Published: 7 March 2024


Interacting safely with low-dose methotrexate

Published 7 March 2024
Prescriber Update 45(1): 15–17
March 2024

Key messages

  • Low-dose methotrexate is used in the treatment of autoimmune conditions, such as psoriasis and rheumatoid arthritis, often in patients taking other medicines.
  • Use of methotrexate with some medicines may increase the risk of methotrexate side effects and toxicity.
  • Consider possible medicine interactions and their appropriate management when starting or changing doses of medicines in patients taking low-dose methotrexate.

Low-dose methotrexate in weekly doses is used as an immunosuppressant to treat conditions such as psoriasis and rheumatoid arthritis. Patients taking low-dose methotrexate may need to take other medicines for long-term conditions or when acutely unwell.

Taking methotrexate with some medicines may increase the risk of methotrexate side effects and toxicity. This article describes some of these interactions.

Characteristics of interactions1,2

Methotrexate is a cytotoxic medicine that inhibits the enzyme dihydrofolate reductase, thereby interfering with folic acid metabolism. Additive toxicity may occur if methotrexate is used with medicines with similar pharmacological effects.

Methotrexate, even at low doses, can cause bone marrow suppression and renal, hepatic, gastrointestinal or pulmonary toxicity. Elevated plasma concentrations of methotrexate may increase the risk of toxicity.

Methotrexate is partly bound to serum albumin following absorption. Concomitant use with medicines competing for the same albumin binding site or inhibiting albumin binding may displace methotrexate, increasing plasma concentrations.

Methotrexate is almost completely excreted through the kidneys by glomerular filtration and active transport. Medicines that affect renal function or renal tubular transport may reduce the clearance of methotrexate, thereby increasing plasma concentrations.

Examples of interactions

Table 1 provides some examples of interactions with methotrexate, showing the effect on methotrexate (increase in plasma levels or pharmacological effect), the mechanism and interacting medicines. Methotrexate can affect other medicines, which are not discussed here. Refer to the methotrexate data sheets for complete information on known interactions.

Table 1: Some examples of interactions increasing methotrexate effects

Effect Mechanism Examples of medicines
Increase in methotrexate plasma levels (pharmacokinetic interactions) Reduced renal clearance of methotrexate Penicillins and sulfonamides (eg, co-trimoxazole), NSAIDs
Reduced renal tubular secretion Probenecid, loop diuretics, ciprofloxacin, NSAIDs
Protein binding displacement Sulfonamides, penicillins, tetracyclines, chloramphenicol, salicylates, NSAIDs, sulfonylureas, phenytoin
Increase in methotrexate pharmacological effect (pharmacodynamic interactions) Additive toxicity (hepatotoxicity) Hepatotoxic medicines such as azathioprine, sulfasalazine, leflunomide, alcohol, cytotoxic medicines, retinoids
Additive toxicity (haemotoxicity) Myelosuppressive medicines such as co-trimoxazole, trimethoprim, leflunomide, allopurinol, ciclosporin, cytotoxic medicines.
Additive toxicity (other) Leflunomide (pulmonary toxicity), cytotoxic medicines (pulmonary, gastrointestinal, renal toxicity), amiodarone (ulcerative skin lesions)

Sources: Trexate and DBL™ Methotrexate Injection New Zealand Data Sheets (accessed 17 January 2024).

Clinical considerations

When starting a new medicine in a patient taking methotrexate, consider whether the medicine may affect the kidneys or liver or cause blood disorders. Depending on the situation, the methotrexate dose may need to be adjusted or doses withheld. An increase in monitoring may be required.1–3

Advise patients to:

  • watch out for signs of potential toxicity and what to do if these occur
  • check with a healthcare professional before taking any over-the-counter medicines, including natural health products.3

New Zealand case reports

Since 2020, there have been five cases of drug interactions with low-dose methotrexate. The medicines involved in these reports were co-trimoxazole (2 cases), trimethoprim, amoxicillin + clavulanic acid, and aspirin and sodium valproate.

The amoxicillin + clavulanic acid case reported deranged liver function tests following four doses of amoxicillin + clavulanic acid. These data sheets are being updated to include an interaction with methotrexate.

More information

See also the following Prescriber Update articles for more information about the New Zealand case reports and/or interactions.


  1. Rex Medical Ltd. 2021. Trexate New Zealand Data Sheet 11 February 2021. URL: (accessed 17 January 2024).
  2. Pfizer New Zealand Ltd. 2023. DBL Methotrexate Injection New Zealand Data Sheet 28 August 2023. URL: (accessed 17 January 2024).
  3. Specialist Pharmacy Service. 2023. Managing interactions with methotrexate 28 December 2023. URL: (accessed 19 January 2024).
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