Leflunomide vs. Methotrexate: Uses, Side Effects, and More

Uses for leflunomide and methotrexate

Leflunomide and methotrexate are both prescribed to treat RA. Methotrexate has other uses as well.

The following table includes details on the conditions each drug treats.

To learn more about using leflunomide or methotrexate to treat your condition, talk with your doctor.

Note: For mycosis fungoides, only methotrexate tablets are approved for this use.

Leflunomide or methotrexate and children

Methotrexate is prescribed for the following uses in children:

• acute lymphoblastic leukemia
• prevention and treatment of meningeal leukemia
• non-Hodgkin’s lymphoma
• osteosarcoma
• polyarticular juvenile idiopathic arthritis

Leflunomide is not approved for use in children.

For more information about leflunomide and children, talk with your child’s doctor.

Dosage, forms, and administration for leflunomide and methotrexate

Here’s an overview of leflunomide and methotrexate dosages and how you would use these drugs for the conditions they both treat.

Methotrexate is also used to treat other conditions, but these uses aren’t addressed here. To learn more about the dosages for all conditions these drugs treat or prevent, see the leflunomide article and methotrexate article.

Dosage for rheumatoid arthritis (RA)

The injection form of methotrexate is only prescribed by a healthcare professional. If you’re prescribed this form of methotrexate, you’ll receive doses from a healthcare professional at a place such as your doctor’s office or clinic.

Side effects of leflunomide and methotrexate

Some people taking leflunomide or methotrexate may experience mild to serious side effects.

For more information about possible side effects, see the leflunomide side effects article and methotrexate side effects article.

Mild side effects

Leflunomide and methotrexate may cause mild side effects. The following table lists examples of mild side effects that have been reported with these drugs.

This table may not include all mild side effects of these drugs. For more information on mild side effects, see the prescribing information for leflunomide, methotrexate oral tablets, and methotrexate injection.

Serious side effects

Serious side effects may also occur in people using leflunomide or methotrexate. The following table includes side effects reported with these drugs.

* See the “What are the warnings of leflunomide and methotrexate?” section for more details.

To learn about your specific risk for serious side effects from leflunomide or methotrexate, talk with your doctor or pharmacist.

Note: The risk of benzyl alcohol toxicity only applies to the injectable form of methotrexate.

Allergic reaction

For some people, leflunomide and methotrexate can cause an allergic reaction. Methotrexate has a boxed warning for the risk of allergic reactions. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). To learn more, see the “What are the warnings of leflunomide and methotrexate?” section.

In general, symptoms of an allergic reaction can be mild or serious.

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 and can determine whether you should keep taking leflunomide.

If you have symptoms of a severe allergic reaction, such as swelling or difficulty 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 leflunomide, they may have you switch to a different treatment.

FAQ about leflunomide and methotrexate

Get answers to some frequently asked questions about leflunomide and methotrexate.

Which is safer, methotrexate or leflunomide?

It depends. Both methotrexate and leflunomide are approved to treat rheumatoid arthritis (RA) in adults. Whether methotrexate or leflunomide is a safer option depends on factors specific to you and your health. It will be up to you and your doctor to decide which treatment is a safer option for you. A few factors that can impact this decision include:

• other medical conditions you have
• other medications you take, including any over-the-counter medications and dietary supplements

If you’re interested in taking either leflunomide or methotrexate for RA, talk with your doctor. Your doctor can help determine which RA treatment is safest for you.

Can methotrexate or leflunomide cause hair loss?

Yes. Hair loss has been reported as a side effect with leflunomide, methotrexate oral tablets, and methotrexate for injection.

Clinical studies of leflunomide, when compared to methotrexate, suggest that rates of hair loss were similar in both medications, but were slightly higher in people who took leflunomide.

Talk with your doctor if you have questions or concerns about hair loss as a side effect of taking leflunomide or methotrexate.

Effectiveness of leflunomide and methotrexate

Leflunomide and methotrexate are both used to treat rheumatoid arthritis. Studies of leflunomide, methotrexate oral tablets, and methotrexate for injection have shown that both drugs are effective for this use.

In addition, the American College of Rheumatology includes both drugs in its treatment recommendations for RA.

It’s important to note that your results from leflunomide or methotrexate may differ from those seen in studies. Talk with your doctor about whether one of these drugs is suitable for you.

If you’d like to read more about how each drug performed in studies, see the prescribing information for leflunomide, methotrexate oral tablets, and methotrexate for injection.

Cost of leflunomide and methotrexate

Whether you have health insurance or not, cost may be a factor when you’re considering these drugs.

Keep in mind that what you’ll pay for either drug will depend on your treatment plan, health insurance, and the pharmacy you use. If you are prescribed methotrexate for injection, you may also pay a cost to receive doses from a healthcare professional at a place such as your doctor’s office or clinic.

Leflunomide and methotrexate are both generic forms.

For other resources that might help you save on the price of these drugs, see the leflunomide cost article and methotrexate cost article.

What are the warnings for leflunomide and methotrexate?

Leflunomide and methotrexate may not be right for you if you have certain medical conditions or other factors that affect your health. The prescribing information for these drugs refers to these factors as warnings.

The drugs share some of the same warnings, but they also have different ones. Some of these warnings are mentioned here. Before you start using leflunomide or methotrexate, be sure to talk with your doctor to check whether these warnings apply to you.

Note: The use of binary terms such as “male” and “female” or “men” and “women” in this article reflects the language of the sources we’ve used. Unless otherwise noted, it’s unclear whether the research we reference included participants with expansive gender identities.

