Drug Interaction Report

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 Peak plasma salmeterol concentrations (Cmax) were increased by 1.4-fold, and three out of 20 subjects (15%) were withdrawn from the combination due to salmeterol-mediated systemic effects (two with QTc prolongation and one with palpitations and sinus tachycardia).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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.