Methotrexate Injection Side Effects and How to Manage Them

If you have an autoimmune disease, you may be interested in learning more about methotrexate. It’s a generic prescription drug used to treat:

Methotrexate comes as an injection given under your skin or into your muscle.

It also comes as a tablet you swallow and an intravenous (IV) infusion (an injection into your vein given over time). But these forms of methotrexate are not covered in this article.

Methotrexate may be used as a long-term treatment. This article describes the drug’s side effects, also referred to as adverse effects. For more information about injectable forms of methotrexate, see this in-depth article.

Some people may experience mild to serious side effects during their methotrexate treatment.

Examples of methotrexate’s commonly reported side effects include:

Read on to learn about other possible mild and serious side effects of methotrexate.

* To learn more about this side effect, see the “Side effects explained” section below.

Some people may have mild side effects while using methotrexate. Examples that have been reported with this drug include:

* To learn more about this side effect, see the “Side effects explained” section below.
† An allergic reaction is possible after using methotrexate. This side effect wasn’t reported in studies, but has been reported since the drug became available for use.

In most cases, these side effects should be temporary. And some may be easily managed. But if you have symptoms that are ongoing or bother you, talk with your doctor or pharmacist. And do not stop using methotrexate unless your doctor recommends it.

Methotrexate may cause mild side effects other than those listed above. See the drug’s prescribing information for details.

Note: After the Food and Drug Administration (FDA) approves a drug, it tracks side effects of the medication. If you’d like to notify the FDA about a side effect you’ve had with methotrexate, visit MedWatch.

Serious side effects are possible with methotrexate. These include:

  • risk of serious side effects that affect multiple organs, which may include the following:
    • lung toxicity (lung damage)
    • severe skin-related side effects†
  • risk of fetal harm‡
  • risk of severe allergic reaction*§

If you develop serious side effects while using methotrexate, call your doctor right away. If the side effects seem life threatening or you think you’re having a medical emergency, immediately call 911 or your local emergency number.

* Methotrexate has a boxed warning for this side effect. This is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “Side effects explained” section below.
† To learn more about this side effect, see the “Side effects explained” section below.
Methotrexate has a boxed warning for this side effect. This is the most serious warning from the FDA. To learn more, see “Pregnancy and breastfeeding while using methotrexate” in the “Methotrexate warnings” section below.
§ An allergic reaction is possible after using methotrexate. This side effect wasn’t reported in studies but has been reported since the drug became available for use.

Get answers to some frequently asked questions about methotrexate’s side effects.

Does methotrexate cause ocular (eye-related) or dental side effects?

Eye-related and dental side effects weren’t reported in studies of methotrexate. But eye-related side effects have been reported since methotrexate became publicly available for use. It isn’t known for certain whether methotrexate was the cause, though.

Examples of eye-related side effects that have been reported with methotrexate include:

Although dental side effects have not been reported, methotrexate may cause mouth sores. To learn more about this side effect, see the “Side effects explained” section below.

Talk with your doctor if have other questions about eye-related side effects, dental side effects, and methotrexate.

Is weight gain a possible side effect of methotrexate?

It’s not likely. Weight gain wasn’t reported as a side effect in studies of methotrexate.

Keep in mind that rheumatoid arthritis (RA), which methotrexate is used to treat, may result in weight gain. If you’re using methotrexate to treat RA, it’s possible you may have weight gain related to your condition.

To learn more about weight gain and methotrexate, talk with your doctor. They can recommend ways to maintain a weight that’s healthy for you.

If I suddenly stop using methotrexate, will I have withdrawal symptoms?

No, probably not. Withdrawal symptoms weren’t reported in studies of methotrexate.

Withdrawal symptoms are side effects that can happen after you’ve suddenly stopped using a drug your body has become dependent on. With dependence, your body needs a drug to function as it usually does. But methotrexate isn’t known to cause these effects.

That said, the symptoms of the condition you were using methotrexate to treat may return after you stop using the drug. For details about possible symptoms that may occur, see these articles about psoriasis, rheumatoid arthritis, and juvenile idiopathic arthritis.

If you’re interested in stopping your methotrexate treatment, talk with your doctor first. If they agree it’s safe to stop, they’ll tell you the best way to do so. For example, they may slowly lower your dosage of methotrexate over time, as this can help reduce the risk of your symptoms returning. They may also prescribe a different treatment for your condition.

Yes, certain side effects of methotrexate are dose-dependent, meaning your risk is greater at higher doses. So your risk of certain side effects could be reduced by using a lower dose.

