Drug and Food Interactions: What Should You Avoid While Taking Methotrexate?

Methotrexate is the first-line treatment for most people with moderate to severe rheumatoid arthritis (RA). Some medications, however, can interact with methotrexate and cause adverse effects.

Beyond RA, methotrexate is also used in the treatment of severe psoriasis and some types of cancer, such as breast cancer, lung cancer, lymphoma, and leukemia. For each condition, methotrexate works by slowing the growth of cells—including cancer cells in cancer and skin cells in psoriasis. In rheumatoid arthritis, methotrexate helps decrease the activity of the immune system.

This article explains drug and food interactions with methotrexate, from mild symptoms to more severe, long-term conditions like liver damage. It will help you to be mindful of these potential drug interactions to make sure you reap the benefit of the medication and keep side effects to a minimum.

Severe Methotrexate Interactions

Methotrexate is known to cause severe drug interactions when taken with many types of medications. Those taking methotrexate should be aware of the drug interactions and speak with their healthcare provider about the drugs or supplements they are taking prior to starting treatment with methotrexate.

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and decrease inflammation. Because NSAIDs can affect kidney function and methotrexate is metabolized by the kidney, monitoring of the creatinine (a waste product found in urine and blood) is recommended.

Some specific NSAIDs that should be avoided while taking methotrexate include:

• Zorprin, Excedrin (aspirin)
• Prolensa, Bromday (bromfenac)
• Lodine (etodolac)
• Nalfon (fenoprofen)
• Advil, Motrin (ibuprofen)
• Aleve, Naprosyn (naproxen)
• Doan's (magnesium salicylate)
• Salsalate

Other RA Medications

For those with RA, which is an autoimmune disease, medication is needed to hinder the overactivity of the immune system. Using two medications that affect the immune system at the same time can hinder the ability of the body's natural defense system to fight off infections. It may also increase the risk of cancer (notably, skin cancer) over long-term treatment.

Some studies find that immunosuppressive medications to avoid while on methotrexate include:

• Enbrel, Erelzi (etanercept)
• Arava (leflunomide)

These medications have been shown to cause adverse side effects when taken with methotrexate, including hypertension, respiratory infections, gastrointestinal distress, and headaches.

However, other researchers find that taking leflunomide with methotrexate offers significant benefits. And some studies show etanercept taken with methotrexate to be more effective in psoriatic arthritis than methotrexate alone. Be sure to discuss methotrexate drug combinations with your healthcare provider.

Drugs such as Voltaren (diclofenac) are more likely to affect the liver, so monitoring of the liver is recommended.

Antivirals

Medications that may affect how the kidneys function, such as the antiviral Adefovir, may increase health risks for someone taking methotrexate. This is because too much methotrexate in the body can lead to toxic effects while antiviral medications are taken at the same time.

Antiviral medications that pose serious risks while taking methotrexate include:

• Hepsera (adefovir)
• Vistide (cidofovir)
• Viread (tenofovir)

The risk may be higher in people who are immunosuppressed. A study of people taking tenofovir as part of human immunodeficiency virus (HIV) treatment found methotrexate may interfere with how effective the antiviral drug is. More study, however, is needed.

Cancer Medications

Methotrexate itself is used in cancer care. For example, high doses used in treating a rare form of non-Hodgkin lymphoma have improved outcomes. It's also used in treating leukemia, and breast and uterine cancers. Methotrexate can be used in combination with other cancer medications.

Methotrexate use in cancer may lead to adverse health effects, such as toxicity. Researchers have found that among people taking high-dose methotrexate, about 60% will experience a reversible case of hepatitis (liver inflammation).

Kidneys can be affected, too, with about 9% of lymphoma patients who take it experiencing toxic kidney effects.

Antibiotics

If you are taking methotrexate, you should completely avoid taking any antibiotic that contains trimethoprim-sulfa, such as Bactrim, Sulfatrim, and Septra. Adverse effects are caused by the antibiotic's ability to reduce methotrexate absorption in the body. When the absorption rate is slowed, it can lead to a buildup of the medication in the body over time and cause toxicity.

Talk to your healthcare provider before taking methotrexate along with antibiotic medications, such as:

• Amoxil, Moxatag, Trimox (amoxicillin)
• Ampi, Omnipen, Principen (ampicillin)
• Spectrobid, Penglobe (bacampicillin)
• Geocillin (carbenicillin)
• Cloxapen, Cloxacap, Tegopen, Orbenin (cloxacillin)
• Dynapen (dicloxacillin)

You should also avoid getting immunized with live vaccines while using higher doses of methotrexate. Speak to your healthcare provider about any possible immunizations you can and cannot receive.

