The question concerns the interaction between lamotrigine and sodium valproate.

Fråga: The question concerns the interaction between lamotrigine and sodium valproate.

Sammanfattning: Concomitant administration of sodium valproate has been reported to increase the elimination half-life of lamotrigine up to two-fold. It has been suggested that this might be due to hepatic competition between sodium valproate or its metabolites and lamotrigine for glucuronidation. A beneficial synergistic effect of a combined treatment with lamotrigine and sodium valproate as compared with either treatment alone has been suggested in some case reports, possibly due to complementary pharmacodynamic actions. This therapeutic advantage may however be limited by potential adverse effects resulting from the valproate-induced rise in serum lamotrigine concentrations.

Svar: Lamotrigine is given in addition to standard antiepileptic drugs in the treatment of partial seizures and generalised tonic-clonic seizures. The drug has a half-life of 25-30h and most of the dose is excreted in the urine as a glucuronide (1,2). Treatment with other antiepileptic agents alters the clearance of lamotrigine. Enzyme-inducing anticonvulsants increase its metabolism and reduce the half-life to approximately 15h. Sodium valproate was found to approximately double the elimination half-life of lamotrigine from 30 to 59h in a clinical trial with patients suffering from intractable epilepsy (1,2). This interaction between lamotrigine and sodium valproate has been investigated in healthy volunteers (2). Six subjects received a single dose of lamotrigine 100 mg, with and without sodium valproate 200 mg 8 hourly. Total clearance was found to be acutely decreased by 21 per cent and the elimination half-life was increased from 37 to 48h. Renal clearance was not impaired. This reduction in metabolic clearance was suggested to be due to competitive inhibition of hepatic enzymes. Only one to three per cent of an administered dose of valproic acid is excreted unchanged in the urine, while most of the parent drug and several of its metabolites undergo conjugation with glucuronic acid (3).

There have been some recent case reports in which the combination of lamotrigine and sodium valproate in some patients was found to be more effective than either drug alone (4,5). However, this improved therapeutic response could not be explained by the increase of lamotrigine concentration by sodium valproate, and was therefore suggested to be due to complementary pharmacodynamic effects of these two drugs. It was suggested by the authors that another explanation could be that lamotrigine raises plasma sodium valproate. However, no clinical trials have been performed which support or demonstrate that this could be the case.

Whether lamotrigine increases the concentration of other antiepileptic drugs is not fully established; inhibition of carbamazepine metabolism has been described in a few patients but this has not been observed in any controlled trial (1).