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Managing interactions with methotrexate

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Topics: AmoxicillinAspirinAtorvastatin · Co-trimoxazoleEsomeprazoleFluconazoleIbuprofenInteractionsIsotretinoinLansoprazoleLevetiracetamMethotrexateMetronidazoleNaproxenOmeprazolePhenytoinSimvastatinSodium valproateTamoxifenTerbinafineTrimethoprim ·

Guidance on frequently asked questions on medicine interactions with low dose methotrexate.

Contents

  1. Using low dose methotrexate
    1. Pharmacokinetics of methotrexate
  3. Clinical considerations
  4. Advice for specific medicines with methotrexate
    1. Antiseizure medicines
    2. Fluconazole
    3. Isotretinoin
    4. Metronidazole
    5. NSAIDs
    6. Penicillins
    7. Proton pump inhibitors
    8. Statins
    9. Tamoxifen
    10. Terbinafine
    11. Trimethoprim and co-trimoxazole
  6. Further information
  7. Update history

Using low dose methotrexate

Methotrexate is an immunosuppressant given once weekly. Low doses of methotrexate, less than 25mg per week, are given for conditions including rheumatoid arthritis and psoriasis. Higher doses of methotrexate are used for cancer. Its use may be associated with several serious side effects, including blood disorders, liver cirrhosis and pulmonary toxicity.

Methotrexate is only prescribed by specialists, for example, rheumatologists. It involves regular monitoring.

Advice is provided for common interactions with low dose methotrexate.

Pharmacokinetics of methotrexate

When given in low doses, methotrexate is rapidly absorbed from the gastrointestinal tract.

It is cleared from the body mainly by the kidneys via glomerular filtration and active transport.

Any medicine that can adversely affect the renal function could cause the concentration of methotrexate in serum and in tissues to increase rapidly. This can lead to toxicity.

Clinical considerations

Consider the following when reviewing medicine interactions with methotrexate:

  • presence of active infection
  • whether the new medicine can impact the kidney, liver or cause blood disorders
  • if an increase in monitoring is required as part of interaction management
  • the duration of the new medicine

Review the interaction on a case-by-case basis as the management advice may vary for different people.

The person taking methotrexate should be counselled to ask about medicine interactions before taking other prescribed medicines or buying medicines over-the-counter.

Advice for specific medicines with methotrexate

The SPS interactions advice has been developed from published evidence, literature reviews and expert opinion, where needed. It includes commonly asked questions on medicine interactions and is not comprehensive for all potential interactions with methotrexate.

Methotrexate toxicity

Some antiseizure medicines including levetiracetam, phenytoin and sodium valproate reduces the clearance of methotrexate leading to increased blood levels of methotrexate. This increases the risk of toxicity.

Reduced antiseizure efficacy

There 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

Taking methotrexate and antiseizure medicines together can increase the risk of liver toxicity.

Management options

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.

Liver toxicity

Taking methotrexate and fluconazole together can increase the risk of liver toxicity.

Management options

Routine monitoring of methotrexate should detect any signs of liver toxicity.

In the presence of a severe acute or chronic infection, some people on stable methotrexate therapy can miss doses of methotrexate whilst taking the course of fluconazole. Restart methotrexate once they feel better.

Liver toxicity

Taking methotrexate and isotretinoin together can increase the risk of liver toxicity.

Management options

Routine monitoring of methotrexate should detect any signs of liver toxicity. The dermatologist may give further advice on the use of these two medicines together.

No interaction

No interactions between metronidazole and methotrexate are expected.

Management options

Although there is no drug interaction, in the presence of a severe acute or chronic infection, some people on stable methotrexate therapy may miss doses of methotrexate whilst taking the course of metronidazole. Restart methotrexate once they feel better.

Renal toxicity

Taking methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, or naproxen together can increase the risk of renal toxicity.

Methotrexate toxicity

Taking methotrexate and NSAIDs can increase the risk of methotrexate toxicity. This is due to reduced renal elimination. Risks of this interaction are greater at high doses of methotrexate and in those with pre-existing renal impairment.