For example, in studies of methotrexate, the risk of liver damage* was greater at higher doses of the drug. Also, the dosage of methotrexate for rheumatoid arthritis is usually below 20 milligrams (mg) per week. This is because dosages above 20 mg weekly can increase your risk of low blood cell levels* as a side effect.

If you have bothersome side effects with methotrexate, talk with your doctor. They can tell you whether the side effect is related to the dosage of methotrexate you’re prescribed.

If your doctor feels the side effect is dose-related, they may lower your dosage slightly to see if the side effect eases. For example, they may lower your dosage by 2.5 mg per week for several weeks to see if the side effect goes away.

To learn more about methotrexate side effects in relation to its dosage, talk with your doctor.

* To learn more about this side effect, see “Risk of serious side effects, including death” in the “Side effects explained” section below.

It’s possible for methotrexate to cause long-term side effects. These include side effects that may start during treatment and continue for a long time. It’s possible certain side effects could continue after methotrexate treatment ends.

Below are a few examples of long-term side effects that can happen with methotrexate:

To learn more about long-term side effects with methotrexate, talk with your doctor or pharmacist.

Learn more about some of the side effects methotrexate may cause.

Allergic reaction, including severe allergic reaction

Like most drugs, methotrexate can cause an allergic reaction in some people. But this side effect wasn’t reported in studies. Symptoms can be mild to serious and can include:

  • skin rash
  • itchiness
  • flushing (temporary warmth, redness, or deepening of skin color)
  • swelling under your skin, usually in your eyelids, lips, hands, or feet
  • swelling of your mouth, tongue, or throat, which can make it hard to breathe

Risk of severe allergic reaction

Methotrexate has a boxed warning for severe allergic reaction. A boxed warning is the most serious warning from the Food and Drug Administration (FDA).

An example of a severe allergic reaction that could occur with methotrexate is anaphylaxis. But it’s important to note that anaphylaxis wasn’t seen during studies of methotrexate. There have been reports of this side effect in people using the drug, but it’s unclear how often this has happened or if methotrexate was the cause.

What might help

If you have mild symptoms of an allergic reaction, such as a mild rash, call your doctor right away. They may suggest a treatment to manage your symptoms. Examples include:

  • an antihistamine you take by mouth, such as Benadryl (diphenhydramine)
  • a product you apply to your skin, such as hydrocortisone cream

If your doctor confirms you’ve had a mild allergic reaction to methotrexate, they’ll decide if you should continue using it.

If you have symptoms of a severe allergic reaction, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms could be life threatening and require immediate medical care.

If your doctor confirms you’ve had a serious allergic reaction to methotrexate, they may have you switch to a different treatment.

Risk of serious side effects, including death

Methotrexate has a boxed warning for the risk of serious side effects, including death. A boxed warning is the most serious warning from the Food and Drug Administration (FDA).

Below are details about serious side effects that may occur with methotrexate.

Lung damage. This includes conditions such as interstitial lung disease (scarring and inflammation around the lungs). In rare cases, lung damage with methotrexate may be fatal.

Liver damage. This includes conditions such as cirrhosis (liver scarring) and liver failure. In rare cases, liver failure with methotrexate may be fatal. Your risk of this side effect may be greater at higher doses of the drug.

Kidney damage. This includes conditions such as kidney failure. Your risk of this side effect may be greater at higher doses of the drug. Your risk may also be higher if you already have kidney damage before starting treatment with methotrexate.

Nerve damage. This side effect may lead to seizures or symptoms that mimic those of a stroke. Examples include confusion, loss of vision, and weakness on one side of the body. In rare cases, nerve damage with methotrexate may be fatal.

Serious infection. Examples of serious infections that may occur include shingles and cytomegalovirus. Methotrexate may also reactivate hepatitis B or tuberculosis (TB) in people who already have the hepatitis B virus or TB bacterium in their bodies. In rare cases, serious infections with methotrexate may be fatal.

Low level of certain blood cells. These include white blood cells, platelets, and red blood cells. Your doctor may check the levels of these blood cells before you start methotrexate. And they may continue checking them from time to time throughout your treatment. They’ll tell you what to do if your blood cell levels become low during your treatment with this drug.

Severe problems with your digestive system. This may lead to diarrhea, vomiting, and mouth sores. (To learn more about this side effect, see “Mouth sores” below.) In rare cases, methotrexate may cause a tear in your stomach or intestines, which could be fatal. Your risk of severe digestive problems is higher if you have peptic ulcers or ulcerative colitis.

