Key takeaways:
Methotrexate (Trexall, Otrexup, others) treats many inflammatory health conditions and cancers, ranging from rheumatoid arthritis to lymphoma.
Many medications can interact with methotrexate, including ibuprofen (Advil, Motrin), omeprazole (Prilosec), and some antibiotics.
Your methotrexate dose can affect how severe some interactions are. Make sure your prescriber and pharmacist have an updated list of all medications and supplements that you take.
Save on related medications
Methotrexate (Trexall, Otrexup, others) is a versatile anticancer and immunosuppressant medication. It treats health conditions ranging from rheumatoid arthritis (RA) and psoriasis to blood cancers such as non-Hodgkin lymphoma. Lower doses of oral methotrexate are used for conditions like RA, while higher doses are given into a vein (IV) to treat cancer.
Alongside its long list of uses, methotrexate can have many side effects. These side effects can happen at normal doses. But if there’s too much methotrexate in your body, it can build up over time and become toxic. Drug interactions can also step in and complicate your experience with methotrexate.
Thankfully, there are many ways your healthcare team can help you prevent methotrexate side effects from happening. This often comes down to navigating drug interactions. Below, we’ll discuss eight notable methotrexate interactions to look out for.
Search and compare options
1. NSAIDs
Your kidneys are important for removing methotrexate from your body. If they’re not working as well as they could, methotrexate levels can build up and lead to side effects like mouth sores or diarrhea.
It’s important to use caution with medications that might hurt your kidneys or make them less effective. One group of medications that could potentially harm your kidneys are nonsteroidal anti-inflammatory drugs (NSAIDs). This includes medications such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), and meloxicam (Mobic). NSAIDs have been reported to rarely cause kidney injury, especially when taken in large amounts or for long periods of time.
As a precaution, your prescriber may want you to avoid NSAIDs altogether if you’re receiving high doses of methotrexate. If you’re taking lower doses of methotrexate, they may just monitor you closely for side effects. Chat with your healthcare team to see which approach is best for you.
2. Certain antibiotics
Penicillin antibiotics, such as amoxicillin (Amoxil), can prevent your kidneys from getting rid of methotrexate efficiently. Another common antibiotic, sulfamethoxazole / trimethoprim (Bactrim), can also do this. This raises the risk of experiencing methotrexate side effects.
What’s more, a few IV antibiotics can also be harmful to your kidneys. Amphotericin B and aminoglycoside antibiotics, such as tobramycin, can slow down your body’s ability to clear methotrexate from your system.
In many cases, your healthcare team will be aware of these interactions and have a plan in place. For example, if you have cancer and need antibiotics, they would likely delay giving IV methotrexate until your infection has resolved.
3. Folic acid
Folic acid (folate, vitamin B9) is a supplement that helps treat conditions such as anemia and folate deficiency. But depending on the situation, it can have positive or negative effects on methotrexate.
Low doses of methotrexate may be prescribed with folic acid to help minimize certain side effects, like nausea and mouth sores. This is because methotrexate can cause low folate levels, which isn’t ideal. However, if you’re taking high doses of methotrexate, folic acid may actually reduce how well it works.
Depending on how much methotrexate you take, your prescriber can tell you if you should take or avoid folic acid supplements.
4. Proton pump inhibitors
Proton pump inhibitors (PPIs), such as omeprazole (Prilosec), are commonly used to treat heartburn and gastroesophageal reflux disease (GERD). They can also interact with methotrexate.
Similar to NSAIDs and some antibiotics, PPIs can affect how your body gets rid of methotrexate. One study found that PPIs may reduce how well your body clears methotrexate, which can worsen the risk for side effects.
As a precaution, your prescriber may recommend a non-PPI acid-lowering medication — such as famotidine (Pepcid) — instead. Medications like famotidine aren’t expected to interact with methotrexate.
5. Medications that are tough on your kidneys
Medications that can hurt your kidneys are called “nephrotoxic medications.” Following a similar trend as described above, many other kidney-affecting medications can worsen your experience with methotrexate. Common examples include:
Diuretics, especially loop diuretics such as furosemide (Lasix)
ACE inhibitors, such as lisinopril (Zestril)
Empagliflozin (Jardiance)
Some HIV antiviral medications, such as tenofovir (Viread)
You may not need to avoid these medications altogether if you’re taking low doses of methotrexate. These interactions are more likely to be significant if you're taking higher doses of methotrexate. Your healthcare team can help you weigh the risks and benefits of taking these medications with methotrexate.
