Atazanavir / ritonavir

Fluticasone

Contraindicated.

No pharmaceutical opinion available for this interaction.

Mechanism

Atazanavir / ritonavir can inhibit the metabolism (CYP 3A4) and increase the plasma concentration of Fluticasone.

Atazanavir / ritonavir

Pharmacodynamic effects

Recommendations

Use an alternative when possible.

Alternative solution(s)

NNRTIs, raltegravir, dolutegravir or maraviroc.

Fluticasone

Pharmacodynamic effects

Possible increase in adverse effects associated with corticosteroids.

Risk of hypercortisolism. Risk of adrenal insufficiency.

Recommendations

Avoid association. Choose an alternative.

Alternative solution(s)

Beclomethasone 100 μg = fluticasone 125 μg.

Monitor

Fluticasone toxicity : Cushing's syndrome (moon face, buffalo hump, obesity, striations, acne, hirsutism, hypertension, osteoporosis, glucose intolerance, increased risk of infections) and adrenal suppression (melanodermia, fatigue, weakness, hypotension, weight loss, digestive disorders).

Tests

ACTH

Cortisol (plasma)

Pharmacokinetic parameters

Comment

See ritonavir + fluticasone.

The pharmacokinetics of fluticasone (cytochrome 3A4 metabolism, long half-life, bioavailability, volume of distribution, lipophilicity, etc.) can lead to accumulation in the presence of CYP3A4 inhibitors.

The accumulation of corticosteroids can cause Cushing's syndrome (moon face, excitation/insomnia, hypertension, increased appetite and weight, ease of doing bruising) and potentially a suppression of the hypothalamic-pituitary axis, which could lead to adrenal insufficiency. Several cases have been reported in the literature, and this in such a short time as 2 weeks.

A pharmacokinetic study demonstrated that ritonavir, a potent CYP 3A4 inhibitor, can increase fluticasone AUC up to 350-fold.

This interaction has been notably a Health Canada warning in 2004 and ritonavir monograph specifie that its association with fluticasone is a risk of serious side effects.

The safest corticosteroid is beclomethasone (Qvar) since its metabolism is mainly by an esterification mechanism.

Ref #2550 and #2551 : A cross-sectional study (n = 11 783) suggests lower prevalence of adrenal insufficiency with beclomethasone than with other corticosteroids currently available on the market. Pharmacokinetic studies with beclomethasone and ritonavir or combination darunavir/ritonavir demonstrated that there were no clinically significant pharmacokinetic interactions. No variation of blood cortisol have been observed.

Fluticasone should not be stopped without consultation with a physician. If the axis hypothalamo-hypophyseal is eliminated, stopping suddenly fluticasone can lead to signs and symptoms of adrenal incapacity. It is recommended to decrease slowly the corticosteroid to avoid the symptoms of craving (fatigue, loss of weight, intoxications, weakness, low postural blood pressure and acute adrenal crisis). Plasma cortisol and ACTH test will document the presence or absence of adrenal insufficiency.

Reference
  • 2447
    St Germain RM, Yigit S, Wells L, Giratto JE, Salazar JC. Cushing’s syndrome and severe adrenal suppression caused by fluticasone and protease inhibitor combination in an HIV-infected adolescent. AIDS Patient Care STDs 2007; 21: 373–377.
  • 2444
    Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir–fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents. Pediatr Infect Dis J 2006;25:1044-1048.
  • 2636
    Valin N, De Castro N, Garrait V, et al. Cushing’s syndrome in HIV-infected patients receiving ritonavir and inhaled fluticasone: description of 4 new cases and review of the literature. J Int Assoc Physicians AIDS Care (Chic). 2009;8(2):113–21
  • 2763
    St Clair K, Maguire JD. Role of fluconazole in a case of rapid onset ritonavir and inhaled fluticasone-associated secondary adrenal insufficiency. Int J STD AIDS 2012; 23: 371–372.
  • 2764
    Kaviani N, Bukberg P, Manessis A, Yen V, Young I. Iatrogenic osteoporosis, bilateral HIP osteonecrosis, and secondary adrenal suppression in an HIV-infected man receiving inhaled corticosteroids and ritonavir-boosted highly active antiretroviral therapy. Endocr Pract 2011; 17: 74–78.
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    Spruyt S, Vlieghe E, Bomans P, Moerman F, Colebunders R, Van den Ende J. Inhaled corticosteroids in persons with HIV infection: not that harmless. Acta Clinical Belgica, 2012; 67-2.
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    Saberi P, Phengrasamy T and Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors : a review of pharmacokinetics, case reports and clinical management. HIV medicine 2013 : 1-11.
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    Jain L. Iatrogenic Cushing’s as a recognised complication of concomitant ritonavir and steroid use: A systematic review of cases and recommendations for clinical practice. BHIVA 2014, Liverpool UK, 1-4 april 2014, abstract P177.
  • 2637
    Santé Canada. Renseignements importants sur l'innocuité-interaction médicamenteuse entre le propionate de fluticasone (Flonase /Flovent /Advair ) et le ritonavir (Norvir /Kaletra). Disponible : http://canadiensensante.gc.ca/recall-alert-rappel-avis/hc-sc/2004/14261a-fra.php. Publié 22 janvier 2004. Consulté le 18 juin 2015.
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    Fluticasone (Flovent HFA/Diskus), GlaxoSmithKline, Ontario, Canada, 26 avril 2018.
  • 1382
    Atazanavir (Reyataz), Bristol-Myers Squibb, Quebec, Canada, 23 nov. 2017.
  • 2808
    Molimard M, Girodet PO, Pollet C et al. Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation. Drug Saf 2008; 31(9): 769-774.
  • 2551
    Boyd A, Hadigan C, Pau A. Darunavir/ritonavir Does Not Significantly Increase Plasma Concentrations of Orally Inhaled Beclomethasone in Healthy Volunteers. Conference on Retroviruses and Opportunistic Infections, Seattle, 2012, Abstract 611.
  • 2550
    Boyd A, Penzak S, Nieman L et al. Co-administration of Orally Inhaled Beclomethasone Dipropionate and HIV Protease Inhibitor Does Not Significantly Alter Adrenal Function in Healthy Volunteers. Conference on Retroviruses and Opportunistic Infections, Seattle, 2012, Abstract 610.
  • 3101
    Lougheed MD, Lemiere C, Ducharme F et al. Canadien Thoracic Society 2012 guideline update: Diagnosis and management of athsma in preschoolers, children and adults. Can Respir J 2012; 19 (2): 127-164.