Levetiracetam and methotrexate: Risk of drug-drug interaction

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Levetiracetam is one of the antiepileptic drugs used as adjunctive treatment or as monotherapy for epilepsy. Methotrexate is a chemotherapy agent and immune system suppressant used to treat certain types of cancer (e.g. breast cancer, gestational choriocarcinoma, lymphosarcoma, lymphocytic and meningeal leukaemia) and autoimmune diseases including rheumatoid arthritis and psoriasis.

Background of Safety Issue

Health Canada reviewed the potential interaction between levetiracetam and methotrexate, concluding that there are risks of serious side effects when these drugs are taken together1. Taking into account the literature available and international post-marketing reports, the interaction between the two drugs may lead to higher amount of methotrexate in the blood and cause serious side effects, which can be fatal, including acute kidney failure1. However, the review of these reports was limited by many factors such as pre-existing diseases, concomitant medications and lack of laboratory data for methotrexate blood levels1.

A possible mechanism responsible for decreased methotrexate elimination when co-administered with levetiracetam has not been proposed2. However, it is well known that methotrexate interacts with multiple medications2. Drugs that are highly protein bound like many antiepileptics, have been shown to reduce renal clearance of methotrexate through protein-drug displacement and lead to increased serum concentration of methotrexate, putting patients at risk of toxicity3.

Both levetiracetam and methotrexate have been labelled for renal toxicity4,5. Since methotrexate is excreted through the kidney, any renal toxicity with concomitant medications may contribute to a delay in excretion of methotrexate.

Local Scenario

Currently, there are 11 products containing levetiracetam and 13 registered products containing methotrexate registered in Malaysia.

The NPRA has received a total of 77 reports with 143 adverse events related to levetiracetam. For methotrexate, the NPRA has received a total of 271 reports with 538 adverse events. However, no case of interaction between levetiracetam and methotrexate has been received to date.


Advice for Healthcare Professionals

  • Co-administration of levetiracetam and methotrexate may result in delayed elimination of methotrexate and increased likelihood of toxicity2.
  • Consider temporarily switching levetiracetam to another antiepileptic (i.e. lorazepam) to prevent interaction with methotrexate2.
  • Monitoring of blood methotrexate and levetiracetam levels should be done when patients are treated with these two drugs at the same time1.
  • Counsel patients on the possible signs and symptoms of methotrexate toxicity, including acute kidney failure.
  • Please report all adverse events suspected to be related to the use of methotrexate or levetiracetam to the NPRA.



  1. Health Canada (2016). Safety Reviews – Levetiracetam and Methotrexate – Assessing the Potential Risk of Drug-drug Interaction.
  2. Emily Bain et al. (2014). Drug-drug Interaction between Methotrexate and Levetiracetam Resulting in Delayed Methotrexate Elimination. Annals of Pharmacotherapy 48(2): 292-296.
  3. Yap. K. et al. (2008). Drug Interactions between Chemotherapeutic Regimens and Antiepileptics. Clin. Ther. 30: 1385-1407.
  4. Methotrexate Package Insert, Malaysia [version: 8 Aug 2011].
  5. Keppra® Package Insert, Malaysia [version: 12 July 2017].



This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.


National Pharmaceutical Regulatory Agency (NPRA)

Lot 36, Jalan Universiti (Jalan Prof Diraja Ungku Aziz), 46200 Petaling Jaya, Selangor, Malaysia.

  • Phone: +603-7883 5400




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