What Medications Cannot Be Taken With Methotrexate?

October 12, 2025 •

3 min read

In 2023, over 24,000 adverse event reports related to methotrexate were submitted to pharmacovigilance databases worldwide. Understanding what medications cannot be taken with methotrexate is crucial for patient safety and treatment efficacy, as many common drugs can lead to serious interactions.

Quick Summary

Methotrexate can interact with many common drugs, including NSAIDs, certain antibiotics, and proton pump inhibitors, potentially leading to increased toxicity. This overview details key interactions and safety measures.

Key Points

NSAIDs: Medications like ibuprofen and naproxen can reduce kidney clearance of methotrexate, increasing toxicity risk, especially at high doses.
Certain Antibiotics: Penicillins and especially trimethoprim-sulfamethoxazole (Bactrim) can dangerously elevate methotrexate levels and should often be avoided.
Proton Pump Inhibitors (PPIs): Drugs like omeprazole (Prilosec) used for heartburn can delay methotrexate elimination, increasing side effect risks.
Alcohol: Consuming alcohol while on methotrexate significantly increases the risk of liver damage (hepatotoxicity) and should be avoided.
Live Vaccines: Receiving live vaccines (e.g., MMR, chickenpox) is unsafe during methotrexate treatment due to a suppressed immune system.
Kidney and Liver Health: Other drugs that are hard on the kidneys (nephrotoxic) or liver (hepatotoxic) can compound the risks associated with methotrexate.
Patient Communication: Always inform your healthcare provider about all medications, including over-the-counter drugs and supplements, to prevent harmful interactions.

Methotrexate is a widely used medication, classified as a disease-modifying antirheumatic drug (DMARD) and an immunosuppressant, prescribed for conditions like rheumatoid arthritis (RA), psoriasis, and certain cancers. While effective, its safety depends heavily on avoiding interactions with other substances that can increase its concentration in the body, leading to severe toxicity. The risk of these interactions often depends on the methotrexate dose; high doses used in cancer chemotherapy carry a greater risk than the lower doses typically used for autoimmune conditions.

Key Drug Classes to Avoid or Use with Caution

Several categories of common medications can interfere with how the body processes and eliminates methotrexate. This interference can elevate methotrexate levels, heightening the risk of side effects like bone marrow suppression, liver damage (hepatotoxicity), and kidney damage (nephrotoxicity).

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs, such as ibuprofen, naproxen, and aspirin, can interact significantly with methotrexate. They may reduce the kidneys' ability to clear methotrexate, potentially leading to toxic accumulation, especially with high-dose methotrexate. While low-dose methotrexate patients may sometimes use NSAIDs under strict medical supervision, it's essential to avoid over-the-counter NSAIDs without consulting a doctor.

Certain Antibiotics

Specific antibiotics like penicillins and trimethoprim-sulfamethoxazole can increase methotrexate levels. Trimethoprim-sulfamethoxazole should generally be avoided due to the high risk of severe bone marrow suppression. Tetracyclines may also increase methotrexate concentrations, though the risk is lower with autoimmune disease doses.

Proton Pump Inhibitors (PPIs)

PPIs, including omeprazole and pantoprazole, can delay the elimination of methotrexate, leading to higher drug levels. This is a greater concern with high-dose methotrexate. H2-receptor antagonists like famotidine may be a safer alternative.

Other Significant Interactions

Combining alcohol with methotrexate significantly increases the risk of liver damage. Medications affecting kidney or liver function can worsen toxicity risk. Live vaccines should not be received while on methotrexate due to immunosuppression. Folic acid may be prescribed with low-dose methotrexate to reduce side effects but can decrease effectiveness in cancer treatment.

Comparison of Interacting Drug Classes


Drug Class	Examples	Mechanism of Interaction	Level of Risk	Management Advice
NSAIDs	Ibuprofen, Naproxen, Aspirin	Reduced renal clearance of methotrexate	High (especially with high-dose MTX)	Avoid or use with extreme caution and close monitoring under medical supervision.
Antibiotics	Penicillins, Trimethoprim-sulfamethoxazole	Reduced renal clearance, additive antifolate effects	High	Avoid combination, especially with Trimethoprim-sulfamethoxazole. Use alternatives when possible.
Proton Pump Inhibitors (PPIs)	Omeprazole, Esomeprazole	Reduced renal clearance of methotrexate	Moderate to High	Temporarily stop PPI before high-dose methotrexate. Consider H2-blockers (e.g., famotidine) as an alternative.
Hepatotoxic Agents	Alcohol, some statins, retinoids	Additive risk of liver damage	High	Avoid alcohol. Monitor liver function closely when combined with other potentially liver-damaging agents.
Live Vaccines	MMR, Varicella (Chickenpox)	Risk of developing a serious infection due to immunosuppression	High	Strictly avoid receiving live vaccines while on methotrexate therapy.

Conclusion

Safe methotrexate treatment requires careful management of potential drug interactions. Key medications to be aware of include NSAIDs, certain antibiotics (like trimethoprim-sulfamethoxazole), and PPIs, which can all raise methotrexate levels and increase the risk of serious side effects. Maintaining open communication with healthcare providers and providing them with a complete list of all medications, including over-the-counter drugs and supplements, is vital for ensuring safe and effective treatment. Regular blood tests are a standard part of therapy to monitor for early signs of toxicity.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional before making any decisions about your medication. {Link: The Royal Children's Hospital Melbourne https://www.rch.org.au/clinicalguide/guideline_index/Methotrexate_High_Dose_and_Drug_Interactions/}

Frequently Asked Questions

You should avoid taking ibuprofen with methotrexate unless specifically approved by your doctor. NSAIDs like ibuprofen can decrease the kidney's ability to clear methotrexate, leading to toxic levels in your body, particularly with high-dose therapy.

No, it is generally recommended to strictly limit or avoid alcohol. The combination significantly increases the risk of liver damage (hepatotoxicity).

Paracetamol (acetaminophen) is often considered a safer option for pain relief than NSAIDs, though it can also affect the liver. Always consult your doctor for the safest choice for your situation and dosage.

Certain antibiotics, like penicillins and trimethoprim-sulfamethoxazole, can interfere with the body's ability to eliminate methotrexate. This can lead to increased methotrexate levels and a higher risk of serious side effects like bone marrow suppression.

PPIs such as omeprazole can reduce the clearance of methotrexate by the kidneys, which may lead to elevated and prolonged levels of the drug in your system and increase toxicity. The risk is greatest with high doses of methotrexate.

No, do not stop unless your doctor tells you to. For patients with autoimmune diseases, folic acid is often prescribed alongside methotrexate to reduce its side effects. However, it may decrease effectiveness in cancer treatment, so follow your doctor's specific instructions.

You should avoid the 'live' nasal spray flu vaccine. However, the inactivated flu shot is generally considered safe and is often recommended. Always check with your doctor before any vaccinations.