Drug Interactions between fluvoxamine and fosphenytoin

MONITOR: Coadministration with fluvoxamine may increase the serum concentrations of phenytoin. The proposed mechanism is fluvoxamine inhibition of CYP450 2C9 and 2C19, the isoenzymes responsible for the metabolic clearance of phenytoin. In one case report, a patient developed ataxia in association with a phenytoin level of 49.1 mcg/mL approximately one month after fluvoxamine 50 mg/day was added to a stable regimen of phenytoin 300 mg/day. Her previous phenytoin level was 16.6 mcg/mL three months prior to addition of fluvoxamine. The patient progressively improved following gradual reduction of phenytoin dosage and fluvoxamine withdrawal. Genotyping of the patient did not show mutations for CYP450 2C9 or 2C19, further supporting the likelihood of an interaction with fluvoxamine. It is not known whether this interaction occurs with other hydantoins.

MANAGEMENT: Caution is advised if phenytoin must be used with fluvoxamine. Pharmacologic response and serum phenytoin levels should be monitored more closely whenever fluvoxamine is added to or withdrawn from therapy, and the phenytoin dosage adjusted as necessary. The same precaution may be applicable during therapy with other hydantoins, although clinical data are lacking. Patients should be advised to contact their physician if they experience symptoms of hydantoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, or changes in mental status.