methotrexate and ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen can reduce renal clearance of methotrexate by inhibiting renal prostaglandin synthesis and decreasing renal blood flow. Additionally, NSAIDs may displace methotrexate from plasma protein binding sites, increasing the free fraction of methotrexate. These effects lead to elevated plasma concentrations of methotrexate and an increased risk of toxicity.

The combination increases the risk of severe methotrexate toxicity, including myelosuppression, hepatotoxicity, nephrotoxicity, and mucositis. This is particularly dangerous with high-dose methotrexate regimens or in patients with pre-existing renal impairment. Fatal outcomes have been reported. Symptoms may appear within days and include oral ulcers, diarrhoea, fever, and signs of bone marrow suppression.

Avoid the concomitant use of methotrexate and ibuprofen, especially in patients with renal impairment, elderly patients, or those receiving high-dose methotrexate. If no alternative anti-inflammatory or analgesic agent is available, monitor closely: check renal function, complete blood counts, and methotrexate levels frequently. Consider dose reduction of methotrexate and ensure adequate hydration and urinary alkalinisation where appropriate.

This interaction is well established and documented in multiple case reports, pharmacokinetic studies, and reviews. Guidelines generally recommend avoiding the combination, particularly in high-risk settings.