Drug Interactions between amoxicillin / clarithromycin / omeprazole and tasimelteon

MONITOR: Coadministration with inhibitors of CYP450 1A2 and/or 3A4 may increase the plasma concentrations of tasimelteon, which is primarily metabolized by these isoenzymes. When tasimelteon was administered after 6 days of treatment with the potent CYP450 1A2 inhibitor fluvoxamine 50 mg/day, tasimelteon peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2- and 7-fold, respectively, compared to tasimelteon administered alone. When administered after 5 days of treatment with the potent CYP450 3A4 inhibitor ketoconazole 400 mg/day, tasimelteon AUC increased by approximately 50%.

MANAGEMENT: Caution is advised if tasimelteon is prescribed in combination with inhibitors of CYP450 1A2 and/or 3A4. Patients should be monitored for excessive sedation and other side effects.

MONITOR: Coadministration with inducers of CYP450 1A2 and/or 3A4 may decrease the plasma concentrations of tasimelteon, which is primarily metabolized by these isoenzymes. When tasimelteon was administered after 11 days of treatment with the potent CYP450 inducer rifampin 600 mg/day, tasimelteon systemic exposure (AUC) decreased by approximately 90% compared to tasimelteon administered alone. No data are available for use with other, less potent inducers.

MANAGEMENT: The potential for diminished therapeutic effects of tasimelteon should be considered during coadministration with inducers of CYP450 1A2 and/or 3A4. Alternative treatments may be required if an interaction is suspected.

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.