Severe skin-related side effects. Examples include erythema multiforme and the death of skin tissue. In rare cases, skin-related side effects with methotrexate may be fatal. To learn more, see “Skin-related side effects” below.

What might help

If you develop any of the side effects listed above during methotrexate treatment, tell your doctor about them right away. But if your symptoms feel severe or life threatening, immediately call 911 or a local emergency number.

If you have serious side effects with methotrexate, your doctor will recommend what to do. In some cases, serious side effects may not go away, even after you’ve stopped treatment with the drug. For more information, see “Can methotrexate cause long-term side effects?” above.

Hair loss

Hair loss was a less common side effect in studies of methotrexate.

Keep in mind that rheumatoid arthritis (RA) and psoriasis, which methotrexate is used to treat, may cause hair loss. So it’s possible you may have hair loss due to your condition while using methotrexate.

What might help

To help reduce hair loss, treat your hair gently while using methotrexate. This includes not using styling tools that are harsh on your hair, such as a curling iron. For more hair loss prevention tips, see this article.

If you have bothersome hair loss from methotrexate, talk with your doctor. They can help determine if your hair loss may be caused by the drug, your condition, or something else. They can also suggest more ways to help manage this side effect.

Mouth sores

Mouth sores were one of the more common side effects in studies of methotrexate. With mouth sores, you may have small cuts or blisters that affect your gums, cheeks, tongue, or the inside of your lips. Other symptoms that can occur with mouth sores include peeling, swelling, or a burning sensation.

Mouth sores with methotrexate may occur on their own and be mild. Or they may occur along with more severe digestive system problems. For details about more severe digestive problems with methotrexate, see “Risk of serious side effects, including death” above.

What might help

Tell your doctor if you have bothersome or painful mouth sores with methotrexate. They can suggest ways to manage this side effect. For example, they may recommend over-the-counter creams or other medications that can help relieve your discomfort.

Skin-related side effects

Skin-related side effects may occur with methotrexate. Mild skin-related side effects, such as skin rash and itchy skin, were common in studies of the drug. In rare cases, severe skin-related side effects may also occur and can be fatal.

Examples of severe skin-related side effects that may occur with methotrexate include:

Symptoms can include:

  • fever
  • blistering rash
  • peeling skin
  • painful skin

What might help

If you have skin-related side effects with methotrexate, tell your doctor right away. They can tell you how to manage them. But if your symptoms seem severe or life threatening, immediately call 911 or your local emergency number.

While using methotrexate, it’s important to limit your sun exposure as much as possible. Doing so can help reduce your risk of skin-related side effects. Be sure to wear a hat, long sleeves, long pants, and sunscreen while outdoors.

Keeping track of side effects

During your methotrexate treatment, consider taking notes on any side effects you’re having. You can then share this information with your doctor. This is especially helpful when you first start taking new drugs or using a combination of treatments.

Your side effect notes can include things such as:

  • what dose of the drug you were taking when you had the side effect
  • how soon you had the side effect after starting that dose
  • what your symptoms were
  • how it affected your daily activities
  • what other medications you were taking
  • any other information you feel is important

Keeping notes and sharing them with your doctor will help them learn more about how methotrexate affects you. They can then use this information to adjust your treatment plan if needed.

Below are several warnings for methotrexate.

Boxed warnings

Methotrexate has the boxed warnings discussed below. Boxed warnings are the most serious warnings from the Food and Drug Administration (FDA).

Risk of severe allergic reaction. Methotrexate may cause a severe allergic reaction, including anaphylaxis. For details, see the “Side effects explained” section above.

Risk of fetal harm. Methotrexate is not safe to use during pregnancy. For details, see “Pregnancy and breastfeeding while using methotrexate” below.

Risk of serious side effects, including death. Methotrexate may cause serious side effects that impact multiple organs. In rare cases, some of these serious side effects may be fatal. For details, see the “Side effects explained” section above.

Other warnings

Methotrexate may not be right for you if you have certain medical conditions. This is known as a drug-condition interaction.

Other factors may also affect whether methotrexate is a good treatment option for you. Talk with your doctor about your health history before starting methotrexate. Factors to consider include those described below.

Peptic ulcers or ulcerative colitis. Before starting methotrexate, tell your doctor if you have peptic ulcers or ulcerative colitis. These conditions can increase your risk of severe digestive problems as a side effect. If you have either of these conditions, your doctor can tell you if methotrexate is safe for you.

Lung problems. Methotrexate can cause new or worsening lung problems, such as interstitial lung disease (scarring and inflammation around the lungs). Be sure to tell your doctor if you have lung problems before starting methotrexate. They may recommend a different treatment for you.

