Clonixin and Methotrexate Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate Injection
Clonixin
No brand names on record
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with NSAIDs may increase methotrexate exposure, 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 reduce the clinical effectiveness of methotrexate1. 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 2. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions 1.
Why it happens (mechanism)
Reduced methotrexate absorption; reduced renal clearance of methotrexate; protein binding displacement
Literature reports
11 reports — tap to read
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 3.
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 4.
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 5.
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 6. 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 7.
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 8.
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 9.
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 10.
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 11.
i) A 36 year-old female with juvenile rheumatoid arthritis was experiencing sarcoidosis with worsening cutaneous lesions. Her arthritis was managed with ibuprofen 600 mg three times daily. Laboratory studies showed no evidence of renal insufficiency or abnormal serum albumin levels, and a platelet count of 195,000/mm(3). One week after her first dose of oral methotrexate 7.5 mg, the patient noticed a prolonged bleeding episode following a superficial laceration and multiple petechiae. Four days later, her platelet count was 25,000/mm(3). Both the ibuprofen and methotrexate were discontinued, and nine days later her platelet count was 185,000/mm(3) 15.
j) Use of NSAIDS, including ketoprofen, with methotrexate has been shown in several case reports to increase methotrexate levels and cause toxicity 11121314.
k) A 74-year-old woman was being treated with methotrexate 2.5 mg three times a week for 3 years for rheumatoid arthritis. Flurbiprofen 100 mg per day was then added to her treatment regimen. One to two weeks later, the patient was hospitalized for a one-week period with hematemesis, diarrhea with melena, nausea, and weakness. Other medications at the time of admission included folic acid, digoxin, gemfibrozil, iron supplements, and dipyridamole. Acute gastrointestinal bleeding was discovered. In addition, the patient was diagnosed with anemia, neutropenia, and thrombocytopenia secondary to methotrexate therapy 16.
Common questions
Can I take Clonixin and Methotrexate Injection together?
Increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Clonixin and Methotrexate Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
Questions for your pharmacist
- Does my dose of Clonixin or Methotrexate Injection need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (16)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Product Information: OTREXUP(TM) subcutaneous injection solution, methotrexate subcutaneous injection solution. Antares Pharma, Inc. (per manufacturer), Ewing, NJ, 2013. DailyMed
- Furst DE, Herman RA, Koehnke R, et al: Effect of aspirin and sulindac on methotrexate clearance. J Pharm Sci 1990; 79:782-786. PubMed
- Stewart CF, Fleming RA, Germain BF, et al: Aspirin alters methotrexate disposition in rheumatoid arthritis patients. Arthritis Rheum 1991; 34:1514-1520. DOI
- Stewart CF, Fleming RA, Arkin CR, et al: Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthritis. Clin Pharmacol Ther 1990; 47:540-546. PubMed
- Skeith KJ, Russell AS, Jamali F, et al: Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis. J Rheumatol 1990; 17:1008-1010.
- Tracy TS, Worster T, Bradley JD, et al: Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol 1994; 37:453-456. PubMed
- Dupuis LL, Shore A, Silverman ED, et al: Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis. J Rheumatol 1990; 17:1469-1473.
- Todd PA & Sorkin EM: Diclofenac: a reappraisal. Drugs 1988; 35:244-285.
- Cassano WF: Serious methotrexate toxicity caused by interaction with ibuprofen (letter). Am J Pediatr Hematol Oncol 1989; 11:481-482.
- Thyss A, Milano G, Kubar J, et al: Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet 1986; 1:256-258. PubMed
- Daly H, Boyle J, Roberts C, et al: Interaction between methotrexate and non-steroidal anti-inflammatory drugs. Lancet 1986; 1:559. DOI
- Maiche AG: Acute renal failure due to concomitant action of methotrexate and indomethacin (letter). Lancet 1986; 1:1390. PubMed
- Singh RR, Malaviya AN, Pandey JN, et al: Fatal interaction between methotrexate and naproxen (letter). Lancet 1986; 1:1390. DOI
- Jih DM & Werth VP: Thrombocytopenia after a single test dose of methotrexate. J Am Acad Dermatol 1998; 39:349-351. PubMed
- Frenia ML & Long KS: Methotrexate and nonsteroidal antiinflammatory drug interactions. Ann Pharmacother 1992; 26:234-237. DOI
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