Published: 3 March 2022

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

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

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 chills^1,7
  • 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

References

1. Waitematā District Health Board. 2019. Methotrexate - Safe Prescribing - Once A Week! Safer Use of High Risk Medicines February 2019. URL: saferx.co.nz/assets/Documents/full/06640c86a2/methotrexate.pdf (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: medicinescomplete.com/#/content/stockley/x13-0743#00012516 (accessed 10 January 2022).
3. Rex Medical Ltd. 2021. Trexate New Zealand Data Sheet 11 February 2021. URL: medsafe.govt.nz/profs/datasheet/t/trexatetab.pdf (accessed 10 January 2022).
4. Viatris Ltd. 2021. TRISUL New Zealand Data Sheet 8 October 2021. URL: medsafe.govt.nz/profs/datasheet/t/Trisultab.pdf (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: onlinelibrary.wiley.com/doi/10.1111/jcpt.12060 (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: medsafe.govt.nz/consumers/cmi/m/methoblastin.pdf (accessed 10 January 2022).
8. New Zealand Formulary. 2022. New Zealand Formulary v115 - Interactions Checker: Methotrexate; Sulfamethoxazole + Trimethoprim 1 January 2022. URL: nzf.org.nz/ (accessed 10 January 2022).