Effects of Valproate on Other Drugs: Neuroleptics, MAO Inhibitors and Antidepressants: Depakine may potentiate the effect of other psychotropics eg, neuroleptics, MAOIs and antidepressants; therefore, clinical monitoring is advised and dosage should be adjusted when appropriate.
Phenobarbital: Depakine increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Primidone: Depakine increases primidone plasma levels with exacerbation of its adverse effects (eg, sedation); these signs cease with long-term treatment. Clinical monitoring is recommended, especially at the beginning of combined therapy with dosage adjustment when appropriate.
Phenytoin: Depakine increases phenytoin total plasma concentration. Moreover, Depakine increases phenytoin in its free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein-binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Effects of Other Drugs on Valproate: Antiepileptics with enzyme-inducing effect (including phenytoin, phenobarbital and carbamazepine) decrease valproate serum concentrations. Dosage should be adjusted according to blood levels in case of combined therapy.
Mefloquine increases valproic acid metabolism and has a convulsant effect: Therefore, epileptic seizures may occur in cases of combined therapy.
In case of concomitant use of valproate and highly protein-bound agents (aspirin), valproate free serum levels may be increased.
Valproate serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Other Interactions: Valproate usually has no enzyme-inducing effect: As a consequence, valproate does not reduce efficacy of estroprogestative agents in women receiving hormonal contraception. Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K-dependent factor anticoagulant.