Ibuprofen can cause dangerous increases in methotrexate blood levels, leading to severe toxicity. Methotrexate toxicity can cause life-threatening bone marrow suppression, kidney failure, liver damage, and fatal infections. This interaction is especially dangerous at higher methotrexate doses used in cancer treatment.
How This Interaction Works (Mechanism)
Ibuprofen reduces renal blood flow by inhibiting prostaglandin synthesis in the kidneys, which decreases the glomerular filtration rate. Since methotrexate is primarily eliminated by the kidneys, reduced renal clearance causes methotrexate to accumulate in the body. Ibuprofen may also compete with methotrexate for tubular secretion in the kidneys. Additionally, ibuprofen can displace methotrexate from plasma protein binding sites, increasing the free (active) fraction.
Source: National Comprehensive Cancer Network Drug Interactions, 2025
Avoid ibuprofen and all NSAIDs while taking methotrexate unless specifically approved by your oncologist or rheumatologist. For pain management, use acetaminophen at recommended doses. If NSAIDs are deemed necessary, your doctor should monitor methotrexate levels and kidney function closely. Report any mouth sores, unusual fatigue, easy bruising, or fever immediately, as these may indicate methotrexate toxicity.
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Sources and standards behind this page
What a drug interaction does, and how strongly it is supported, is documented in public labeling and federal safety references rather than in any one summary, and the sources below are the primary ones. They are linked so a reader can check a claim without taking this page's word for it.
- DailyMed carries the current FDA labeling for every marketed drug product, including the warnings and drug interaction sections.
- Drugs@FDA is the federal database of approved drug products and their approval documents.
- FDA: Drug interactions, what you should know explains how drug-drug, drug-food and drug-condition interactions are described on labels.
- FDA Drug Safety Communications publishes the agency's safety alerts and label changes as they are issued.
- FDA MedWatch is the program for reporting and reviewing adverse events, including suspected interactions.
- openFDA provides public access to FDA labeling and adverse event data.
- MedlinePlus drug information is the National Library of Medicine's consumer reference for what a medicine is and how it is taken.
- NIAAA: Harmful interactions documents which medicines interact with alcohol and how.
- NCCIH: Herb-drug interactions summarises the evidence on interactions between herbal products and medicines.
- National Library of Medicine maintains the drug and health databases the sources above draw on.
This page describes how this interaction works and where it is documented. It is not medical advice: a prescriber or pharmacist decides what applies to a particular patient and medication.
Frequently Asked Questions
Methotrexate and Ibuprofen have a severe interaction and should generally not be taken together without close medical supervision. The combination can cause serious, potentially life-threatening side effects. Contact your doctor immediately if you are currently taking both medications.
Ibuprofen can cause dangerous increases in methotrexate blood levels, leading to severe toxicity. Methotrexate toxicity can cause life-threatening bone marrow suppression, kidney failure, liver damage, and fatal infections. This interaction is especially dangerous at higher methotrexate doses used in cancer treatment.
Yes. Anytime you are taking multiple medications, supplements, or substances, you should inform your doctor and pharmacist. They can evaluate your specific risk factors (age, kidney function, other medications, medical conditions) and determine whether the Methotrexate and Ibuprofen combination is safe for you, or whether adjustments are needed.
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