Drug Interaction Report

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 Both phenytoin and the H2-receptor antagonist may need to be withdrawn until the patient recovers.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 reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.