Is it safe to use methotrexate and ibuprofen (Non-Steroidal Anti-Inflammatory Drug (NSAID)) concurrently?

From the Guidelines

Using methotrexate and ibuprofen together is generally not recommended due to potential serious interactions, and instead, acetaminophen (Tylenol) should be considered for pain relief. These medications can interact in ways that increase methotrexate levels in the blood, potentially leading to toxic effects 1. The combination may reduce how quickly methotrexate is cleared from the body through the kidneys, which can increase the risk of serious side effects such as bone marrow suppression, liver damage, and kidney problems.

Key Considerations

• Methotrexate and ibuprofen can interact in ways that increase the risk of toxic effects, including bone marrow suppression, liver damage, and kidney problems 1
• The combination may reduce how quickly methotrexate is cleared from the body through the kidneys, increasing the risk of serious side effects
• Acetaminophen (Tylenol) is a safer alternative for pain relief in patients taking methotrexate
• In some cases, doctors may allow occasional or low-dose NSAID use with careful monitoring of kidney function and methotrexate levels

Monitoring and Precautions

• Patients taking methotrexate and ibuprofen concurrently should be closely monitored for signs of toxicity, including elevated liver function tests, anemia, and kidney problems
• Regular monitoring of kidney function and methotrexate levels is necessary to minimize the risk of adverse effects
• Patients should be educated on the potential risks and benefits of combining these medications and should be instructed to report any signs of toxicity to their healthcare provider immediately.

From the FDA Drug Label

Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate 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 methotrexate and ibuprofen (a Non-Steroidal Anti-Inflammatory Drug (NSAID)) concurrently is not recommended, especially with high doses of methotrexate, due to the increased risk of severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs, such as ibuprofen, are administered concomitantly with lower doses of methotrexate. Key considerations include:

• Elevated and prolonged serum methotrexate levels
• Severe hematologic and gastrointestinal toxicity
• Fatal bone marrow suppression and aplastic anemia It is essential to carefully weigh the potential benefits and risks of concurrent use and closely monitor patients for signs of toxicity 2, 2.

From the Research

Methotrexate and Ibuprofen Interaction

• The concomitant use of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen may result in a clinically significant drug interaction 3.
• Studies have shown that the coadministration of methotrexate and NSAIDs can lead to increased risk of methotrexate toxicity, including acute renal failure and pancytopenia 3, 4.
• The exact mechanism of the interaction is not fully understood, but suggested theories include reduction in methotrexate clearance, displacement of methotrexate from plasma proteins, and competition for renal tubular excretion 3.
• A study conducted in Denmark found that concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, including liver toxicity, acute renal failure, and cytopenia 4.
• Another study found that methotrexate and most NSAIDs are substrates of human organic anion transporter 3 (OAT3) and compete for tubular secretion, which is the major mechanism of the interaction between methotrexate and NSAIDs 5.

Safety Considerations

• The use of methotrexate and ibuprofen concurrently may not be safe for all patients, particularly those with pre-existing renal or hepatic impairment 3, 4.
• Patients taking methotrexate and NSAIDs should be closely monitored for signs of toxicity, including renal function, liver function, and blood cell counts 3, 4.
• Alternative treatments or dose adjustments may be necessary to minimize the risk of adverse events 4.
• The risk of gastrointestinal complications, such as ulcers or bleeding, should also be considered when using NSAIDs like ibuprofen 6.