Drug Interactions between amoxicillin / clarithromycin / omeprazole and tofacitinib

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tofacitinib, which is metabolized by the isoenzyme. In study subjects, administration with the potent CYP450 3A4 inhibitor ketoconazole increased tofacitinib systemic exposure (AUC) by greater than 2-fold compared to administration of tofacitinib alone. Side effects including lymphopenia, neutropenia, anemia, serious infections, and hyperlipidemia may be increased.

MANAGEMENT: The dosage of tofacitinib should be reduced by 50% when used with potent CYP450 3A4 inhibitors. For example, the dose for patients receiving 10 mg twice daily should be reduced to 5 mg twice daily and the dose for patients receiving 5 mg twice daily should be reduced to 5 mg once daily. For patients receiving 11 mg once daily of the extended-release formulation, the dose should be reduced to 5 mg once daily of the immediate-release formulation. The dose for patients receiving 3.2 mg twice daily should be reduced to 3.2 mg once daily and the dose for patients receiving 4 mg twice daily should be reduced to 4 mg once daily.

ADJUST DOSE: Coadministration with one or more medications that may result in both moderate inhibition of CYP450 3A4 and potent inhibition of CYP450 2C19 may significantly increase the plasma concentrations of tofacitinib, which is primarily metabolized by the former isoenzyme with minor contribution from the latter. In study subjects, administration with the moderate CYP450 3A4 and potent CYP450 2C19 inhibitor fluconazole increased tofacitinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 27% and 79%, respectively, compared to administration of tofacitinib alone. Side effects including lymphopenia, neutropenia, anemia, serious infections, and hyperlipidemia may be increased.

MANAGEMENT: The dosage of tofacitinib should be reduced by 50% when used concomitantly with one or more medications that may result in both moderate inhibition of CYP450 3A4 and potent inhibition of CYP450 2C19. For example, the dose for patients receiving 10 mg twice daily should be reduced to 5 mg twice daily and the dose for patients receiving 5 mg twice daily should be reduced to 5 mg once daily. For patients receiving 11 mg once daily of the extended-release formulation, the dose should be reduced to 5 mg once daily of the immediate-release formulation. The dose for patients receiving 3.2 mg twice daily should be reduced to 3.2 mg once daily and the dose for patients receiving 4 mg twice daily should be reduced to 4 mg once daily. Moderate inhibitors of CYP450 3A4 include amiodarone, aprepitant, ciprofloxacin, crizotinib, darunavir, dalfopristin-quinupristin, diltiazem, dronedarone, erythromycin, fluconazole, fusidic acid, grapefruit juice, imatinib, isavuconazonium, netupitant, and verapamil. Potent inhibitors of CYP450 2C19 include fluconazole, fluvoxamine, esomeprazole, lansoprazole, and omeprazole. Inhibitors of CYP450 2C19 alone are unlikely to substantially alter the pharmacokinetics of tofacitinib.

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.