Methotrexate and anticonvulsants

Methotrexate toxicity with anticonvulsants (antiseizure medicines)

• some antiseizure medicines including levetiracetam, phenytoin and sodium valproate reduce the clearance of methotrexate leading to increased blood levels of methotrexate
  • leads to an increased risk of toxicity

• reduced antiseizure efficacy
  • are case reports of decreased efficacy of phenytoin and sodium valproate when given with methotrexate
  • risks of these interactions are greater at high doses of methotrexate

• liver toxicity
  • co-administration of methotrexate and antiseizure medicines together can increase the risk of liver toxicity

Suggested management options (1):

• routine monitoring of methotrexate should detect any signs of methotrexate or liver toxicity
  • inform the specialist looking after methotrexate therapy if antiseizure medicines are started
  • monitor for any changes in seizure activity
• counsel the person to report signs of methotrexate toxicity, for example sore throat, mouth ulcers, unexplained bruising or bleeding

Reference:

1. NHS Specialist Pharmacy Service (June 30th 2025). Managing interactions with methotrexate