Kidney problems. If you have kidney problems, such as kidney failure, tell your doctor before starting methotrexate. Having kidney problems can cause methotrexate to build up in your system. And this can increase your risk of side effects from the drug.

Methotrexate can also cause kidney problems as a side effect, which could worsen any kidney problems you already have. If you have kidney problems, your doctor can tell you whether methotrexate is a safe treatment option. In some cases, they may prescribe a lower than usual dosage of the drug for you.

Liver problems. If you have liver problems, be sure to tell your doctor before starting methotrexate. Examples include cirrhosis (liver scarring) and liver failure. Methotrexate can cause liver problems as a side effect, which could worsen any liver problems you already have.

Having liver problems can also cause methotrexate to build up in your system which can increase your risk of side effects from the drug.

If you have liver problems, your doctor can tell you whether methotrexate is safe for you. In some cases, they may prescribe a lower than usual dosage of the drug for you.

Allergic reaction. If you’ve had an allergic reaction to methotrexate or any of its ingredients, your doctor will likely not prescribe it for you. Ask them about other medications that might be better options.

Planned surgery with nitrous oxide anesthesia. Before having surgery, be sure your surgeon knows you’re using methotrexate. It may not be safe to use nitrous oxide while you’re using methotrexate. (Nitrous oxide is a kind of anesthesia commonly known as “laughing gas.”)

Your surgeon can tell you the kind of anesthesia you’ll be receiving and whether it’s safe to use it with methotrexate.

Alcohol and methotrexate

You should not use methotrexate with alcohol. Drinking large amounts of alcohol with methotrexate can increase the risk of liver damage as a side effect of the drug. To learn more about liver damage, see “Risk of serious side effects, including death” in the “Side effects explained” section above.

If you have questions about methotrexate and alcohol, talk with your doctor.

Pregnancy and breastfeeding while using methotrexate

Below is information about using methotrexate during pregnancy and while breastfeeding.

Methotrexate and the risk of fetal harm during pregnancy

Methotrexate has a boxed warning about fetal harm (commonly known as birth defects) if the drug is used during pregnancy. A boxed warning is the most serious warning from the Food and Drug Administration (FDA).

Studies of methotrexate have shown that the drug may cause pregnancy loss. In addition, using this drug while pregnant can result in serious problems with fetal development. These may include abnormalities of the brain, head, face, heart, arms, or legs.

Due to these risks, your doctor will likely recommend that you do not use methotrexate if you’re pregnant or planning a pregnancy. If you’re able to become pregnant, your doctor will confirm you aren’t by giving you a pregnancy test before you start methotrexate.

If you or your partner can become pregnant, you should use effective birth control throughout your methotrexate treatment. Females* should continue to use birth control for at least 6 months after their last dose of the drug. And males* should continue using birth control for at least 3 months after their last dose.

If you’re pregnant or planning a pregnancy, talk with your doctor before starting methotrexate. They may recommend a different drug for your condition.

* In this article, we use the terms “female” and “male” to refer to someone’s sex assigned at birth. For information about the difference between sex and gender, see this article.

Methotrexate and breastfeeding

It’s recommended that you avoid breastfeeding while using methotrexate. This drug may pass into breast milk which could cause side effects in a child who is breastfed.

To be safe, you should avoid breastfeeding while using methotrexate and for at least 1 week after your last dose.

Before starting methotrexate, tell your doctor if you’re breastfeeding or planning to breastfeed. They may discuss other treatment options with you or suggest other healthy ways to feed your child.

Methotrexate is used to treat certain autoimmune diseases. Some people have mild side effects from this drug, such as headache. But more serious side effects are possible.

If you have any questions about side effects that methotrexate can cause, talk with your doctor. Below are a few questions you may want to ask to help decide if this treatment is right for you:

  • Do any medical conditions I have increase my risk of side effects from methotrexate?
  • How do the side effects of methotrexate compare with those of other drugs used to treat my condition?
  • Will any other drugs I’m taking increase my risk of side effects from methotrexate?

You can also ask your doctor about Otrexup, Rasuvo, or Reditrex, which are the brand-name versions of methotrexate. A generic drug and its brand-name version are expected to have the same side effects because they contain the same active ingredient. (An active ingredient is what makes a drug work.)

To learn more about methotrexate, see these articles:

To get information on different conditions and tips for improving your health, subscribe to any of Healthline’s newsletters. You may also want to check out the online communities at Bezzy. It’s a place where people with certain conditions can find support and connect with others.

Disclaimer: Healthline 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.

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