Drug Interaction Report

MONITOR: Coadministration of a macrolide or ketolide antibiotic (clarithromycin, erythromycin, telithromycin) with cobicistat is expected to increase the plasma concentrations of both drugs. The mechanism may involve both competitive and noncompetitive inhibition of CYP450 3A4, since these drugs are all substrates as well as inhibitors of the isoenzyme. No pharmacokinetic data are currently available. Clinically, high plasma levels of macrolide or ketolide antibiotics may increase the risk of QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Caution and close clinical monitoring are recommended if clarithromycin, erythromycin, or telithromycin are used in combination with cobicistat. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. Some authorities recommend avoiding the concomitant use of fixed combination antiretroviral products containing cobicistat with these antibiotics. For clarithromycin, a dosage reduction by 50% has been recommended in patients with CrCl between 30 and 60 mL/min. Data are not available in patients with CrCl less than 30 mL/min. However, in patients receiving atazanavir or ritonavir concomitantly with clarithromycin, it has been suggested that the dose of clarithromycin be reduced by 75% in patients with a CrCl of less than 30 mL/min. A similar dosage reduction may be appropriate when clarithromycin is used with cobicistat.

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.