Drug Interactions between Advair Diskus and voriconazole

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure to fluticasone following intranasal administration or oral inhalation. Fluticasone undergoes extensive first-pass and systemic metabolism via CYP450 3A4, thus inhibition of the isoenzyme may significantly increase systemic bioavailability of the drug. However, the extent of interaction may depend on route of fluticasone administration and the specific formulation. In 18 healthy subjects, coadministration of fluticasone propionate nasal spray (200 mcg once daily) with the potent CYP450 3A4 inhibitor ritonavir (100 mg twice daily) for 7 days resulted in an approximately 25-fold increase in fluticasone Cmax and 350-fold increase in AUC, accompanied by an 86% decrease in mean plasma cortisol AUC. In another study, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mcg) with ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In a study using intranasal fluticasone furoate, 6 of 20 subjects who were coadministered ketoconazole (200 mg once a day for 7 days) had measurable but low levels of fluticasone furoate compared to 1 of 20 subjects who received placebo. There was an estimated 5% reduction in 24-hour serum cortisol levels with ketoconazole relative to placebo. Similarly, when fluticasone furoate-vilanterol oral inhalation (200 mcg-25 mcg once daily for 7 days) was coadministered with ketoconazole (400 once daily for 11 days) in healthy subjects, fluticasone AUC was increased 36% relative to coadministration with placebo, and the increase was associated with a 27% reduction in 24-hour weighted mean serum cortisol. A study of 17 lung transplant patients found that mean fluticasone trough level in subjects receiving fluticasone propionate (1 mg twice daily by oral inhalation for 14 days) with itraconazole was 2.5 times that observed in subjects not receiving itraconazole. Clinically, systemic glucocorticoid adverse effects may occur in association with the interaction. Adrenal suppression, Cushing's syndrome, osteoporosis, and exacerbation of diabetes mellitus have been reported during worldwide postmarketing use of orally inhaled or intranasal fluticasone, primarily in combination with ritonavir. However, there have also been a few case reports of adrenal suppression associated with concomitant use of inhaled fluticasone propionate and azole antifungal agents. 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: Concomitant use of most orally inhaled fluticasone preparations with potent CYP450 3A4 inhibitors is not recommended unless the potential benefit outweighs the risk of systemic side effects. Alternatives to fluticasone should be considered whenever possible. A less potent, less lipophilic, and/or shorter-acting agent such as beclomethasone or flunisolide may be appropriate. The lowest effective dosage of orally inhaled corticosteroid should be used, and further adjustments made as necessary according to therapeutic response and tolerance. Intranasal fluticasone and fluticasone furoate-vilanterol oral inhalation powder may be used cautiously in combination with potent CYP450 3A4 inhibitors except ritonavir. 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. 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 a potent CYP450 3A4 inhibitor, 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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GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the systemic levels and pharmacologic effects of salmeterol, which is primarily metabolized by the isoenzyme. Because salmeterol prolongs the QT interval in a dose-dependent manner, high systemic levels of salmeterol may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In a placebo-controlled, crossover drug interaction study consisting of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily) and the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) for 7 days resulted in a 16-fold increase in plasma salmeterol exposure (AUC) mainly due to increased bioavailability of the swallowed portion of the dose. Peak plasma salmeterol concentrations (Cmax) were increased by 1.4-fold, and three out of 20 subjects (15%) were withdrawn from the combination due to salmeterol-mediated systemic effects (two with QTc prolongation and one with palpitations and sinus tachycardia). Coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on mean heart rate, blood potassium, or blood glucose. Although there was no statistical effect on the mean QTc, the combination was associated with more frequent increases in QTc duration than salmeterol and placebo.

MANAGEMENT: Concomitant use of salmeterol with potent CYP450 3A4 inhibitors is not recommended. Some authorities recommend avoiding concomitant use of salmeterol during and for 2 weeks after treatment with itraconazole. Other authorities consider concomitant use of salmeterol and atazanavir-cobicistat to be contraindicated.

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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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