Drug Interactions between famotidine / ibuprofen and fosphenytoin

MONITOR: Coadministration with famotidine or ranitidine may rarely increase the plasma concentrations of phenytoin, resulting in toxicity. The mechanism of interaction is unknown. Neither famotidine nor ranitidine has been shown to significantly inhibit CYP450-mediated oxidative metabolism at therapeutic dosages. In addition, no effects on clearance or plasma levels of phenytoin were reported during coadministration with famotidine or ranitidine in separate pharmacokinetic studies. Data suggesting a potential interaction are limited to isolated case reports of phenytoin toxicity shortly after initiation or dosage increase of the H2-receptor antagonist. In at least a couple cases, the patient was elderly and had underlying conditions that may have contributed to the development of toxicity (e.g., renal dysfunction, hypoalbuminemia).

MANAGEMENT: Until more information is available, caution is advised if phenytoin is prescribed in combination with famotidine or ranitidine, particularly in elderly patients. Clinicians should be alert for signs and symptoms of phenytoin toxicity such as ataxia, incoordination, tremor, nystagmus, hypotension, slurred speech, lethargy, nausea, vomiting, mental confusion, and psychosis. The possibility of an interaction should be considered if toxicity occurs shortly (e.g., within a month) after initiation or change of dosage of the H2-receptor antagonist. Both phenytoin and the H2-receptor antagonist may need to be withdrawn until the patient recovers.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.