• lamotrigine (LTG)in combination with valproic acid (VPA) may work synergistically to provide superior seizure control than each drug independently
  • VPA inhibits LTG metabolism by UGT1A4 glucuronidation, increasing plasma LTG concentrations[1]
  • Valproic acid (VPA) decreases lamotrigine (LTG) clearance by 30% at 125 mg/day and 50% at 250 mg and higher[2]
  • maximal inhibition of LTG clearance by VPA occurs at doses of 500 mg/day
  • when converting from VPA plus LTG therapy to LTG monotherapy: LTG may be kept steady until VPA is dropped to 125 mg/day, then raised by 30% and doubled on VPA discontinuation
  • when converting from LTG monotherapy to a polytherapy regimen with VPA, the dose of LTG can be cut by 50% (without affecting stable LTG concentrations) on the day that VPA is started at doses of 250mg/day or higher
  • when LTG is added to VPA, the risk of rash may increase unless LTG is introduced at a low dose and tapered up slowly but adding VPA per se to an LTG regimen does not increase this risk because the patient has already taken LTG long enough to become desensitised to this effect[3]
References

Milosheska, D., Lorber, B., Vovk, T., Kastelic, M., Dolžan, V., & Grabnar, I. (2016). Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. British Journal of Clinical Pharmacology, 82(2), 399–411. doi:10.1111/bcp.12984

Gidal, B. E., Sheth, R., Parnell, J., Maloney, K., & Sale, M. (2003). Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy. Epilepsy Research, 57(2–3), 85–93. doi:10.1016/j.eplepsyres.2003.09.008

Kanner, A. M. (2004). When thinking of lamotrigine and valproic acid, think ‘pharmacokinetically’! Epilepsy Currents, 4(5), 206–207. doi:10.1111/j.1535-7597.2004.04515.x

Milosheska D, Lorber B, Vovk T, Kastelic M, Dolžan V, Grabnar I. Pharmacokinetics of lamotrigine and its metabolite N-2-glucuronide: Influence of polymorphism of UDP-glucuronosyltransferases and drug transporters. Br J Clin Pharmacol. 2016 Aug;82(2):399-411. doi: 10.1111/bcp.12984. Epub 2016 May 29.

Cite this: CNKE contributors.Valproic acid and Lamotrigine combination. CNKE.org, The Child Neurology Knowledge Environment. 26 July 2025. Available at: https://cnke.org/articles/312 Accessed  26 July 2025.