Lamotrigine × Valproic acid

Valproate inhibits glucuronidation, the main elimination route of lamotrigine, and the lamotrigine half-life nearly doubles (lamotrigine and valproate SmPCs). According to the US Food and Drug Administration (FDA) label, lamotrigine concentrations rise slightly more than 2-fold with valproate. The risk of serious lamotrigine rash is higher with a high starting dose, with a fast dose increase and with concomitant valproate (lamotrigine SmPC).

Rash, usually within the first 8 weeks of lamotrigine; nearly all life-threatening cases occur within 2–8 weeks. Severe forms: Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) with fever, swollen lymph nodes, facial oedema and blood, liver and kidney involvement. Fever and swollen lymph nodes can appear before the rash. Children have a higher risk of serious rash than adults.

The labels do not ban the pair, but with valproate lamotrigine follows a separate, lower-dose schedule, and neither the starting dose nor the rate of increase may be exceeded (lamotrigine SmPC). In epilepsy, adults and adolescents from 13 years: 25 mg every other day in weeks 1 and 2, 25 mg/day in weeks 3 and 4, then increases of no more than 25–50 mg every 1–2 weeks to the usual maintenance dose of 100–200 mg/day (lamotrigine SmPC). This schedule applies with valproate even if the patient takes other drugs; in children aged 2–12 the dose is calculated per kilogram of body weight from a separate table (lamotrigine SmPC). In bipolar disorder, when valproate is added to a stable lamotrigine dose, the lamotrigine dose is halved from the first week, for example from 200 to 100 mg/day; the maximum dose with valproate is 200 mg/day (lamotrigine SmPC). The US Food and Drug Administration (FDA) valproate label also requires a lower lamotrigine dose. At the first sign of rash, lamotrigine is stopped at once unless the rash is clearly unrelated to it (lamotrigine SmPC).