Methotrexate, Methotrexate (pf)

Medically reviewed by Victor Nguyen, PharmD, MBA on May 17, 2023
Written by Amber Watson, PharmD

Specifically, the Food and Drug Administration (FDA) has approved methotrexate to treat:

• rheumatoid arthritis in adults
• juvenile idiopathic arthritis in children
• psoriasis in adults
• certain cancers in adults and children

These approved uses differ based on the form of methotrexate your doctor prescribes.

This article describes methotrexate’s uses, side effects, and more. Below you’ll also find some coupon options to help save on the cost of methotrexate.

Boxed warnings

Methotrexate has boxed warnings, which are serious warnings from the FDA. These include:

• risk of fetal harm with methotrexate oral tablet and liquid solution for injection
• risk of serious allergic reaction with methotrexate oral tablet and liquid solution for injection
• risk of benzyl alcohol toxicity with methotrexate liquid solution for injection
• risk of serious side effects with methotrexate oral tablet and liquid solution for injection

For details, see the “Interactions and warnings for methotrexate” section below.

Methotrexate may cause mild or serious side effects (also known as adverse effects). More common mild side effects of methotrexate and its serious side effects are listed below. This article doesn’t include all possible side effects of the drug. Side effects can vary based on your age, overall health, and any other medications you take.

To learn more about methotrexate’s side effects, ask your doctor or pharmacist. You can also read the prescribing information* for methotrexate.

* To view methotrexate’s prescribing information, see the “Article resources” section below.

Mild side effects

More common mild side effects reported with some forms of methotrexate are listed below. These side effects may differ based on the form of methotrexate you’re prescribed and the condition it’s prescribed to treat.

This article doesn’t include all possible mild side effects of the drug. To learn more about methotrexate’s side effects based on the form, see the prescribing information* for methotrexate.

With many drugs, mild side effects may go away within a few days or a couple of weeks. If the side effects are bothersome, tell your doctor or pharmacist. They may be able to suggest ways to manage them.

Mild side effects of methotrexate oral tablet and liquid solution for injection include:

• mouth ulcers
• mild digestive system problems, such as nausea and upset stomach
• fatigue (low energy)
• dizziness
• mild allergic reaction†

* To view methotrexate’s prescribing information, see the “Article resources” section below.
† For details about this side effect, see the “Interactions and warnings for methotrexate” section below.

Serious side effects

Serious side effects of methotrexate are listed below. These side effects may differ based on the form of methotrexate you’re prescribed and the condition it’s prescribed to treat.

This article doesn’t include all possible serious side effects of the drug. To learn more about methotrexate’s side effects based on the form, see the prescribing information* for methotrexate.

With many drugs, serious side effects are possible but not common. If you have serious side effects from this drug, call your doctor right away. If you’re having severe symptoms or a medical emergency, call 911 or a local emergency number.

In general, methotrexate’s serious side effects include:

• tumor lysis syndrome (a condition that happens when tumor cells release their contents into your blood)
• certain cancers, such as skin cancer and blood cancer
• reproductive problems, such as infertility
• boxed warning: risk of fetal harm†
• boxed warning: risk of benzyl alcohol toxicity†
• boxed warning: risk of serious side effects†
• boxed warning: risk of serious allergic reaction†

* To view methotrexate’s prescribing information, see the “Article resources” section below.
† For details about this side effect, see the “Interactions and warnings for methotrexate” section below.

The Food and Drug Administration (FDA) approves prescription drugs such as methotrexate for certain conditions. Approved uses for methotrexate are described below. These uses differ based on the form of methotrexate prescribed.

Use for autoimmune disorders, such as rheumatoid arthritis or psoriasis

Doctors may prescribe methotrexate oral tablet and liquid solution for injection to treat certain autoimmune disorders. Specifically, they’re used for:

• rheumatoid arthritis (RA) in adults
• juvenile idiopathic arthritis (JIA) in children of any age
• psoriasis in adults

For these uses, methotrexate is usually prescribed as a long-term treatment.

