Drug Interaction Report

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

Based on in vitro data, coadministration with potent inhibitors of CYP450 3A4 and/or 2C19 may be expected to increase the plasma concentrations of ambrisentan, which is a substrate of these isoenzymes. However, administration with ketoconazole (potent CYP450 3A4 inhibitor) or omeprazole (potent CYP450 2C19 inhibitor) did not result in clinically relevant changes in ambrisentan exposure.

Based on in vitro data, coadministration with potent inhibitors of CYP450 3A4 and/or 2C19 may be expected to increase the plasma concentrations of ambrisentan, which is a substrate of these isoenzymes. However, administration with ketoconazole (potent CYP450 3A4 inhibitor) or omeprazole (potent CYP450 2C19 inhibitor) did not result in clinically relevant changes in ambrisentan exposure.

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.