What are the interactions between Diclofenac (nonsteroidal anti-inflammatory drug (NSAID)) and Methotrexate (antifolate) when used concomitantly?

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Last updated: May 12, 2025View editorial policy

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From the Guidelines

Diclofenac tablets should not be used with methotrexate due to a potentially dangerous drug interaction. This combination can increase methotrexate levels in the blood, raising the risk of serious toxicity including bone marrow suppression, kidney damage, and severe gastrointestinal effects. If you're taking methotrexate, avoid all NSAIDs including diclofenac unless specifically approved by your doctor. The interaction occurs because both medications compete for protein binding and kidney elimination, with diclofenac reducing methotrexate clearance from the body. This effect is particularly dangerous with higher methotrexate doses used for cancer or severe autoimmune conditions.

Some key points to consider when taking methotrexate and considering pain relief options include:

  • Avoiding NSAIDs like diclofenac to prevent increased risk of toxicity
  • Considering alternative pain relief options like acetaminophen (Tylenol) under the guidance of a healthcare provider
  • Informing all doctors about all medications being taken to prevent potentially harmful drug interactions
  • Being aware of the potential for increased risk of gastrointestinal toxicity with NSAID use, as discussed in studies like 1, which highlights the importance of careful medication management.

It's essential to prioritize caution and consult with a healthcare provider before taking any medication, especially when combining drugs like methotrexate and diclofenac, to minimize the risk of adverse effects and ensure the best possible outcome in terms of morbidity, mortality, and quality of life.

From the FDA Drug Label

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).

The use of diclofenac tablets with methotrexate may increase the risk of methotrexate toxicity.

  • Key concerns include:
    • Neutropenia
    • Thrombocytopenia
    • Renal dysfunction
    • Bone marrow suppression
    • Aplastic anemia
    • Gastrointestinal toxicity During concomitant use of diclofenac potassium tablets and methotrexate, monitor patients for methotrexate toxicity 2.

From the Research

Diclofenac Tablet Use with Methotrexate

  • There is no direct evidence in the provided studies regarding the use of diclofenac tablets with methotrexate 3, 4, 5, 6.
  • Methotrexate is a first-line antirheumatic drug used to treat various conditions, including rheumatoid arthritis, and its toxicity and side effects need to be understood and managed 3.
  • Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) that can cause gastrointestinal injury and other side effects, and its use should be carefully considered, especially in patients with compromised renal function 4, 6.
  • The safety profiles of different NSAIDs, including diclofenac, celecoxib, and etoricoxib, have been compared in various studies, with differences in gastrointestinal and cardiovascular risks observed 4, 5, 6.
  • Patients with renal deficiency or compromised renal function may require lower initial doses and closer monitoring when using methotrexate or NSAIDs like diclofenac 3.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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