Published: 3 March 2022


Interaction reminder: Bone marrow suppression with methotrexate and trimethoprim or co-trimoxazole

Published 3 March 2022
Prescriber Update 43(1): 6–7
March 2022

Key messages

  • Severe bone marrow suppression has been reported in patients on methotrexate who have received trimethoprim or co-trimoxazole (trimethoprim with sulfamethoxazole). Some cases have been fatal.
  • Whenever possible, trimethoprim and co-trimoxazole should be avoided in patients taking methotrexate.
  • If this drug combination cannot be avoided, warn patients about the symptoms of bone marrow suppression. Advise them to seek immediate medical attention should these symptoms occur.

The Centre for Adverse Reactions Monitoring (CARM) recently received a fatal report of methotrexate toxicity in a patient who had also received trimethoprim.

Trimethoprim and co-trimoxazole have additive bone marrow suppression effects with methotrexate

Trimethoprim or co-trimoxazole (trimethoprim with sulfamethoxazole), when used with methotrexate, increase the risk of bone marrow suppression (also known as myelosuppression).1 The evidence for this interaction consists of case reports of severe bone marrow suppression in patients on methotrexate who have received trimethoprim or co-trimoxazole. Some cases have been fatal.2

Although the mechanism for this interaction is not fully understood, trimethoprim can have additive antifolate effects and when used with methotrexate, lead to increased myelosuppression.3 Additionally, sulfamethoxazole (in co-trimoxazole) may displace methotrexate from protein binding sites and compete with the renal transport of methotrexate, leading to increased free methotrexate levels.4

It is unclear whether increases in free methotrexate levels also occurs with prophylactic doses of co-trimoxazole. Some studies suggest that prophylactic doses might not delay methotrexate clearance. Monitoring of full blood count is recommended.2,5,6

Avoid trimethoprim and co-trimoxazole in patients taking methotrexate

In patients taking methotrexate, avoid trimethoprim and co-trimoxazole.1 In circumstances where the combination cannot be avoided, healthcare professionals should consider the following.

  • Seek specialist advice for safely prescribing trimethoprim or co-trimoxazole antimicrobial therapy for patients on methotrexate in primary care.
  • Educate patients to seek immediate medical attention if they notice symptoms of bone marrow suppression. These symptoms may include:
    • mouth ulcers, sore throat, fever or chills1,7
    • new or non-resolving infections3
    • bruising or bleeding more easily than usual7
    • anaemia symptoms such as shortness of breath, dizziness and pallor.7
  • Monitor full blood count. If any abnormalities arise, consider this interaction as a possible cause8 and seek urgent specialist advice. More frequent monitoring of other laboratory tests such as renal function may be required3 – refer to local clinical guidelines and the advice from relevant specialists.
  • Ensure regular folate supplement is continued or started.4


  1. Waitematā District Health Board. 2019. Methotrexate - Safe Prescribing - Once A Week! Safer Use of High Risk Medicines February 2019. URL: (accessed 10 January 2022).
  2. Baxter K and Preston CL (eds). 2021. Stockley's Drug Interactions (online): Methotrexate + Antibacterials; Co-trimoxazole or Trimethoprim 3 April 2019. URL: (accessed 10 January 2022).
  3. Rex Medical Ltd. 2021. Trexate New Zealand Data Sheet 11 February 2021. URL: (accessed 10 January 2022).
  4. Viatris Ltd. 2021. TRISUL New Zealand Data Sheet 8 October 2021. URL: (accessed 10 January 2022).
  5. Al-Quteimat OM and Al-Badaineh MA. 2013. Methotrexate and trimethoprim–sulphamethoxazole: extremely serious and life-threatening combination. Journal of Clinical Pharmacy and Therapeutics 38(3): 203–5. URL: (accessed 11 January 2022).
  6. Watts CS, Sciasci JN, Pauley JL, et al. 2016. Prophylactic trimethoprim-sulfamethoxazole does not affect pharmacokinetics or pharmacodynamics of methotrexate. Journal of Pediatric Hematology/Oncology 38(6): 449–52. DOI: 10.1097/MPH.0000000000000606 (accessed 18 January 2022).
  7. Pfizer New Zealand Limited. 2021. Methoblastin Consumer Medicine Information August 2021. URL: (accessed 10 January 2022).
  8. New Zealand Formulary. 2022. New Zealand Formulary v115 - Interactions Checker: Methotrexate; Sulfamethoxazole + Trimethoprim 1 January 2022. URL: (accessed 10 January 2022).
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