Interactions between valproic-acid(valproic acid) and Lamictal blue (lamotrigine)
valproic acid and lamotrigine (Major Drug-Drug)
ADJUST DOSE: Coadministration with valproic acid has been shown to significantly increase the plasma concentrations of lamotrigine and the risk of potentially serious and life-threatening rash induced by lamotrigine, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe, disabling tremors and ataxia have also been reported. The mechanism is competitive inhibition of lamotrigine glucuronidation by valproic acid. Pharmacokinetic data indicate that valproic acid can more than double the elimination half-life of lamotrigine, whether given with or without enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, phenytoin, and phenobarbital. In a study of eight patients treated with lamotrigine, half of whom also received EIAEDs, valproic acid 200 mg/day and 1000 mg/day (each for 3 weeks) increased the dose-corrected area under the plasma concentration-time curve (AUC) of lamotrigine by an average of 84% and 160%, respectively. Corresponding lamotrigine half-life increased by an average of 37% and 150%. Additive or synergistic pharmacodynamic effects may also contribute to the interaction, which some investigators suggest is responsible in some patients for enhanced antiepileptic efficacy beyond that attained from mere increases in plasma lamotrigine levels. Lamotrigine appears to have negligible to minor effects on the pharmacokinetics of valproic acid.
MANAGEMENT: When coadministered with valproic acid, the dosage of lamotrigine should be half that required in the absence of valproic acid. Patients should be advised to promptly notify their physician if they experience early manifestations of hypersensitivity such as fever, angioedema, and lymphadenopathy, even if a rash is not evident. Lamotrigine should be discontinued if an alternative etiology for these symptoms cannot be established. Likewise, the drug should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
