Methotrexate with Tolfenamic Acid Interaction Details

Brand Names Associated with Methotrexate

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

Interaction Effect

Increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy

Interaction Summary

Coadministration of methotrexate with NSAIDs may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with NSAIDs may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. In general, do not administer NSAIDs prior to or concomitantly with high-dose methotrexate (ie, doses used in cancer therapy) as this may increase and prolong methotrexate exposure and increase the risk of methotrexate toxicities. Severe, and sometimes fatal, cases of gastrointestinal and hematological toxicities have occurred with coadministration of NSAIDs and methotrexate (usually in high doses). Concomitant administration of low-dose methotrexate (ie, doses used for arthritis, 7.5 to 15 mg/week) and NSAIDs has been well tolerated in many patients; however, caution is advised. Higher doses of methotrexate, such as those used in psoriasis, in combination with NSAIDs have not been fully evaluated . If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions .

Severity

Major

Onset

Delayed

Evidence

Theoretical

How To Manage Interaction

Coadministration of methotrexate with NSAIDs may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with NSAIDs may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. In general, do not administer NSAIDs prior to or concomitantly with high-dose methotrexate (ie, doses used in cancer therapy) as this may increase and prolong methotrexate exposure and increase the risk of hematologic and gastrointestinal toxicities. Concomitant administration of low-dose methotrexate (ie, doses used for arthritis, 7.5 to 15 mg/week) and NSAIDs has been well tolerated in many patients; however, caution is advised. Higher doses of methotrexate, such as those used in psoriasis, in combination with NSAIDs have not been fully evaluated . If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions ..

Mechanism Of Interaction

Decreased renal clearance of methotrexate; protein binding displacement

Literature Reports

A) The pharmacokinetics of low dose methotrexate were evaluated in 12 rheumatoid arthritis patients in the presence and absence of chronically dosed aspirin or sulindac. The patients all had been receiving methotrexate for at least 1 year and had been on a steady dose for at least 2 months prior to the study. The study was a 3-way crossover design with patients receiving either aspirin 45 to 50 mg/kg/day in 3 doses per day for 16 days, sulindac 200 mg every 12 hours for 16 days, or no NSAID treatment. On day 14, methotrexate 10 mg/m(2) was administered by IV bolus and plasma levels were obtained. No difference in methotrexate clearance was found with any of the 3 treatments. However, the AUC for the active metabolite 7-OH-methotrexate was increased, meaning the body was exposed to the metabolite for a longer period of time with the sulindac treatment and to a greater extent with aspirin treatment. The implications of this metabolite in rheumatoid arthritis treatment are not completely understood, but it is believed to have some cytotoxic activity and to be capable of inducing renal damage. Until the significance of 7-OH-methotrexate's activity and the effect of prolonged exposure to it are known, the use of these nonsteroidal antiinflammatory agents, especially aspirin, should be used with caution in combination with methotrexate .

B) The unbound fraction of methotrexate was higher and the systemic and renal clearance of methotrexate were lower with concomitant oral aspirin (3900 mg/day) and low-dose IV methotrexate (10 mg) in 15 rheumatoid arthritis patients. Single-dose disposition studies were performed prior to and after 1 weeks aspirin therapy. No hematologic, renal, or hepatic toxicity was noted .

C) The lack of effect of naproxen on the disposition of low-dose methotrexate in 12 patients with rheumatoid arthritis and with normal renal function has been demonstrated. Patients received oral or IV methotrexate 15 mg, alone or in combination with naproxen 1000 mg daily. 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 .

D) There was no observable interaction between low-dose methotrexate and either ibuprofen 800 mg 3 times daily or flurbiprofen 100 mg 3 times daily in 6 patients with rheumatoid arthritis with respect to AUC, Cmax, time to peak serum concentrations, or half-life. Assessments were made both 48 hours prior to NSAID dosing and after 6 days of NSAID while maintaining a fixed dose of methotrexate. Similar results were obtained after both oral and IM methotrexate. All patients had normal renal function and none were on corticosteroids . After 6 days of treatment with flurbiprofen 3 mg/kg/day, ketoprofen 3 mg/day, piroxicam 20 mg/day in patients stabilized on methotrexate for at least 3 months, no change in methotrexate clearance (oral or renal), unbound fraction, or amount excreted unchanged was noted .

E) 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 .

F) Concomitant administration of diclofenac and methotrexate has resulted in severe, sometimes fatal, toxicity in patients with rheumatoid arthritis or malignant neoplasms. Diclofenac and other NSAIDs appear to inhibit the renal elimination of methotrexate, leading to toxic serum concentrations of methotrexate. Concomitant administration should be avoided .

G) Severe renal toxicity associated with concomitant administration of high-dose methotrexate (12 g) and ibuprofen 400 mg every 4 hours was reported in a 18-year-old man with osteogenic sarcoma. Twenty hours after the initiation of a 6-hour methotrexate infusion, the patient had a serum creatinine of 2.3 mg/dL with a methotrexate level of 1.8 x 10(-4) M. Sixty-eight hours after the infusion, the serum creatinine was 3.5 mg/dL. Immediate and intensive rescue with folinic acid and thymidine resulted in a serum creatinine of 1.6 mg/dL at hour 284 .

H) Concomitant administration of ketoprofen and high-dose methotrexate 800 to 8300 mg/m(2) has resulted in severe methotrexate toxicity and fatality. Ketoprofen had been given simultaneously in 4 of 118 cycles of high-dose methotrexate therapy in 36 patients, with all 4 cycles being associated with severe methotrexate toxicity and fatality in 3 cases. It is speculated that a renal mechanism accounted for the interaction, possibly related to inhibition of renal prostaglandin synthesis by ketoprofen, resulting in a decreased renal perfusion rate and inhibition of methotrexate clearance. Competitive renal secretion was also suggested. In another patient in this series, diclofenac administration was associated with severe methotrexate toxicity, and other NSAIDs may also be implicated in causing this reaction .

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.

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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.