Drug Interaction Report

MONITOR: A possible interaction between phenytoin and intravenous immunoglobulin (IVIG) was suspected in a case of fatal hypersensitivity myocarditis. The mechanism of interaction has not been described. The case patient was a 43-year-old man with a past history of alcohol abuse who had been receiving phenytoin for the treatment of partial epilepsy for eight years. He was given intravenous immunoglobulin 0.4 g/kg for 5 days for suspected Guillain-Barre syndrome. On the second day after the last administration, the patient complained of abdominal pain, aching shoulders, and backache. He subsequently developed hypotension and died after attempts at resuscitation. An autopsy confirmed Guillain-Barre syndrome and revealed signs of a slight hepatitis with eosinophils as well as hypersensitivity (eosinophilic) myocarditis. There were no signs of alcoholic cardiomyopathy. Since phenytoin alone has been associated with hypersensitivity myocarditis, a contributory role for IVIG could not be established. Moreover, IVIG has been used successfully in some cases to treat anticonvulsant hypersensitivity syndrome, including that associated with phenytoin.

MANAGEMENT: Due to the serious nature of the possible interaction, clinicians should consider monitoring hematologic parameters such as eosinophil counts as well as blood pressure and ECG tracings if immunoglobulins are used in patients receiving phenytoin.

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ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

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