Published: 2 March 2023


Administration of methotrexate in patients taking sodium valproate may reduce seizure or mood control

Published: 2 March 2023
Prescriber Update 44(1): 15–16
March 2023

Key messages

  • Some case reports describe a significant reduction in the serum level of sodium valproate soon after administration of methotrexate, resulting in seizures.
  • Competitive protein binding, displacement from albumin and rapid metabolism are possible causes of the reduction in serum sodium valproate levels.
  • When starting methotrexate therapy in valproate patients, monitor the patient’s clinical response (seizure control or mood control) and serum valproate levels as appropriate.


The sodium valproate (Epilim) data sheet has been updated to include an interaction with methotrexate. Some case reports describe a significant reduction in the serum level of sodium valproate after administration of methotrexate, resulting in seizures.1

This article highlights the published case reports, plus the possible mechanism for this drug-drug interaction and its management.

Case reports

Two case reports in the literature have documented this drug-drug interaction. The first case involved the use of low-dose weekly methotrexate for the treatment of psoriasis2 while the second case involved the use of high-dose methotrexate infusion for childhood leukaemia.3 In both cases, significant reductions in serum sodium valproate levels were observed soon after administration of methotrexate, resulting in seizures.2,3

As of 1 December 2022, no cases of this drug-drug interaction had been reported to the Centre for Adverse Reactions Monitoring.

Proposed mechanism for the interaction

Methotrexate (a weak acid and 75% bound to albumin) competes with sodium valproate (90% bound to albumin) for binding to albumin. Following the displacement of sodium valproate from albumin, a larger unbound proportion is available for metabolism by the liver, resulting in decreased serum sodium valproate levels.2

Management of the interaction

Where concurrent use of sodium valproate and methotrexate is indicated, healthcare professionals should be aware of the potential for reduction in seizure or mood control.1

Monitor the patient’s clinical response from sodium valproate treatment and consider monitoring serum sodium valproate levels as appropriate.1

Management of this interaction may require dose adjustment of sodium valproate. If clinically appropriate, a non-interacting alternative to methotrexate should be considered in patients taking sodium valproate.2


  1. Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics. 2022. Epilim New Zealand Data Sheet 15 September 2022. URL: (accessed 22 December 2022).
  2. Cherian A, Shetty SC, Divya KP, et al. 2021. Weekly methotrexate may reduce valproate levels causing relapse of genetic generalized epilepsy. Epilepsy & Behavior Reports 16(7 May): 100457. DOI: (accessed 22 December 2022).
  3. Schrøder H and Ostergaard JR. 1994. Interference of high-dose methotrexate in the metabolism of valproate? Pediatriatric Hematology and Oncology 11(4): 445-9. DOI: 10.3109/08880019409140546 (accessed 10 January 2023).
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