Drug Interactions between amoxicillin / clarithromycin / omeprazole and fosphenytoin

MONITOR: Coadministration with phenytoin may reduce the plasma concentrations and antimicrobial efficacy of erythromycin and other macrolide antibiotics. The mechanism is induction of CYP450 3A metabolism by phenytoin. Additionally, plasma concentrations of phenytoin may be increased. One study has suggested that the pharmacokinetic disposition of phenytoin is not significantly altered in patients receiving erythromycin. However, occasional large changes in phenytoin clearance were noted in some patients.

MANAGEMENT: If concomitant use is medically necessary, caution and monitoring for altered efficacy and safety of both medications is recommended.

MONITOR: Omeprazole may increase phenytoin serum concentrations and the risk of toxicity. The proposed mechanism is decreased clearance due to omeprazole-mediated inhibition of CYP450 2C19. Omeprazole may interact in a similar manner with other hydantoins. The clinical significance is unknown; however, higher omeprazole doses (more than 40 mg/day) may be more likely to interact.

MANAGEMENT: Clinical and laboratory monitoring may be appropriate whenever omeprazole is added to or withdrawn from therapy with phenytoin. Dosage adjustments may be considered if an interaction is suspected. Patients should be advised to notify their doctor if they experience symptoms of phenytoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia).

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.