Drug Interactions between Depakote and phentermine / topiramate

MONITOR: Coadministration with topiramate may increase the plasma concentrations of phentermine. The exact mechanism of interaction has not been established. When a single 15 mg dose of phentermine was administered with a 92 mg dose of topiramate, phentermine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 13% and 42%, respectively, compared to phentermine administered alone. No significant changes were observed in the pharmacokinetics of topiramate.

MANAGEMENT: Caution is advised when phentermine is used in combination with topiramate. Patients should be monitored for potentially increased adverse effects of phentermine such as dizziness, restlessness, insomnia, tremor, headache, euphoria, dysphoria, palpitation, tachycardia, and blood pressure elevation.

MONITOR: Coadministration of topiramate and valproic acid has been reported to decrease mean valproic acid systemic exposure (AUC) by 11% and topiramate AUC by 14%. The mechanism of interaction may involve increased metabolism of both drugs. Pharmacodynamically, concomitant administration of these agents may be associated with an increased risk of hyperammonemia, with or without encephalopathy, relative to topiramate alone and in patients who have tolerated either drug alone. In clinical investigational programs, hyperammonemia was observed in adolescents receiving topiramate monotherapy for migraine prophylaxis (incidence above normal: 26% for 50 mg/day and 41% for 100 mg/day vs. 22% for placebo) and in pediatric patients aged 1 to 24 months receiving adjunctive topiramate for partial onset epilepsy (9% to 10% for topiramate 5 to 25 mg/kg/day vs. 8% for placebo). Although topiramate is not indicated for use in infants and toddlers, valproic acid clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal: 7% to 17% for 5 to 25 mg/kg/day vs. 0% for placebo). Markedly increased, dose-related hyperammonemia (0% for 5 mg/kg/day, 7% for 15 mg/kg/day and 8% for 25 mg/kg/day vs. 0% for placebo) also occurred in these patients. In addition, hypothermia with and without hyperammonemia has been reported after initiating topiramate or increasing the dosage. The mechanism is unknown.

MANAGEMENT: Pharmacologic response to topiramate and valproic acid should be monitored more closely following addition or withdrawal of one or the other drug. Dose adjustments may be required if an interaction is suspected. Patients should be advised to notify their physician if they experience loss of seizure control. Patients should also be monitored for clinical symptoms of hyperammonemic encephalopathy, which often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Monitoring of ammonia levels should be considered if such symptoms occur. Signs and symptoms usually abate with discontinuation of either drug. Discontinuation of topiramate or valproic acid should be considered if hypothermia occurs. Patients should be monitored for symptoms such as lethargy, confusion, coma, and cardiovascular or respiratory system changes.