With autoimmune disorders, your immune system mistakenly attacks healthy tissues in your body. With RA and JIA, your immune system attacks your joints. This can lead to stiffness, swelling, and pain in your joints. With psoriasis, your immune system attacks your skin. This can lead to skin patches that are dry, itchy, or scaly.

Use for certain cancers

Doctors may prescribe methotrexate oral tablet and liquid solution for injection to treat certain cancers.

They’re used for:

• a certain kind of skin cancer in adults
• a certain kind of bone cancer in adults and children of any age
• a certain kind of head and neck cancer in adults
• a certain pregnancy-related cancer in adults
• certain kinds of leukemia and lymphoma in adults and children of any age
• breast cancer in adults

These approved uses differ based on the form of methotrexate your doctor prescribes. For cancers, methotrexate may be prescribed as a long-term treatment.

With cancer, abnormal cells form and multiply uncontrollably in your body. These cells may eventually form tumors or travel to other areas of your body. Symptoms will depend on the specific cancer you have. But in general, cancer may cause fatigue (low energy), weight loss, and swollen lymph nodes.

Methotrexate is prescribed together with chemotherapy (traditional drugs used to treat cancer) for certain cancers. These include bone cancer, pregnancy-related cancer, breast cancer, leukemia, and lymphoma.

Below you’ll find answers to a few commonly asked questions about methotrexate.

Can methotrexate be used for ectopic pregnancy?

Yes, methotrexate can be prescribed to treat an ectopic pregnancy. But this is an off-label use of the drug. This means doctors may prescribe methotrexate for this condition even though the drug is not approved to treat it.

To learn more about ectopic pregnancy and its treatment options, talk with your doctor.

Is it safe to take or receive methotrexate with folic acid?

It depends. If you take or receive methotrexate for certain autoimmune disorders, your doctor may advise you to take folic acid. Doing so can help lower your risk of certain side effects of the drug, such as mouth ulcers.

If you take or receive methotrexate for certain cancers, your doctor may advise you to avoid folic acid. This is because taking or receiving the drug with folic acid could make methotrexate less effective for treating cancer.

Your doctor will recommend whether it’s safe for you to take or receive methotrexate with folic acid for your specific condition.

Will low dose methotrexate cause fewer side effects than higher doses of the drug?

It’s possible that low doses of methotrexate may reduce your risk of certain side effects, including low blood cell levels.* However, the risk of most methotrexate’s side effects are expected to be similar regardless of the dosage you follow. (For lists of possible side effects, see the “Side effects of methotrexate” section above.)

To learn more about what to expect during methotrexate treatment, talk with your doctor or pharmacist.

* Methotrexate has a boxed warning about the risk of serious side effects, which includes low blood cell levels. For details, see the “Interactions and warnings for methotrexate” section below.

Is methotrexate a steroid?

No, methotrexate isn’t a steroid. Instead, it belongs to a group of drugs called antimetabolites. Like steroids, methotrexate can be prescribed to treat certain autoimmune disorders and certain cancers.

To learn more about how methotrexate and steroids are alike and different, talk with your doctor or pharmacist.

Does methotrexate work in the same way as leflunomide?

No, methotrexate doesn’t work in the same way as leflunomide (Arava).

Both methotrexate and leflunomide are prescribed to treat rheumatoid arthritis. And both drugs work by blocking the action of certain proteins involved with your immune system. But each drug blocks a different protein.

To learn more about how methotrexate works, see “How does methotrexate work?” right below. To learn more about how leflunomide works, talk with your doctor or pharmacist.

How does methotrexate work? And how long does it take to start working?

Methotrexate is prescribed to treat certain autoimmune disorders and certain cancers.

With autoimmune disorders, your immune system mistakenly attacks healthy tissues in your body. For this use, methotrexate works by blocking the action of a certain protein involved with your immune system. In doing so, methotrexate helps lessen the activity of your immune system. As a result, the drug helps ease symptoms of autoimmune disorders.

With cancer, abnormal cells form and multiply uncontrollably in your body. For this use, methotrexate works by blocking the action of a certain protein that helps cancer cells grow. As a result, the drug helps kill cancer cells and prevent new ones from forming.

