Ritonavir

Budesonide

Avoid association.

No pharmaceutical opinion available for this interaction.

Mechanism

Ritonavir can inhibit the metabolism (CYP 3A4) and increase the plasma concentration of Budesonide.

Ritonavir

Pharmacodynamic effects

Recommendations

Use an alternative when possible.

Alternative solution(s)

NNRTIs, raltegravir, dolutegravir or maraviroc.

Budesonide

Pharmacodynamic effects

Possible increase in adverse effects associated with corticosteroids.

Risk of hypercortisolism. Risk of adrenal insufficiency.

Recommendations

Avoid this association. Use with caution if it can not be avoided.

Use an alternative when possible.

In patients already being treated with this combination and tolerating it, if deemed appropriate, keep actual treatment and exercise close monitoring of adverse effects.

Alternative solution(s)

Beclomethasone 100 μg = budesonide 200μg.

Monitor

Budesonide 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).

Although budesonide can be an alternative to fluticasone, cases of Cushing's syndrome have also been reported with budesonide. It is recommended to avoid in combination with potent CYP3A4 inhibitors. There is a greater risk with fluticasone because it has the longest glucocorticoid receptor-binding half-life and is 300 times more lipophilic than budesonide.

Tests

Cortisol (plasma)

ACTH

Pharmacokinetic parameters

Comment

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.

Ref #2682 : Case report of a patient HIV+ who developed a cushing’s syndrome with budesonide/formoterol as well as ritonavir/lopinavir, tenofovir and emtricitabine. The patient was taking budesonide because she had previously presented a cushing ‘s syndrome with fluticasone, and the symptoms quickly reappeared with budesonide. The dose of ritonavir was decreased without any improvement, and only the replacement of the budesonide by the montelukast allowed to go back to normal.

Réf #2683 : Publication of 3 case reports of children HIV positive who were treated with ritonavir and who have developed a cushing’s syndrome with budesonide inhaled. The first case is with a 4-year-old girl treated with budesonide inhaled and nasal for a daily dose maximal of 1200µg and with ritonavir 300mg/m2. The diagnosis of cushing’s syndrome was done 3 months after the initiation of budesonide. The dose was decreased until 200µg a day but showed no improvement one week later so budenoside was thus stopped. The cortisol went back to the normal 3 weeks after the end of the treatment. The second case presents a 4-year-old girl under lopinavir/ritonavir (ritonavir 235mg / m2) and budesonide 200µg a day. She has presented a cushing’s syndrome 2 years after the initiation of the budesonide. Lopinavir/ritonavir was changed for efavirenz, and the cortisol went back to normal 4 weeks later. The last case presents a 7-year-old boy having presented a cushing’s syndrome with fluticasone.

Ref #2807 : A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide.

Ref #2806, 2851, 2852 and 2853 : Cases of Cushing's syndrome have been reported with the use of itraconazole (a potent CYP3A4 inhibitor) and budesonide.

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.

Budesonide should not be stopped without consultation with a physician. If the axis hypothalamo-hypophyseal is eliminated, stopping suddenly budesonide 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
  • 2094
    Woods DR, Arun CS, Corris PA, and Perros P. Cushing’s syndrome without excess cortisol. Br Med J 2006; 332:469-470.
  • 2682
    Kedem E, Shahar E, Hassoun G, Pollack S. Iatrogenic Cushing’s syndrome due to coadministration of ritonavir and inhaled budesonide in an asthmatic human immunodeficiency virus infected patient. J Asthma. 2010;47(7):830–1.
  • 2683
    Gray D, Roux P, Carrihill M, Klein M. Adrenal suppression and Cushing’s syndrome secondary to ritonavir and budesonide. S Afr Med J. 2010;100(5):296–7.
  • 2733
    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.
  • 2806
    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.
  • 2807
    Yoganathan K, David L, Williams C et al. Cushing’s syndrome with adrenal suppression induced by inhaled budenoside due to a ritonavir drug interaction in a woman with HIV infection. Int J STD AIDS 2012 ; 23: 520-521.
  • 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.
  • 2851
    Bolland MJ, Bagg W, Thomas MG et al. Cushing’s syndrome due to interaction between inhaled corticosteroids and itraconazole. Ann Pharmacother 2004; 38(1):46–9.
  • 2852
    De Wachter E, Vanbesien J, De Schutter I et al. Rapidly developing Cushing’s syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 2003; 162(7–8): 488–9.
  • 2853
    Main KM, Skov M, Sillesen IB, et al. Cushing’s syndrome due to pharmacological interaction in a cystic fibrosis patient. Acta Paediatr 2002; 91(9): 1008–11.
  • 3137
    Budésonide (Mylan-Budesonide AQ), Mylan Pharmateucicals ULC, Ontario, Canada, 16 mai 2018.
  • 122
    Ritonavir (Norvir), Corporation AbbVie, Quebec, Canada, 25 septembre 2018.
  • 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.