What Medications Should Not Be Taken With Methotrexate?

October 12, 2025 •

4 min read

According to reports, fatal bone marrow suppression has occurred in patients taking methotrexate with certain antibiotics, particularly trimethoprim-sulfamethoxazole. This highlights the critical importance of understanding what medications should not be taken with methotrexate to prevent severe toxicity and life-threatening complications. Open communication with your healthcare provider is key to managing medication safety.

Quick Summary

A comprehensive guide to potentially dangerous drug interactions with methotrexate, detailing the risks associated with NSAIDs, certain antibiotics, and proton pump inhibitors, and explaining why these combinations must be avoided or managed with caution.

Key Points

NSAIDs Increase Toxicity: Nonsteroidal anti-inflammatory drugs (NSAIDs) can dangerously elevate methotrexate levels by reducing its renal clearance, increasing the risk of serious side effects like kidney and liver damage.
Trimethoprim-Sulfamethoxazole is High-Risk: The antibiotic trimethoprim-sulfamethoxazole (Bactrim) should generally be avoided, as it has an additive antifolate effect with methotrexate that can cause life-threatening bone marrow suppression.
Proton Pump Inhibitors Cause Accumulation: PPIs like omeprazole can delay the clearance of methotrexate from the body, increasing the risk of toxicity, especially with high methotrexate doses or kidney impairment.
Avoid Alcohol and Some Herbal Supplements: Combining methotrexate with alcohol significantly increases the risk of liver toxicity. Certain herbal supplements like St. John's wort and white willow bark can also interact adversely.
Handle Folic Acid Carefully: Folic acid supplementation requires careful management alongside methotrexate. It is used to mitigate side effects in autoimmune disease but can interfere with the drug's effectiveness in cancer treatment.

Methotrexate is a powerful medication used to treat a variety of conditions, including certain types of cancer and autoimmune diseases like rheumatoid arthritis and psoriasis. However, its effectiveness and safety can be severely compromised by interactions with other drugs, which can lead to increased toxicity and dangerous side effects. Patients must be aware of these potential interactions to prevent serious health complications. This article provides a comprehensive overview of the medications that should not be taken with methotrexate and explains the reasons behind these vital precautions.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

The interaction between methotrexate and NSAIDs is one of the most well-documented and potentially dangerous combinations, particularly with high-dose methotrexate. NSAIDs, such as ibuprofen, naproxen, and diclofenac, can interfere with the kidneys' ability to clear methotrexate from the body. This can cause methotrexate levels to rise to toxic concentrations, even when taking the low doses prescribed for rheumatic conditions. The risk is highest for patients with pre-existing kidney impairment.

How NSAIDs increase methotrexate toxicity

NSAIDs can reduce the renal clearance of methotrexate by inhibiting prostaglandin synthesis in the kidneys, leading to decreased blood flow and slower excretion. This results in increased methotrexate levels in the bloodstream and a higher risk of serious side effects like liver damage, kidney failure, and bone marrow suppression.

Important considerations for NSAID use

Short-term, low-dose NSAID use may be permitted under strict medical supervision. Acetaminophen (Tylenol) is generally a safer alternative for pain relief.

Certain Antibiotics

Several antibiotics can interact dangerously with methotrexate. Trimethoprim-sulfamethoxazole (Bactrim) is particularly concerning.

Trimethoprim-Sulfamethoxazole (Bactrim)

Trimethoprim-sulfamethoxazole and methotrexate both interfere with folic acid metabolism, which can lead to severe and potentially fatal bone marrow suppression and pancytopenia. Sulfamethoxazole can also slow the kidney's removal of methotrexate, increasing its concentration in the blood and raising the risk of severe toxicity, including mucositis and serious blood disorders.

Penicillin and Tetracycline classes

Penicillin antibiotics, such as amoxicillin, can compete with methotrexate for kidney excretion, potentially increasing methotrexate levels. Tetracyclines may also increase methotrexate levels, but the impact is less clear with low doses. Your doctor might recommend temporarily pausing your methotrexate dose while on a course of an interacting antibiotic.

Proton Pump Inhibitors (PPIs)

PPIs, including omeprazole, lansoprazole, and pantoprazole, are used for acid reflux but can interfere with methotrexate clearance, especially at high methotrexate doses or with kidney problems.

How PPIs affect methotrexate

PPIs can inhibit the renal tubular secretion of methotrexate, causing it to accumulate in the body. This increases the risk of toxicity, including bone marrow suppression and kidney issues. H2 receptor antagonists like famotidine may be safer alternatives.

Vitamins and Supplements

Interactions with supplements, particularly folic acid, are important.

