3A4.…”