Ritonavir Fluticasone

PK parameter Fluticasone alone Fluticasone + ritonavir Ratio... 

There have been reports of Cushing s syndrome after prolonged use of intranasal betamethasone 0.1% for chronic catarrh in two boys (443) and from an interaction of nasal fluticasone with ritonavir (444). 

The authors thought it likely that inhibition of cytochrome P-450 by ritonavir increased the systemic availability of fluticasone and thus caused Cushing s syndrome in this patient. 

Hillebrand-Haverkort ME, Prummel MF, ten Veen JH. Ritonavir-induced Cushing s syndrome in a patient treated with nasal fluticasone. AIDS 1999 13(13) 1803. 

Cushing s syndrome occurred in a 44-year-old HIVpositive patient who used inhaled fluticasone (500 micrograms qds) for severe asthma for 2 years (153). Stavudine and nevirapine were replaced by abacavir and ritonavir + lopinavir and 2 months later he developed the typical features of Cushing syndrome. 

In this case an interaction of ritonavir + lopinavir with fluticasone was suspected, because fluticasone is metabolized by CYP3A4, which ritonavir inhibits. 

Rouanet I, Peyriere H, Mauboussin JM, Vincent D. Cushing s syndrome in a patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Med 2003 4 149-50. 

Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR. Cushing s syndrome and severe adrenal suppression in patients treated with ritonavir and inhaled nasal fluticasone. Sex Transm Infect 1999 75(4) 274. 

CORTICOSTEROIDS PROTEASE INHIBITORS-RITONAVIR t plasma levels of betamethasone, dexamethasone, hydrocortisone, prednisolone and both inhaled and intranasal budesonide and fluticasone with ritonavir (with or without lopinavir) Inhibition of CYP3A4-mediated metabolism Monitor closely for signs of corticosteroid toxicity and immunosupression, and i dose as necessaiy. Consider using inhaled bedometasone... 

Ritonavir, a potent inhibitor of CYP3A4, caused Cushing s sjmdrome in a patient using fluticasone propionate 1000 micrograms/day (126). 

Clinically important, potentially hazardous interactions with aminophylline, anticonvulsants, aprepitant, bedomethasone, bosentan, budesonide, cigarette smoking, danazol, efavirenz, exenatide, flucloxacillin, flunisolide, fluticasone, hydrocortisone, insulin detemir, lamotrigine, licorice, lymecycline, methylprednisolone, modafinil, nelfinavir, prednisolone, prednisone, rifabutin, rifampin, ritonavir, saw palmetto, selegiline, St John s wort, triamcinolone, troleandomycin, tuberculostatics, ursodeoxycholic acid, zolmitriptan... 

TABLE 7.8 Pharmacokinetic parameters of fluticasone nasal spray (200 xg once daily) +7 days with ritonavir (100 mg twice daily). 

Several cases of Cushing s syndrome have been seen in patients using inhaled or intranasal fluticasone when ritonavir was also given. Ritonavir may reduce the clearance of prednisone, and ritonavir or nelflnavir may increase levels of the active metabolite of ciclesonide. Dexamethasone may reduce the levels of indinavir and saquinavir. 

There are reports of at least 9 other patients, including 2 children, who have developed Cushing s syndrome within 2 to 5 months of using regimens of inhaled " or intranasal fluticasone, with ritonavir, ritonavir/ amprenavir, ritonavir/lopinavir, ritonavir/saquinavir, ... 

Ritonavir, and all protease inhibitors, inhibit the cytochrome P450 isoenzyme CYP3A4 to varying degrees. Fluticasone is metabolised by this isoenzyme and therefore the protease inhibitors cause its plasma levels to rise. The active metabolite of ciclesonide is also metabolised by CYP3A4, and is therefore similarly affected. 

Gillett MJ, Cameron PU, N yen HV, Hurley DM, Mallal SA. latrc enic Cushii s syndrome in an HIV-infected patient treated with ritonavir and inhaled fluticasone. AIDS (2( 5) 19, 740-1. 

Soldatos G, Sztal-Mazer S, Woolley I, Stockigt J. Exogenous glucocorticoid excess as a result of ritonavir-fluticasone interaction. IntemMedJ (2005) 35, 67-8. 

Li AM, Ritonavir and fluticasone beware of this potentially fatal combination, J Pediatr (2006) 148, 294-5,... 

Arrington-Sanders R, Hutton N and Siberry GK (2006) Ritonavir-fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents. Pediatr... 

Drug-drug iuteractions Ritonavir Inhaled fluticasone interacts with ritonavir, resulting in steroid accumulation, adrenal suppression, and even florid Cushing s syndrome. Fluticasone is metabolized by CYP3A4, which is inhibited by ritonavir. A systematic review of the hterature on adrenal suppression and Cushing s... 

Foisy MM, Yakiwchuk EMK, Chiu I, Singh AE. Adrenal suppression and Cushing s syndrome secondary to an interaction between ritonavir and fluticasone a review of the literature. HIV Med 2008 9(6) 389-96. 

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