Folic acid and multivitamins

Low-dose folic acid is often prescribed for autoimmune conditions to reduce methotrexate side effects without compromising effectiveness. However, for cancer treatment, folic acid can reduce efficacy and should only be taken as directed. Timing is crucial; for weekly methotrexate, folic acid is typically taken on a different day.

Herbal supplements

Some herbal supplements like St. John's wort and dong quai can increase photosensitivity, adding to methotrexate's similar effect. White willow bark should be avoided as it contains salicylates that can increase methotrexate levels.

Other Interacting Medications

Other drugs can interact with methotrexate by affecting its clearance or increasing organ toxicity. These include drugs that compete for protein binding or affect liver function.

Drug Interaction Comparison Table


Medication Category	Examples	Mechanism of Interaction	Potential Risk	Management
NSAIDs	Ibuprofen, Naproxen, Diclofenac	Reduced renal clearance of methotrexate	Increased methotrexate toxicity, kidney damage	Avoid or use with caution under strict medical supervision. Consider acetaminophen alternatives.
Certain Antibiotics	Trimethoprim-sulfamethoxazole (Bactrim)	Additive antifolate effects, delayed renal clearance	Severe bone marrow suppression, GI toxicity	Avoid if possible; consider temporary hold of methotrexate under physician guidance if needed.
PPIs	Omeprazole (Prilosec), Pantoprazole	Reduced renal clearance, increased methotrexate levels	Increased methotrexate toxicity, kidney issues	Use alternative acid-reducers (e.g., famotidine) or hold PPI temporarily for high-dose regimens.
Folic Acid/Multivitamins	Folic acid supplements	Potential interference with therapeutic effect	Reduced efficacy (for cancer); improper timing can be detrimental.	Follow doctor's specific dosing instructions and timing. Do not take the same day as weekly methotrexate.
Anticonvulsants	Phenytoin (Dilantin)	Competition for protein binding, altered clearance	Increased methotrexate toxicity, decreased seizure control.	Close monitoring of drug levels and regular blood tests.
Immunosuppressants	Azathioprine, Sulfasalazine	Potential for additive hepatotoxicity or blood toxicity	Increased risk of liver damage or bone marrow suppression.	Close monitoring of liver enzymes and blood counts.
Alcohol	Alcoholic beverages	Increased risk of liver toxicity	Serious liver damage, exacerbated side effects	Avoid or severely limit alcohol intake while on methotrexate.

What to Do If You Need an Interacting Medication

If a potentially interacting medication is necessary, your doctor will implement a plan to minimize risk. This may involve holding your methotrexate dose, increasing monitoring with regular blood tests, or prescribing an alternative medication that does not interact.

Conclusion

Understanding which medications and supplements to avoid is crucial for safe methotrexate treatment. Key interactions involve NSAIDs, trimethoprim-sulfamethoxazole, and PPIs, which can cause dangerous methotrexate accumulation and organ damage. Other drugs affecting liver function or protein binding also pose risks. Always provide your healthcare team with a complete list of all medications and supplements. Following medical guidance and exercising caution significantly reduces the risk of adverse drug interactions and maximizes the benefits of methotrexate.

Frequently Asked Questions

Using ibuprofen or other NSAIDs with methotrexate can increase methotrexate levels in the blood, potentially causing toxicity. While the risk may be lower with low doses and proper monitoring, you should not take NSAIDs without explicit permission from your doctor, who may suggest safer alternatives like acetaminophen.

This combination is considered high-risk and should be avoided whenever possible. Both drugs interfere with folic acid metabolism and can lead to severe, sometimes fatal, bone marrow suppression. Your doctor will likely prescribe a different antibiotic if you need treatment for an infection.

No, you should avoid or severely limit alcohol consumption while on methotrexate. Both alcohol and methotrexate can cause liver damage, and combining them significantly increases this risk.

Multivitamins often contain folic acid. While prescribed folic acid is commonly used to reduce methotrexate side effects in autoimmune conditions, timing is important. For weekly methotrexate doses, avoid taking folic acid on the same day. Always follow your doctor's specific instructions and inform them of all supplements you take.

No, you should avoid proton pump inhibitors (PPIs) like omeprazole. PPIs can reduce the kidneys' ability to clear methotrexate, increasing toxicity. Your doctor may suggest a different class of acid-reducing medication, such as an H2 blocker like famotidine.

Many herbal supplements have not been adequately tested for interactions with prescription medications. Some, like St. John's wort and white willow bark, are known to interact and should be avoided. It is essential to consult your healthcare provider before taking any herbal remedies.

Blood tests are crucial for monitoring methotrexate levels and checking for signs of organ damage. Intensified monitoring is necessary if your doctor prescribes a potentially interacting medication to ensure that any signs of toxicity, such as liver or kidney dysfunction, are detected and managed promptly.