Drug interactions between Advair Diskus and clarithromycin

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 Peak plasma salmeterol concentrations (Cmax) were increased by 1.4-fold, and three out of 20 subjects (15%) were withdrawn from the combination due to salmeterol-mediated systemic effects (two with QTc prolongation and one with palpitations and sinus tachycardia).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: The use of salmeterol in combination with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics is not recommended.

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the systemic exposure of fluticasone propionate administered intranasally or by oral inhalation due to inhibition of its metabolism. In eight healthy volunteers, coadministration of a single dose of orally inhaled fluticasone propionate (1000 mcg) with multiple doses of ketoconazole (200 mg) to steady state resulted in increased plasma fluticasone propionate exposure, a reduction in plasma cortisol levels by 7%, and no effect on urinary excretion of cortisol compared to coadministration with placebo. Adverse effects were not reported. Coadministration of fluticasone nasal spray twice daily and erythromycin 500 mg twice daily did not affect fluticasone levels but reduced plasma cortisol levels by 2%. Coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics.

MANAGEMENT: Caution is advised if fluticasone is prescribed with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. Patients should be monitored for systemic glucocorticoid effects including symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, irregular menstruations), adrenal suppression (which reduces patient's ability to respond to stress situations), immunosuppression, osteoporosis, glucose intolerance, and exacerbation of diabetes mellitus.