Leflunomide boxed warnings

Leflunomide has boxed warnings. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). It alerts doctors and patients about drug effects that may be dangerous.

Risk of fetal harm: Doctors typically won’t prescribe leflunomide during pregnancy. In animal studies, the drug caused fetal harm when given to pregnant animals at doses lower than those prescribed to people taking leflunomide. If you can become pregnant, your doctor will likely order a pregnancy test to ensure it’s negative before prescribing leflunomide. They’ll likely also recommend using effective birth control throughout your treatment. If you become pregnant while taking leflunomide, immediately stop taking it and call your doctor. There are steps that can be taken to get leflunomide out of your system as soon as possible, which your doctor can discuss with you.

Risk of liver damage: There are reports of liver damage in people taking leflunomide. In rare cases, this damage can be severe or even cause death. Due to this risk, doctors typically won’t prescribe leflunomide to people with an existing liver condition, such as cirrhosis. Before you begin taking leflunomide, be sure to tell your doctor about all medications you take. If you’re taking other medications that can cause liver damage, your doctor may prefer to prescribe a treatment other than leflunomide to you. If you’re prescribed leflunomide, your doctor will likely regularly order liver function tests throughout treatment. Your doctor may temporarily or permanently stop your leflunomide treatment depending on your liver function test results.

Methotrexate boxed warnings

Methotrexate has boxed warnings. A boxed warning is the most serious warning from the Food and Drug Administration (FDA). It alerts doctors and patients about drug effects that may be dangerous.

Risk of fetal harm: Based on how it works and reports since the drug was approved, doctors typically won’t prescribe methotrexate during pregnancy due to the risk of fetal harm. If you can become pregnant, your doctor will likely advise you to use effective birth control during treatment and for at least 6 months after your last dose. If you’re male and have a sexual partner who may become pregnant, your doctor will likely advise you to use effective birth control during treatment and for at least 3 months after your last dose.

Risk of allergic reactions: Allergic reactions have been reported with methotrexate treatment. Due to this risk, doctors usually won’t prescribe methotrexate tablets or injection if you’ve previously had an allergic reaction to methotrexate. Instead, they can discuss safer treatments for your condition with you.

Risk of certain serious side effects: Methotrexate treatment can cause serious side effects affecting different body parts and systems, including your digestive tract, lungs, kidneys, liver, skin, and bone marrow. In rare cases, these side effects can cause death. These side effects have been reported with both methotrexate oral tablets and methotrexate for injection. Due to the risk of these side effects, your doctor will likely order lab tests throughout your treatment to monitor your health. You should also pay close attention to new symptoms that may be a sign of serious methotrexate side effects. If you develop symptoms, let your doctor know right away. For symptoms that feel life threatening, skip calling your doctor and go to the closest emergency room or dial your local emergency number (such as calling 911 in the United States). Examples of these serious side effects include:

• kidney damage symptoms can include pain between your hips and ribs, and slow, sluggish movements
• liver damage symptoms can include yellowing of your skin or the whites of your eyes (jaundice)
• lung damage symptoms can include shortness of breath and a consistent dry cough
• nerve damage symptoms can include new or worsening seizures and confusion
• digestive system side effects, including holes in your intestines
• blood cell problems, including severe neutropenia or thrombocytopenia
• increased risk of serious infections, such as tuberculosis

Risk of benzyl alcohol toxicity: The injectable form of methotrexate carries a warning regarding benzyl alcohol toxicity if used in neonates and low birth-weight infants. Due to this risk, doctors typically won’t use this form of methotrexate if the medication must be used in a neonate or low birth-weight infant. They’ll prescribe a different medication or use a safer form of methotrexate (such as an injectable methotrexate that does not contain benzyl alcohol as a preservative) instead.

Other warnings

In addition to boxed warnings, leflunomide and methotrexate have other warnings.

Before using leflunomide or methotrexate, talk with your doctor if any of the following conditions or health factors apply to you.

• Warnings for leflunomide:
  • if you are taking the medication teriflunomide
  • if you have a weakened immune system
  • if you have a blood cell problem, such as neutropenia
  • if you have cancer or have had cancer in the past
  • if you have high blood pressure
• Warnings for methotrexate:
  • if you have a kidney condition, including if you receive dialysis
  • if you have seizures or have had them in the past
  • if you have ascites (fluid retention in or around your stomach area)
  • if you have upcoming surgery scheduled, including dental surgery
  • if you have stomach ulcers
  • if you have ulcerative colitis
• Warnings for both leflunomide and methotrexate:
  • if you’ve had an allergic reaction to either drug or any of its ingredients
  • if you’re pregnant or planning to become pregnant
  • if you’re breastfeeding or planning to breastfeed
  • if you have a liver problem
  • if you have peripheral neuropathy or another nerve condition
  • if you have a lung condition, such as interstitial lung disease
  • if you have recently received or are scheduled to receive a vaccine

To learn more about these drugs, see the leflunomide and methotrexate overviews.

Switching between leflunomide and methotrexate

The short answer: It’s possible.

Details: Leflunomide and methotrexate are both approved for treating rheumatoid arthritis (RA) in adults. If you’re taking leflunomide or methotrexate to treat RA and are interested in switching to the other medication, talk with your doctor. If you and your doctor agree that switching medications is safe for you, your doctor can provide instructions on how to switch.

Reminder: You should not switch drugs or stop your current treatment unless your doctor recommends it.

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.