6. Medications that are tough on your liver
Medications that can hurt your liver are called “hepatotoxic medications.” Methotrexate itself is one example of a hepatotoxic medication. And when it’s combined with other medications that also affect your liver health, the effects can be more severe. The combination can also worsen methotrexate side effects.
Common medications that can be tough on your liver include:
Acetaminophen (Tylenol)
Diclofenac (Cambia)
Amiodarone (Pacerone)
Some anti-seizure medications, such as carbamazepine (Tegretol) and levetiracetam (Keppra)
In most cases, you won’t need to completely avoid these medications while taking methotrexate. Your healthcare team may just monitor you a little more closely.
7. Medications that attach to proteins in your blood
Once it’s in your body, about half of methotrexate binds (attaches) to proteins in your blood. Methotrexate that isn’t bound to proteins is what’s active throughout your body. This unbound medication is what promotes methotrexate’s beneficial health effects, but it also contributes to side effects.
Many medications bind to the same blood proteins as methotrexate. This can increase levels of unbound methotrexate, raising your risk of side effects.
Top protein-bound drugs that may cause a stir with methotrexate include:
Blood thinners, such as warfarin (Coumadin, Jantoven)
Salicylates, such as aspirin
Sulfonylureas, such as glipizide
Tetracyclines, such as doxycycline
Phenytoin (Dilantin, Phenytek)
8. Alcohol
Alcohol can cause problems with methotrexate, too. Each can contribute to liver problems on their own, and the risk goes up when you take them together. Try to avoid the combination if you can.
What’s more, large or frequent amounts of alcohol can decrease the effectiveness of certain cancer treatments. It can also exacerbate symptoms of autoimmune conditions and raise the risk of developing cancer down the line.
The interaction between alcohol and methotrexate is discussed in depth in another GoodRx Health article.
When should you contact a healthcare professional about a methotrexate interaction?
When you start a new medication, it’s always a good idea to remind your prescriber and pharmacist about all of the prescription and over-the-counter medications you take. It helps if you provide them with an updated list of all medications you take so they can screen for interactions. After all, it’s much better to prevent an interaction than to treat one in the moment.
Still, not all interactions are preventable. If you experience any side effects or toxicities after starting methotrexate, make sure to notify your healthcare team right away. You can work together to figure out if a drug interaction is a contributing factor.
The bottom line
Many methotrexate (Trexall, Otrexup) interactions are possible. Keep an eye out for NSAIDs, PPIs, and some antibiotics. Medications that affect your kidney or liver health can also be a sizable concern. Always let your prescriber and pharmacist know about all medications and supplements you’re taking before starting methotrexate.
Why trust our experts?
References
Bezabeh, S., et al. (2012). Accumulating evidence for a drug–drug interaction between methotrexate and proton pump inhibitors. The Oncologist.
Dixit, M., et al. (2010). Significant acute kidney injury due to non-steroidal anti-inflammatory drugs: Inpatient setting. Pharmaceuticals.
Hikma Pharmaceuticals USA Inc. (2023). Methotrexate [package insert].
Howard, S. C., et al. (2016). Preventing and managing toxicities of high-dose methotrexate. The Oncologist.
Inoue, K., et al. (2014). Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metabolism and Pharmacokinetics.
Izzedine, H., et al. (2005). Antiviral drug-induced nephrotoxicity. American Journal of Kidney Disease.
Mingeot-Leclercq, M-P., et al. (1999). Aminoglycosides: Nephrotoxicity. Antimicrobial Agents and Chemotherapy.
Sawaya, B. P., et al. (1995). Amphotericin B nephrotoxicity: the adverse consequences of altered membrane properties. Journal of the American Society of Nephrology.
Wiczer, T., et al. (2016). Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity. Journal of Oncology Pharmacy Practice.
Whittle, S. L., et al. (2004). Folate supplementation and methotrexate treatment in rheumatoid arthritis: A review. Rheumatology.
