Methotrexate with Naproxen Interaction Details

Brand Names Associated with Methotrexate

Brand Names Associated with Naproxen

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 17, 2023

Interaction Effect

Methotrexate toxicity (leukopenia, thrombocytopenia, anemia, nephrotoxicity, mucosal ulcerations)

Interaction Summary

The concomitant administration of naproxen with methotrexate should be used with caution. Use of NSAIDs, including naproxen, with methotrexate has been shown in several case reports to increase methotrexate levels and cause toxicity  resulting in deaths from severe hematologic and gastrointestinal toxicity . However, naproxen was used concurrently with methotrexate in one pharmacokinetic study in rheumatoid arthritis patients, and it did not affect methotrexate disposition . During concomitant use, monitor patients for methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction) .

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Use caution when prescribing naproxen to patients receiving methotrexate therapy due to a risk of methotrexate toxicity. During concomitant use, monitor patients for methotrexate toxicity (eg, neutropenia, thrombocytopenia, renal dysfunction) .

Mechanism Of Interaction

Decreased methotrexate clearance

Literature Reports

A) The lack of effect of naproxen on the disposition of low-dose methotrexate was reported in 12 rheumatoid arthritis patients with normal renal function. Patients received oral or intravenous methotrexate 15 mg, alone or in combination with naproxen 1000 mg/day. Systemic clearance, renal clearance, or protein binding of methotrexate were not statistically altered by naproxen. Methotrexate toxicity was not apparent with or without concomitant administration of naproxen .

B) The interaction between several NSAIDs (tolmetin, indomethacin, naproxen, and aspirin) and methotrexate was studied in 7 children with chronic arthritis. In all 7 patients, the average elimination half-life of methotrexate was significantly increased when coadministered with an NSAID, but methotrexate clearance, AUC, and volume of distribution did not change significantly. While alterations in methotrexate clearance were not statistically significant, a wide variation in changes was observed. In 6 of 7 patients, AUC increased from 19% to 140%, suggesting that some children may experience clinically significant increases in methotrexate levels with concomitant NSAID administration .

Methotrexate Overview

• Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, and sometimes other medications to treat severe active rheumatoid arthritis (RA; a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) that cannot be controlled by certain other medications. Methotrexate is also used to treat certain types of cancer including cancers that begin in the tissues that form around a fertilized egg in the uterus, breast cancer, lung cancer, certain cancers of the head and neck, certain types of lymphoma, and leukemia (cancer that begins in the white blood cells). Methotrexate is in a class of medications called antimetabolites. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to stop scales from forming. Methotrexate may treat rheumatoid arthritis by decreasing the activity of the immune system.

Naproxen Overview

• Prescription naproxen is used to relieve pain, tenderness, swelling, and stiffness caused by osteoarthritis (arthritis caused by a breakdown of the lining of the joints), rheumatoid arthritis (arthritis caused by swelling of the lining of the joints), juvenile arthritis (a form of joint disease in children), and ankylosing spondylitis (arthritis that mainly affects the spine). Prescription naproxen tablets, extended-release tablets, and suspension are also used to relieve shoulder pain caused by bursitis (inflammation of a fluid-filled sac in the shoulder joint), tendinitis (inflammation of the tissue that connects muscle to bone), gouty arthritis (attacks of joint pain caused by a build-up of certain substances in the joints), and pain from other causes, including menstrual pain (pain that happens before or during a menstrual period). Nonprescription naproxen is used to reduce fever and to relieve mild pain from headaches, muscle aches, arthritis, menstrual periods, the common cold, toothaches, and backaches. Naproxen is in a class of medications called NSAIDs. It works by stopping the body's production of a substance that causes pain, fever, and inflammation.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.