Moderate Methotrexate Interactions

Taking methotrexate and some medications will pose a moderate risk of drug interactions. These interactions are not as dangerous as those above, but they do pose health risks.

NSAIDs

Since low doses of methotrexate are typically used to treat inflammatory arthritis like RA, the interaction with NSAIDs is typically not significant. A review of 28 studies found no meaningful clinical significance, though there is some evidence of higher concentrations of methotrexate in the body when NSAIDs also are used.

Some NSAIDs can be used under direct supervision in people who take low-dose methotrexate, including:

• Celebrex (celecoxib)
• Flector, Pennsaid, Rexaphenac, Solaraze, Voltaren (diclofenac topical)
• Tylenol, Paracetamol (acetaminophen)

Mental Disorder Medications

Taking methotrexate with some medications for mental health disorders can pose a moderate risk for adverse health effects. The antipsychotic medications that increase the risk for adverse effects are those that affect the liver. One such medication is chlorpromazine. Another medication that can increase the risk for liver toxicity is Cymbalta (duloxetine).

Diabetes Medication

People with diabetes are often at an increased risk of liver disease and infection, and the use of methotrexate together with some diabetes medications may increase that risk even further. Using methotrexate over a long period of time has also been linked to liver conditions such as cirrhosis.

Specific medications that should be avoided or used with caution include:   

• Accupril (quinapril)
• Precose (acarbose)
• Actos (pioglitazone)
• Avandia (rosiglitazone)
• Byetta, Bydureon (exenatide)

Diuretics

For those taking diuretics, methotrexate may pose a moderate risk because methotrexate may hinder the actions of the diuretic medication, diminishing its therapeutic effect. Some specific diuretics that you should look out for when taking or starting methotrexate include:

• Thorazine, Largactil (chlorpromazine)
• Natrilix, Indipam XL, Rawel XL, Tensaid XL, Alkapamid XL (indapamide)
• Aprinox, Neo-Naclex (bendroflumethiazide)

Antiepileptics

Methotrexate has been reported as a seizure inducer and should be avoided by most on antiepileptic drugs. Some antiepileptic medications have been shown to reduce how well methotrexate works. Some specific seizure medications that should not be taken with methotrexate include:

• Dilantin, Phenytek (phenytoin)
• Tegretol (carbamazepine)
• Valproic acid

Minor Drug Interactions

Some medications can be taken safely with methotrexate and may cause only minor effects. Typically, taking these drugs along with methotrexate wouldn’t require any change in dose or medication.

Immunosuppressants

When used in conjunction with methotrexate, many immunosuppressants should be avoided. However, some are safe to use. For example, Imuran and Azasan (azathioprine) are immunosuppressants that can be taken with methotrexate safely and effectively.

Antipsychotics

An antipsychotic medication that doesn’t have severe or moderate interactions with the medication is Haldol (haloperidol).

Antiepileptics

Since some people may need to take a seizure medication as well as methotrexate, it may be comforting to know that some epilepsy medications don’t pose a severe or moderate risk when taken with the drug. Anticonvulsants that are safe to take while on methotrexate include:

• Lamictal (lamotrigine)
• Keppra (levetiracetam)

NSAIDs

Although many NSAIDs should not be taken with methotrexate because of the increased risk of liver toxicity, Tham (tromethamine) is one that can be safely taken with only a small risk of increasing the natural side effects of methotrexate alone. 

Food Interactions

Many people don’t consider food interactions when taking new medications. When it comes to methotrexate, some foods or nutritional supplements can lead to adverse health effects or worsen the existing side effects of the drug.

Caffeine

There is some debate about whether caffeine poses a moderate risk of adverse effects when taking methotrexate. Some research suggests that it can limit the efficacy of methotrexate, while others have found that adding caffeine to a treatment plan can actually reduce symptoms of methotrexate intolerance. Although caffeine is listed as having the ability to reduce the efficacy of methotrexate in arthritis treatment, much of the literature suggests that claim is not accurate.  

Alcohol

Methotrexate may cause liver damage if taken for an extended period of time, so those who take the medication should avoid alcohol as much as they can. Drinking alcohol while taking this medication has been shown to increase the risk of liver toxicity.

Other Foods and Beverages

Some research has shown that those who drink grapefruit juice regularly should speak to their healthcare provider prior to starting methotrexate. It's also suggested that taking willow bark while on methotrexate could lead to adverse interactions.

Summary

Methotrexate has the potential to improve your quality of life significantly by helping you manage your condition, but it also has the potential to add to your existing health problems through drug interactions.

If you’re already taking methotrexate, it’s also important to speak with your healthcare provider before taking any new natural health supplements or medications. If you do experience any side effects, be sure to contact your healthcare provider.