Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C9 and/or 3A4 may increase the plasma concentrations of valdecoxib, which is metabolized by these isoenzymes. According to the product labeling for valdecoxib, multi-dose administration of fluconazole (CYP450 2C9/3A4 inhibitor) and ketoconazole (CYP450 3A4 inhibitor) increased the area under the plasma concentration-time curve (AUC) of a single 20 mg dose of valdecoxib by 62% and 38%, respectively. Parecoxib, a prodrug of valdecoxib, may be similarly affected.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of valdecoxib or parecoxib, including serious adverse effects such as gastrointestinal ulceration and bleeding, should be considered during concomitant therapy with CYP450 2C9 or 3A4 inhibitors, particularly combination (2C9/3A4) inhibitors such as fluconazole, fluvoxamine, imatinib, and zafirlukast. Dose reductions of the COX-2 inhibitor may be required.

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.

Coadministration with valdecoxib or its prodrug, parecoxib, may increase the plasma concentrations of omeprazole. The mechanism is valdecoxib inhibition of CYP450 2C19 and 3A4, the isoenzymes responsible for the metabolic clearance of omeprazole. According to product labeling, coadministration of valdecoxib (40 mg twice a day) and omeprazole (40 mg once a day) resulted in a 46% increase in the systemic exposure (AUC) of omeprazole compared to administration of omeprazole alone. The pharmacokinetics of valdecoxib were not significantly affected. Because higher dosages (up to 360 mg/day) of omeprazole are tolerated in Zollinger-Ellison patients, no dosage adjustment for omeprazole is indicated at normally recommended dosages. However, drugs whose absorption is sensitive to pH (e.g., some cephalosporins such as cefditoren, cefpodoxime, and cefuroxime; antiretroviral agents including atazanavir, delavirdine, and fosamprenavir; cyanocobalamin; ketoconazole; enteric coated preparations) may be negatively impacted by concomitant administration of omeprazole and valdecoxib or parecoxib. Coadministration of valdecoxib with dosages of omeprazole higher than 40 mg/day has not been studied.

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.