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Patients taking the commonly prescribed drug methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP), which is used to treat certain autoimmune diseases and several types of cancer, should be aware that it has clinically important interactions with many other prescription and over-the-counter medications.
The Food and Drug Administration initially approved methotrexate in 1953 to treat cancer.[1] The agency subsequently approved the drug for treatment of severe forms of rheumatoid arthritis...
Patients taking the commonly prescribed drug methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP), which is used to treat certain autoimmune diseases and several types of cancer, should be aware that it has clinically important interactions with many other prescription and over-the-counter medications.
The Food and Drug Administration initially approved methotrexate in 1953 to treat cancer.[1] The agency subsequently approved the drug for treatment of severe forms of rheumatoid arthritis and psoriasis that have not adequately responded to first-line medications (for example, nonsteroidal anti-inflammatory drugs [NSAIDs] and oral or injected corticosteroids for rheumatoid arthritis and topical corticosteroids for psoriasis).
Drugs that increase risk of methotrexate toxicity[2]
The Table below provides examples of 22 different oral drugs that, when taken concomitantly (simultaneously) with methotrexate, may increase methotrexate in the blood to toxic levels or enhance certain toxic effects of methotrexate in other ways. The list includes certain antibiotics, diuretics (water pills), NSAIDs, proton pump inhibitors for suppressing stomach acid and seizure drugs.
Examples of Oral Drugs That Increase the Risk of Methotrexate Toxicity
| Generic Name | Brand Name(s)† | Drug Class |
|---|---|---|
| amoxicillin | AMOXIL, LAROTID | Antibiotic |
| aspirin | BAYER, DURLAZA, ECOTRIN, VAZALORE | Nonsteroidal anti-inflammatory drug |
| dantrolene | DANTRIUM | Drug for muscle spasm due to neurologic disorders |
| dexlansoprazole* | DEXILANT | Proton pump inhibitor |
| diclofenac** | CAMBIA, ZIPSOR, ZORVOLEX | Nonsteroidal anti-inflammatory drug |
| dicloxacillin | generic only | Antibiotic |
| doxycycline* | ACTICLATE, DORYX, MONODOX, ORACEA, VIBRAMYCIN | Antibiotic |
| esomeprazole* | NEXIUM | Proton pump inhibitor |
| flurbiprofen | generic only | Nonsteroidal anti-inflammatory drug |
| hydrochlorothiazide* | MICROZIDE | Diuretic (water pill) |
| ibuprofen | ADVIL, IBU-TAB, IBUPROHM, MIDOL LIQUID GELS, MOTRIN IB, TAB-PROFEN | Nonsteroidal anti-inflammatory drug |
| indomethacin** | INDOCIN, TIVORBEX | Nonsteroidal anti-inflammatory drug |
| ketoprofen | generic only | Nonsteroidal anti-inflammatory drug |
| lansoprazole* | PREVACID | Proton pump inhibitor |
| leflunomide** | ARAVA | Rheumatoid arthritis drug |
| levetiracetam | ELEPSIA XR, KEPPRA, ROWEEPRA, SPRITAM | Seizure drug |
| omeprazole* | PRILOSEC | Proton pump inhibitor |
| pantoprazole* | PROTONIX | Proton pump inhibitor |
| penicillin | generic only | Antibiotic |
| phenytoin | DILANTIN, PHENYTEK | Seizure drug |
| sulindac* | generic only | Nonsteroidal anti-inflammatory drug |
| triamterene** | DYRENIUM | Diuretic (water pill) |
†Brand name combination products were excluded.
*Designated as Limited Use
**Designated as Do Not Use
One of the most common ways that many of these interacting drugs increase the risk of methotrexate toxicity is by interfering with the removal of methotrexate from the body by the kidneys.
Methotrexate toxicity can cause a wide range of serious and life-threatening adverse effects, including
- anemia (low red blood cell levels);
- low blood platelet levels, which can lead to bleeding;
- low white blood cell levels, which can lead to serious infections;
- liver damage; and
- kidney failure.[3]
Symptoms of methotrexate toxicity may include fatigue, chills, fever, dizziness, mouth sores, nausea, vomiting, diarrhea, easy bruising and hair loss.
Other important drug interactions
Concomitant use of methotrexate and the anticoagulant (blood thinner) warfarin (COUMADIN, JANTOVEN) can increase blood levels of warfarin.[4] This can increase the risk of bleeding complications. Patients who take warfarin should undergo more frequent monitoring of warfarin levels during therapy with methotrexate and initially after discontinuing methotrexate.
In contrast, concomitant use of methotrexate and the breast cancer drug tamoxifen (SOLTAMOX) increases the risk of dangerous blood clots, such as deep vein thrombosis (typically clots in the large veins of the legs) and pulmonary embolism (blood clots in the lungs).[5] The mechanism of this interaction is unknown.
What You Can Do
If you need treatment with methotrexate, review all your other medications with your doctor to assess your risk for potentially significant drug interactions. If you are taking certain medications that interact with methotrexate, you may need a lower dose of methotrexate or more frequent monitoring for signs of methotrexate toxicity, or your doctor may advise you to stop the interacting drug. Be aware that other drugs not listed in this article also may have dangerous interactions with methotrexate.
References
[1] Orion Corporation. Label: methotrexate tablets. February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8f1260de-b60c-4f0e-8af6-0e957b0a281b. Accessed October 28, 2019.
[2] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “methotrexate.” Accessed October 28, 2019.
[3] Orion Corporation. Label: methotrexate tablets. February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8f1260de-b60c-4f0e-8af6-0e957b0a281b. Accessed October 28, 2019.
[4] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Search term: “methotrexate.” Accessed October 28, 2019.
[5] Ibid.
