Drug Interactions between clonazepam and fosphenytoin

MONITOR: Coadministration with some benzodiazepines may alter the serum concentrations of phenytoin. Both increases and decreases have been cited by case reports and pharmacokinetic studies, while a few reported no changes. The exact mechanism of interaction is unknown, and it is uncertain whether other hydantoins are also affected. Phenytoin toxicity has been reported in patients treated with various benzodiazepines, including clobazam, chlordiazepoxide, clonazepam, and diazepam. Conversely, phenytoin may reduce the plasma concentrations of some benzodiazepines by inducing their metabolism via hepatic microsomal enzymes. In one study, pretreatment with phenytoin (4.3 mg/kg/day for 19 days) increased the clearance of clonazepam (0.03 mg/kg single oral dose) by 46% to 58% and decreased its half-life by 31% in eight healthy volunteers. In another study, mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of midazolam (15 mg oral dose) in six epileptic patients treated concomitantly with phenytoin or carbamazepine were 7.4% and 5.7%, respectively, of those observed in seven control subjects who were not receiving enzyme inducers. The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects.

MANAGEMENT: Pharmacologic response and serum hydantoin levels should be monitored more closely whenever a benzodiazepine is added to or withdrawn from therapy, and the hydantoin dosage adjusted as necessary. 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. The potential for diminished or inadequate benzodiazepine effects should be considered during concomitant use with phenytoin.