Elvitegravir / Cobicistat

Budesonide

Avoid association.

No pharmaceutical opinion available for this interaction.

Mechanism

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

Elvitegravir / Cobicistat

Pharmacodynamic effects

Recommendations

Use an alternative when possible.

Alternative solution(s)

NRTIs, 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 200 μg.

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

ACTH

Cortisol (plasma)

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.

Indeed, some cases of Cushing's syndrome and adrenal failure have been reported in the literature with the combination of budesonide and protease inhibitors, including ritonavir which is a potent inhibitor of cytochrome 3A4 as cobicistat. See ritonavir 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
  • 2570
    Elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild), Gilead, Ontario, Canada, 17 septembre 2018.
  • 3137
    Budésonide (Mylan-Budesonide AQ), Mylan Pharmateucicals ULC, Ontario, Canada, 16 mai 2018.
  • 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.
  • 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.
  • 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.
  • 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.
  • 3281
    Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide(Genvoya), Gilead, Ontario, Canada, 17 septembre 2018.