Management options

Use NSAIDs in combination with methotrexate with caution on the advice of the specialist (for example, rheumatologist). Aspirin given as an antiplatelet can be continued in people taking methotrexate. Routine monitoring of methotrexate should detect any signs of methotrexate toxicity.

Ensure you counsel people taking methotrexate to avoid buying NSAIDs over-the-counter (e.g. oral ibuprofen or analgesic doses of aspirin) without discussing with their doctor or pharmacist first.

Counsel the person to report signs of methotrexate toxicity, for example sore throat, mouth ulcers, unexplained bruising or bleeding.

Methotrexate toxicity

Penicillins (for example, amoxicillin) may reduce the clearance of methotrexate via the kidneys by competitive inhibition. This increases the risk of methotrexate toxicity.

Management options

If the duration of penicillin is short (up to 10 days), consider using with caution and advise to monitor for signs of toxicity. For example, sore throat, bruising and bleeding.

In the presence of a severe acute or chronic infection, some people on stable methotrexate therapy can miss doses of methotrexate whilst taking the course of penicillin antibiotics. Restart methotrexate once they feel better.

Methotrexate toxicity

Proton pump inhibitors (for example, lansoprazole, omeprazole or pantoprazole) reduces the clearance of methotrexate via the kidneys and increase the risk of methotrexate toxicity. Evidence to support a clinically significant interaction is limited. Risks of this interaction are greater at high doses of methotrexate and in those with renal impairment.

Management options

No additional action is required. Routine monitoring of methotrexate should detect any signs of methotrexate toxicity. Counsel the person to report signs of methotrexate toxicity, for example sore throat, mouth ulcers, unexplained bruising or bleeding.

Consider use of H2-receptor antagonists as an alternative if required.

Liver toxicity

Taking methotrexate and statins (for example, atorvastatin or simvastatin) can increase the risk of liver toxicity.

Management options

No additional action is required. Routine monitoring of methotrexate should detect any signs of liver toxicity.

Liver toxicity

Taking methotrexate and tamoxifen together can increase the risk of liver toxicity.

Management options

Routine monitoring of methotrexate should detect any signs of liver toxicity. The cancer specialist may give further advice on the use of these two medicines together.

Liver toxicity

Taking methotrexate and terbinafine together can increase the risk of liver toxicity.

Management options

Routine monitoring of methotrexate should detect any signs of liver toxicity.

In the presence of a severe acute or chronic infection, some people on stable methotrexate therapy can miss doses of methotrexate whilst taking the course of terbinafine. Restart methotrexate once they feel better.

Co-trimoxazole is a combination antibiotic containing trimethoprim and sulfamethoxazole.

Methotrexate toxicity

Taking methotrexate with trimethoprim or co-trimoxazole can increase the risk of bone marrow suppression. The mechanism is not fully understood but may be due to additive antifolate effects.

The sulfamethoxazole component of co-trimoxazole can also increase the amount of free plasma methotrexate, through competitive plasma protein binding or decreased renal clearance.

The interaction may be delayed and has occurred in people who have taken co-trimoxazole after recently stopping methotrexate.

Management options

Avoid prescribing co-trimoxazole or trimethoprim with methotrexate, due to the risk of severe bone marrow suppression. Consult your local microbiologist to consider alternative antibiotics.

If concurrent use cannot be avoided:

  • counsel the person to report signs of myelosuppression, such as sore throat, mouth ulcers, fever or chills, unexplained bruising or bleeding, and shortness of breath
  • monitor the full blood count (FBC) frequently to detect any signs of bone marrow suppression
  • consider the additional FBC monitoring, above routine monitoring (SPS page), for at least 2 months

The suggested 2-month monitoring period is based on a case report of bone marrow hypoplasia. This adverse effect occurred over 2 months after completion of a 10-day course of co-trimoxazole in combination with methotrexate.

Further information

Drug interactions: resources to support answering questions signposts to common resources for checking medicine interactions.

Using folic acid with methotrexate in rheumatoid arthritis provides information on administration and dosing.

Primary care healthcare professionals in England can seek further advice from our Medicines Advice service if the information is not available on the SPS website, or if the clinical scenario is complex.

Update history

  1. Section on interaction with trimethoprim and co-trimoxazole added
  1. Republished
  1. Published