PlainMeds provides educational information only. This is not medical advice. Always consult your doctor or pharmacist.

Diflunisal and Methotrexate Interaction

Drug interaction information between Diflunisal and Methotrexate.

Diflunisal and Methotrexate have a documented moderate interaction in FDA labeling.

FDA drug labeling documents a moderate-severity interaction between Diflunisal and Methotrexate. Major interactions are generally avoided, moderate ones may need monitoring or a dose adjustment, and minor ones are usually low-risk. This page shows the documented mechanism and guidance. Label-documented interactions are not a complete safety review, so always confirm your own medications with a pharmacist or doctor. Educational information, not medical advice.

Drug A

Diflunisal

Nonsteroidal Anti-Inflammatory Drug (NSAID)

Drug B

Methotrexate

Disease-Modifying Antirheumatic Drug (DMARD)

How They Interact

Diflunisal can prevent your kidneys from clearing methotrexate out of your system, which can lead to toxic levels of the drug in your blood. This makes the side effects of methotrexate much more dangerous.

What To Do

Be very careful when using these drugs together and make sure your doctor monitors your health and blood work closely.

FDA Label Information

Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Diflunisal Also Interacts With

View all Diflunisal interactions →

Methotrexate Also Interacts With

View all Methotrexate interactions →

Frequently Asked Questions

Can I take Diflunisal and Methotrexate together?

This is a moderate interaction. Be very careful when using these drugs together and make sure your doctor monitors your health and blood work closely.

How serious is the interaction between Diflunisal and Methotrexate?

This interaction is classified as "moderate" severity by the FDA. Moderate interactions may worsen your condition or change how your medications work.

Why do Diflunisal and Methotrexate interact?

Diflunisal can prevent your kidneys from clearing methotrexate out of your system, which can lead to toxic levels of the drug in your blood. This makes the side effects of methotrexate much more dangerous.

Understanding the Diflunisal and Methotrexate Interaction

FDA-approved prescribing information for these two drugs flags their combination as a moderate-severity interaction. Diflunisal belongs to the Nonsteroidal Anti-Inflammatory Drug (NSAID) class and Methotrexate belongs to the Disease-Modifying Antirheumatic Drug (DMARD) class - two categories that can collide when co-prescribed. The mechanism described in FDA labeling is: Diflunisal can prevent your kidneys from clearing methotrexate out of your system, which can lead to toxic levels of the drug in your blood. Severity tiers matter: major flags generally advise avoidance, moderate flags often require monitoring or dose adjustment, and minor flags may only call for awareness.

Context around a specific patient determines real-world impact. Diflunisal has 17 total documented interactions on file in this dataset, and Methotrexate has 38. Each additional medication compounds the interaction surface, which is why pharmacists run full-profile checks rather than evaluating one pair at a time. FDA-derived guidance for this pair is: Be very careful when using these drugs together and make sure your doctor monitors your health and blood work closely. Timing of doses, renal and hepatic function, age, and other concurrent prescriptions all shape whether a labeled interaction matters clinically.

An interaction flag is not a verdict. A large share of labeled interactions are managed routinely in clinical practice, the fix may be as simple as spacing doses or adding a monitoring test. Others require the prescriber to choose a different medication entirely. This page surfaces FDA-sourced labeling and openFDA data for educational purposes only; it is not medical advice and cannot account for your full clinical picture. Never start, stop, or adjust either Diflunisal or Methotrexate based on a web page, speak with your prescriber or pharmacist before making any change.

Sources: FDA Drug Labels (SPL) via openFDA (2026). This is for informational purposes only and is not medical advice. Always consult your healthcare provider about drug interactions.