Drug Interactions between meperidine / promethazine and phenytoin

GENERALLY AVOID: Phenytoin may induce the metabolism of meperidine to normeperidine, the latter of which has been associated with adverse effects such as lethargy, agitation, and seizures. The interaction may decrease the therapeutic effects of meperidine while increasing its adverse effects. In four healthy volunteers, phenytoin (300 mg daily for 10 days) increased the systemic clearance of meperidine by 26%, decreased its elimination half-life by 33%, and decreased its oral bioavailability by 30%. Systemic exposure (AUC) of normeperidine from intravenous and oral meperidine increased by 53% and 25%, respectively, during coadministration with phenytoin.

MANAGEMENT: Meperidine product labeling recommends that the combination of meperidine and phenytoin be avoided. The same precaution may be applicable to other hydantoins, although clinical data are lacking.

ADJUST DOSE: The central nervous system and respiratory depressant effects of meperidine may be potentiated by concomitant use of other agents with CNS depressant effects. An increased risk of serious adverse reactions such as respiratory depression, hypotension, profound sedation, syncope, coma, and even death should be considered, particularly in elderly or debilitated patients.

MANAGEMENT: Caution and dosage adjustments are advisable when meperidine is used in combination with other narcotic analgesics, general anesthetics, phenothiazines, sedative-hypnotics, tranquilizers, tricyclic antidepressants, or other CNS depressants such as alcohol. A lower dosage of meperidine should be considered initially, then titrated carefully according to pain level and clinical response. Meperidine dosage reductions of 25% to 50% have been recommended for patients receiving phenothiazines and other tranquilizers. Patients should be advised to avoid rising abruptly from a sitting or recumbent position, and to notify their physician if they experience dizziness, lightheadedness, orthostasis, syncope, tachycardia, or excessive CNS effects that interfere with their normal activities. Patients should also avoid driving or operating hazardous machinery until they know how these medications affect them.

MONITOR: Concurrent use of phenothiazines and phenytoin may increase the effect of phenytoin and decrease the effect of the phenothiazine. The mechanism is unknown and clinical data have been inconsistent.

MANAGEMENT: Close monitoring for clinical and laboratory evidence of phenytoin toxicity is indicated. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.