Drug Interactions between fluticasone / vilanterol and Viekira XR

GENERALLY AVOID: Coadministration with ritonavir may significantly increase the systemic exposure to fluticasone following intranasal administration or oral inhalation. The mechanism is ritonavir inhibition of fluticasone metabolism via hepatic and intestinal CYP450 3A4. In 18 healthy subjects, administration of fluticasone propionate nasal spray (200 mcg once daily) in combination with ritonavir (100 mg twice daily) for 7 days resulted in an approximately 25-fold increase in fluticasone peak plasma concentration (Cmax) and 350-fold increase in systemic exposure (AUC) compared to administration alone. These changes were accompanied by an 86% decrease in mean plasma cortisol AUC. Systemic glucocorticoid adverse effects such as adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported during postmarketing use of orally inhaled or intranasal fluticasone in patients receiving ritonavir-containing antiretroviral regimens. In an analysis of 25 suspected cases of the interaction reported in the medical literature, the mean dosage of orally inhaled fluticasone was 992 mcg/day (range 500 to 2000 mcg/day) in adult cases and 455 mcg/day (range 200 to 1000 mcg/day) in pediatric cases. Dosages of ritonavir used included both low, "boosting" dosages (100 to 200 mg daily) and high, "treatment" dosages (800 to 1200 mg/day). The average onset of cushingoid appearance was approximately 2.75 months (range 2 weeks to 6 months) in adult cases and 2.1 months (range 2 weeks to 3 months) in pediatric cases. For the three cases involving intranasal fluticasone, the dosage used ranged from 200 to 800 mcg/day and the onset of cushingoid appearance ranged from 5 to 18 months of concomitant use with ritonavir. Recovery of adrenal function was reportedly slow in some patients following discontinuation of fluticasone. Investigators suggest that this could be related to the highly lipophilic nature of fluticasone, which allows for prolonged seepage of drug into the circulation from fat stores.

MANAGEMENT: The use of intranasal or orally inhaled fluticasone in combination with ritonavir is not recommended unless the potential benefit outweighs the risk of systemic side effects. Alternatives to fluticasone should be considered whenever possible if ritonavir must be used. A less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone, budesonide, flunisolide or triamcinolone may be appropriate, although probably most, if not all, corticosteroids can interact with ritonavir to some extent. The lowest effective dosage of orally inhaled corticosteroid should be used, and further adjustments made as necessary according to therapeutic response and tolerance. Patients should be monitored for signs and symptoms of hypercorticism such as acne, striae, thinning of the skin, easy bruising, moon facies, dorsocervical "buffalo" hump, truncal obesity, increased appetite, acute weight gain, edema, hypertension, hirsutism, hyperhidrosis, proximal muscle wasting and weakness, glucose intolerance, exacerbation of preexisting diabetes, depression, and menstrual disorders. It is important to distinguish between hypercorticism and the lipodystrophy syndrome caused by antiretroviral treatment, as the overlap of certain clinical features may delay the recognition and diagnosis of Cushing's syndrome. In general, the lack of peripheral atrophy and the presence of abdominal striae, easy bruising, and facial plethora would suggest iatrogenic Cushing's syndrome rather than antiretroviral-related lipodystrophy. Other systemic glucocorticoid effects may include adrenal suppression, immunosuppression, posterior subcapsular cataracts, glaucoma, bone loss, and growth retardation in children and adolescents. Following extensive use with ritonavir, a progressive dosage reduction may be required over a longer period if fluticasone is to be withdrawn from therapy, as there may be a significant risk of adrenal suppression. Signs and symptoms of adrenal insufficiency include anorexia, hypoglycemia, nausea, vomiting, weight loss, muscle wasting, fatigue, weakness, dizziness, postural hypotension, depression, and adrenal crisis manifested as inability to respond to stress (e.g., illness, infection, surgery, trauma). Systemic glucocorticoids may be necessary until adrenal function recovers.

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MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure to vilanterol following oral inhalation, as it is primarily metabolized by the isoenzyme. The interaction has been studied with fluticasone-vilanterol and ketoconazole. When fluticasone-vilanterol (200 mcg-25 mcg once daily for 7 days) was coadministered with ketoconazole (400 once daily for 11 days) in healthy subjects, fluticasone and vilanterol systemic exposure (AUC) were 36% and 65% higher, respectively, compared to coadministration with placebo. The increase in fluticasone exposure was associated with a 27% reduction in 24-hour weighted mean serum cortisol, whereas the increase in vilanterol exposure was not associated with an increase in beta-2 adrenergic systemic effects on heart rate or blood potassium.

MANAGEMENT: Due to the risk of cardiovascular adverse effects such as increases in pulse rate and blood pressure and ECG changes such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, caution is recommended when medications containing vilanterol are coadministered with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. An increased risk of systemic corticosteroid effects should also be considered when fluticasone-vilanterol is used.

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Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.

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