Methotrexate starts working right after you take it. But it may take several weeks for the symptoms of your condition to ease after starting treatment with the drug.

If you have questions about how methotrexate works or how long it takes to start working, talk with your doctor or pharmacist.

The dosage of methotrexate your doctor prescribes may vary based on your condition and certain other factors. Talk with your doctor about the dosage you should follow.

Taking and injecting methotrexate

Methotrexate oral tablet is swallowed with or without food. Your doctor will talk with you about how to take methotrexate oral tablet. They’ll explain how much to take and how often. Always follow your doctor’s recommendation.

Methotrexate liquid solution is given as an injection by a healthcare professional. They’ll explain how methotrexate liquid solution will be given to you and where you’ll receive it. Your doctor will also tell you how much you’ll receive and how often.

Overdose of methotrexate

You should not take more methotrexate than your doctor prescribes. For some drugs, doing so may lead to serious side effects or overdose.

If you think you’ve taken too much methotrexate, call your doctor or pharmacist right away. Or you could call 800-222-1222 to speak with someone at America’s Poison Centers. You can also use its online resource. If you have concerning symptoms, call 911 or a local emergency number immediately. You can also go to the closest emergency room.

Below, you’ll find information about methotrexate’s possible interactions and warnings.

Interactions of methotrexate

For some medications, certain things may affect how the drug works. These include getting vaccines, consuming alcohol or certain foods, or taking the drug with other medications. This effect is called a drug interaction.

Before you start methotrexate, ask your doctor to check for possible interactions. Be sure to tell them about any of the following you take or use:

• prescription medications
• over-the-counter medications
• vitamins, herbs, or supplements

To learn about drug-condition interactions, see the “Warnings for methotrexate” section below.

Warnings for methotrexate

Some people should not take or receive methotrexate, and others should take or receive it cautiously.

Boxed warnings

Methotrexate has boxed warnings about the following risks. Boxed warnings are serious warnings from the Food and Drug Administration (FDA).

To learn more about these warnings, read below. You can also talk with your doctor or pharmacist.

Risk of fetal harm. For more information about this risk, see the “Pregnancy or breastfeeding and methotrexate” section below.

Risk of serious allergic reaction. Taking methotrexate may lead to a serious allergic reaction. This side effect was not reported in studies of methotrexate oral tablet or liquid solution for injection. But it has been reported since methotrexate became available for use.

Symptoms may include swelling under the skin of your hands, feet, eyelids, or lips. You may also have swelling of your mouth, throat, or tongue that can lead to breathing problems.

If you have symptoms of a serious allergic reaction, call 911 or your local emergency number. And be sure to tell your doctor if you have a serious allergic reaction to methotrexate. They’ll likely advise you to stop treatment with the drug and can recommend safer options for your condition.

Risk of benzyl alcohol toxicity. Receiving methotrexate liquid solution for injection may lead to benzyl alcohol toxicity in infants. (Benzyl alcohol is a preservative found in some injectable drugs.) This side effect was not reported in studies of methotrexate oral tablet or liquid solution for injection. But it has been reported since methotrexate liquid solution for injection became available for use.

Symptoms may include gasping for air, seizures, and low blood pressure.

Due to this risk, doctors will not prescribe infants any injectable form of methotrexate that contains benzyl alcohol. Your child’s doctor can recommend which forms of methotrexate injection are safe for an infant.  

Risk of serious side effects. Taking methotrexate may lead to certain serious side effects. Some of these side effects were rare in studies of methotrexate oral tablet and liquid solution for injection. Others were not reported in studies but have been reported since methotrexate became available for use.

Specifically, methotrexate may cause:

• low levels of certain blood cells, including red blood cells, white blood cells, and platelets
• liver problems, such as liver failure
• kidney problems, such as kidney failure
• lung problems, such as inflammation in the lungs
• brain and spinal cord problems, such as inflammation in the brain
• severe digestive system problems, such as bleeding in the intestines
• severe skin reactions, such as Stevens-Johnson syndrome
• severe infections, such as a certain kind of pneumonia

If you have concerns about serious side effects with methotrexate, tell your doctor. They can advise you on your risk of these side effects and symptoms to watch for. They can also recommend other treatment options for your condition.

