The Journal of Pediatrics
Volume 148, Issue 3 , Pages 294-295, March 2006

Ritonavir and fluticasone: Beware of this potentially fatal combination

  • Albert Martin Li, MB

      Affiliations

    • Corresponding Author InformationReprint requests: Dr Albert M. Li, Chinese University of Hong Kong, Department of Pediatrics, Prince of Wales Hospital, 6/F, Clinical Sciences Building, Shatin, Hong Kong

Chinese University of Hong Kong, Department of Pediatrics, Prince of Wales Hospital, Shatin, Hong Kong

Received 3 December 2005; accepted 23 December 2005.

Article Outline

Abbreviations:  FP, Fluticasone propionate , ICS, Inhaled corticosteroids , PI, Protease inhibiting agent

 

Across the globe, AIDS is responsible for an increasing number of deaths each year. Of the 3.1 million killed in 2005, more than half a million were children under 15 years of age. At the end of 2005, an estimated 2.3 million children globally are living with HIV.1 Appropriate antiretroviral therapy and treatment of associated infections and malignancies are essential in the treatment of this vulnerable group of patients. Early intervention may prevent damage to the immune system and potentially limit infection dissemination. Protease inhibiting agents (PIs) are commonly used HIV medications, which prevent the late stages of viral replication by interfering with the formation of structural proteins of the virion core. Ritonavir, a PI, is a potent inhibitor of the cytochrome P450 3A-enzyme activity. The combination of small doses of ritonavir (≤200 mg/d) with other PIs leads to significant increases in the systemic availability of the second PI. This drug-drug interaction is clinically beneficial because it reduces pill burden and increases dosing intervals; hence, there is an advantage in terms of adherence to antiretroviral therapy.2, 3 Through the same mechanism, ritonavir augments the systemic effects of other medications, and one example is inhaled corticosteroids (ICS). Of all ICS available on the market, fluticasone propionate (FP) is the most suppressive on the hypothalamic-pituitary-adrenal axis.4 This is related to its unique pharmacokinetic properties, namely, enhanced lipophilicity, greater volume of distribution, long elimination half-life, increased lung deposition, and prolonged glucocorticoid-receptor occupancy.5 Overt Cushing syndrome is uncommon when FP is prescribed within the recommended dose range. Over the past 10 years, there was only one pediatric case reported of adrenal suppression in a 9-year-old asthmatic child after 6 months’ treatment with FP at a dose of 550 μg/d.6 However, Cushing syndrome as a result of the concomitant use of FP and ritonavir is being reported increasingly.7, 8, 9, 10, 11, 12, 13 This potentially fatal complication is possible even at an FP dose as low as 500 μg/d and treatment duration as short as 2 months.7 The manufacturers currently do not recommend the coadministration of the two drugs, unless benefits outweigh the risk.

In this issue of The Journal, Johnson et al14 report two adolescents with Cushing syndrome and secondary adrenal insufficiency as a result of concomitant use of ritonavir and FP. The dose of ritonavir was within the recommended range, and that for FP varied between 500 and 1000 μg/d. Both cases exhibited significant weight gain (an early warning sign) at an interval of 4 to 13 weeks after commencement of the combination therapy. The diagnosis of Cushing syndrome with overt adrenal suppression was confirmed by detecting abnormally low levels of serum cortisol and ACTH, and, in one case, the abnormal results of hormone tests took 6 months to normalize. So, what clinically relevant issues are raised from this report? First, it is important that clinicians are aware that most of the therapeutic benefit of FP is achieved with a total daily dose of 70 to 170 μg, well within the maximum licensed dose for children (200 μg/d).15 It has also been shown that the therapeutic ratio of FP actually declines above 200 μg/d, and there are no data to suggest further increase in efficacy above this dose in children.16 It is not stated clearly in the report, especially for the second case, whether any attempt has been made to reduce FP to a lower dose or whether other second-line treatments have been tried. A useful recent publication offered an evidence-based approach in the treatment of asthmatic patients who remain symptomatic despite moderate dosage of ICS.17 Using a combination of lung function parameters, bronchodilator response, and noninvasive inflammatory markers, treatment for symptomatic asthmatic patients can now be individualized and appropriate therapy instituted rather than simply increasing further the dose of ICS.17 Another important evaluation not reported by the authors is the patients’ lung function. The lung bioavailability of FP is directly related to the predicted forced expiratory volume in the first second, such that systemic absorption is reduced in more severe asthma. The second issue is how individuals receiving FP and ritonavir should be monitored for hypothalamic-pituitary-adrenal activity. Urinary free cortisol concentrations discriminate adrenal activity poorly. Cortisol appears in the urine only when the circulating carrier proteins are saturated, and that requires high circulating cortisol levels, as seen in Cushing disease, thus not applicable to patients receiving ICS.18 Suppressed early morning cortisol levels do not necessarily confirm adrenal insufficiency unless they are undetectable, as cortisol secretion is pulsatile and superimposed on the circadian rhythm.18 Measurement of 24-hour secretion rates of total cortisol and cortisol metabolites derived from gas chromatography–mass spectroscopy may be a better approach but this method is technically demanding.19 The finding of reduced serum dehydroepiandrosterone sulfate levels after the initiation of ICS has recently been recommended as an early indication of adrenal suppression, but methodology and reference ranges have yet to be standardized and validated.20 Without a widely accepted guideline for the early detection of adrenal suppression in patients receiving ICS, clinical findings remain important diagnostically. Because of the overlapping features of lipodystrophy secondary to HIV and endogenous corticosteroid excess, constant vigilance is required from clinicians to recognize subtle physical signs such as easy bruising, abdominal striae, and facial plethora, which may serve to distinguish one condition from the other. Clinicians caring for HIV-positive patients must be aware of the potentially severe and fatal interactions between antiretroviral therapy and other drugs. When inhaled corticosteroid therapy is required in patients who are receiving ritonavir, the ICS should be given at the lowest effective dose, and the less systemically available ICS should be chosen. Patients also should be warned of the inherent complications associated with this combination therapy and against abrupt cessation of the ICS.

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References 

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 Dr Li received financial support to attend postgraduate meetings from Glaxo SmithKline, which makes inhaled fluticasone.

PII: S0022-3476(05)01243-6

doi:10.1016/j.jpeds.2005.12.057

Refers to article:

  • Cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and fluticasone

    Susan R. Johnson, Alicia A. Marion, Teri Vrchoticky, Patricia J. Emmanuel, Jorge Lujan-Zilbermann
    The Journal of Pediatrics March 2006 (Vol. 148, Issue 3, Pages 386-388)

The Journal of Pediatrics
Volume 148, Issue 3 , Pages 294-295, March 2006

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