Other warnings

Methotrexate could cause harm to people with certain health conditions. This effect is called a drug-condition interaction. Other factors can also affect whether methotrexate is a safe option for you. These warnings may differ based on the form of methotrexate you’re prescribed.

Ask your doctor about specific warnings for methotrexate, and be sure to tell your doctor about your:

• current health, including any allergies to medications
• past health conditions or surgeries

Allergic reaction

Methotrexate can cause an allergic reaction in some people. Severe allergic reactions are rare but possible. In fact, the drug has a boxed warning about the risk of a serious allergic reaction. For more information about this risk, see the “Warnings for methotrexate” above.

If you’ve had an allergic reaction to methotrexate or any of its ingredients, your doctor will likely not prescribe methotrexate. They can tell you about medications that are safer options for you.

A mild allergic reaction may cause the following symptoms:

• skin rash
• itchiness
• flushing (temporary warmth, redness, or deepening of skin color)

A severe allergic reaction may cause the following symptoms:

• swelling under your skin, usually in your hands, feet, eyelids, or lips
• swelling of your mouth, throat, or tongue, which can cause breathing problems

If you have an allergic reaction to methotrexate, call your doctor right away. If you have severe symptoms, call 911 or a local emergency number.

Pregnancy or breastfeeding and methotrexate

Information about methotrexate and pregnancy and breastfeeding is described below.

Note: Methotrexate may cause problems with fertility in some people. To learn more about this, talk with your doctor.

Risk of fetal harm

When taken or received during pregnancy, methotrexate may cause pregnancy loss or problems with fetal development (commonly known as birth defects). Examples include problems with the brain, spinal cord, heart, arms, or legs. This side effect has been reported since methotrexate oral tablet and liquid solution for injection became available for use.

Due to this risk, doctors may not prescribe methotrexate for autoimmune conditions during pregnancy. There are risks associated with methotrexate treatment for certain cancers during pregnancy. But there are also risks of having untreated cancer while pregnant.

If you’re planning a pregnancy or can become pregnant, talk with your doctor before taking this medication. Together, you can discuss the risks and benefits of your treatment options and decide whether you should take or receive methotrexate during pregnancy.

Your doctor may suggest birth control options to use during treatment with methotrexate and for at least 3 months after your last dose of the drug.

Methotrexate and pregnancy

Methotrexate may not be prescribed during pregnancy. The drug has a boxed warning about the risk of fetal harm. For more information about this risk, see “Risk of fetal harm” above.

Methotrexate and breastfeeding

Methotrexate should not be taken or received while breastfeeding. It’s recommended that you avoid breastfeeding until at least 1 week after your last dose of the drug.

If you’re currently breastfeeding or planning to do so, talk with your doctor before starting treatment with this medication. Your doctor may recommend other ways to feed your child during treatment with methotrexate.

You may be able to save money on your prescription for methotrexate by using our Perks discount coupons. They can be found at the end of this article.

If you have questions about how to pay for methotrexate, talk with your doctor or pharmacist.

Note: Optum Perks coupons cannot be used with insurance copays or benefits.

This article describes methotrexate’s uses and dosage, ways to save on cost, and more. Let your doctor know if you have questions about methotrexate or would like more details about it.

Here’s a list of some possible questions you may want to ask your doctor:

• Can methotrexate cause long-term side effects?
• What brand names are available for methotrexate?
• Are hair loss or eye-related side effects possible with methotrexate?

• Food and Drug Administration. (2023). Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
• Methotrexate injection, for intravenous, intramuscular, subcutaneous, or intrathecal use. (2023). https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/3989d30d-56e5-4e8d-9379-c30fecc894f2/spl-doc
• Methotrexate tablets, for oral use. (2023). https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/d35193e4-0b0e-4a0a-acd8-aa90cc075a2b/spl-doc

Disclaimer: Optum Perks has made every effort to make certain that all information is factually correct, comprehensive, and up to date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or another healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.