What is Methotrexate

Methotrexate is a Disease Modifying Anti-Rheumatic Drug (DMARD) that is also known as Trexall, Folex PFS, Rheumatrex Dose Pack, and Methoxtrexate Sodium. Low dose methotrexate is a very common treatment for rheumatoid arthritis, psoriatic arthritis, and many other types of arthritis. Methotrexate is also known as a treatment for cancer. As a cancer treatment, it is prescribed at significantly higher doses than for arthritis treatment. Methotrexate is also occasionally used to treat certain other diseases as well. Methotrexate is understood to work by altering how the body uses folic acid (vitamin B9), a vitamin that is needed for cell growth.

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Dr. John Wade, MD, FRCPC, Rheumatologist, talks about what Methotrexate is typically used for and the standard dosing schedules commonly used.

Quiz: Do You Understand Methotrexate?

Test your knowledge by answering the following questions:


Methotrexate is commonly used to treat rheumatoid arthritis (RA) but not psoriatic arthritis.

Methotrexate is a disease-modifying anti-rheumatic drug (DMARD). It is commonly used to treat inflammatory conditions including rheumatoid arthritis (RA), psoriatic arthritis, vasculitis and systemic lupus erythematosus.

There are two ways to take methotrexate.

There are two ways to take methotrexate. One is to take a pill or a number of pills once a week. Or, you can auto-inject a dose under the skin once a week.

It may take up to 52 weeks for maximum effect of methotrexate.

Methotrexate won’t relieve your symptoms right away - that’s why it’s called a slow disease-modifying agent. Typically, you’ll notice the effects between 6 and 12 weeks, and a maximum effect may take up to 52 weeks.

Liver inflammation is not a side effect of methotrexate.

Side effects of methotrexate include fatigue, stomach upset, small ulcerations in the nose or mouth, liver inflammation and thinning of the hair.

Methotrexate is a safe option if you're pregnant or planning to become pregnant.

If you take methotrexate, your rheumatologist or doctor will want to do regular blood test monitoring. If you’re pregnant or planning to become pregnant, methotrexate is not an option for you.
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Dr. John Wade, MD, FRCPC, Rheumatologist, talks about what Methotrexate and the side effects that some patients may experience and how to mitigate them

Dr. John Wade, MD, FRCPC, Rheumatologist, talks about how Methotrexate can require regular blood testing to monitor for safety of the liver.

Important Tests and Risks

Methotrexate is generally a safe medication that is tolerated by most patients taking the lower dosages used to treat arthritis.

Blood Tests

Patients should have their blood tested every 1-3 months so their doctor can monitor for potential side effects on the liver or blood counts.

Interaction with Sulfa Antibiotics

Methotrexate should not be taken with sulfa antibiotics such as co-trimoxazole (Septra) or trimethoprim.

Interaction with Alcohol

People taking methotrexate should avoid drinking alcohol. Alcohol significantly increases the risk for liver damage while taking methotrexate.

Rare Lung Reaction

Methotrexate can very rarely cause an unusual lung reaction that is more likely to occur in older patients with underlying lung disease.


How Methotrexate Works

Scientists don’t yet completely understand exactly how methotrexate works inside the body to help arthritis.

It is known that methotrexate changes how cells inside the body uses folic acid (vitamin B9), which is needed for cell growth. It is not well understood how exactly this effect, or other possible effects of methotrexate, work to help improve arthritis.

What is known is that the lower doses of methotrexate used in the treatment of arthritis can help patients by:

  • reducing the pain and swelling (inflammation) in arthritic joints
  • improving day to day function
  • preventing long-term damage caused by joint inflammation


Side Effects

The most common side effect of methotrexate is nausea, feeling unwell, or feeling tired for 24 to 48 hours after taking a dose. This usually gets better over time as the body gets used to the medication. This side effect can also be reduced by lowering the dose or switching to the injected form from tablets.

Methotrexate very rarely causes a serious lung problem. Patients should call their doctor and STOP taking methotrexate if they experience:

  • New shortness of breath while resting, but don’t have a heavy cold (no runny nose or fever)
  • A new dry cough lasting weeks, especially in the absence of a cold

Patients must NOT take sulfa antibiotics, such as co-trimoxazole (Septra) or trimethoprim, while taking methotrexate. Patients should always check with their doctor or pharmacist before starting a new medication.

A doctor should review blood test results every 1-3 months to keep an eye out for any potential side effects to the liver or blood counts. It is important for patients who take methotrexate to remember to get these blood tests done.

Patients taking methotrexate should not drink alcohol.

Methotrexate may cause birth defects and result in miscarriage. Women should AVOID PREGNANCY.

The information sheets given by pharmacists do not distinguish between high and low dose Methotrexate. Arthritis treatment does not involve the high doses used in cancer treatments. The side-effects which may be seen with low-dose Methotrexate include the following:

MORE COMMON side-effects include:

  • Nausea, indigestion, and diarrhea.
  • Feeling generally unwell after taking the methotrexate.
  • Headaches & irritability.

RARE side-effects include:

  • Hair loss (rare at low doses)
  • Sensitivity to the sun (rare)
  • Liver: Methotrexate may irritate the liver. This does not usually cause symptoms but may be found on blood tests. It is uncommon and usually reversible when regularly monitored with blood tests.
  • Blood Counts: Methotrexate can cause a drop in the numbers of white blood cells (which are needed to fight infection) and platelets (which help to stop bleeding). If a patient is good at getting regular blood tests, it is unusual for this to be a serious problem.
  • Lungs: Methotrexate may irritate the lungs. If a person taking this medicine develops a cough, fever, or shortness of breath, they should STOP taking it and call their doctor immediately.
  • Infection: Any infections or fevers should be taken seriously and reviewed by a doctor.
  • Sores in the mouth.

How to minimize the side-effects of Methotrexate:

  • Take methotrexate ONCE A WEEK as prescribed by a doctor.
  • Tablets can be split up and taken at two times over a 24 hour period (i.e. take them with breakfast and dinner).
  • Taking Methotrexate before bed can sometimes help as patients may sleep through any nausea or general feelings of being unwell.
  • Taking folic acid may help to reduce the side effects of the methotrexate.
  • Some patients find switching from pills to injections helps reduce side effects.

People taking methotrexate should talk to their doctor if they are concerned about any side effects.

Methotrexate – Administration, Dose, Frequency

To treat arthritis, methotrexate is taken once a week. It is available in oral tablet form (2.5 mg tablets) and in liquid injectable form (25 mg/mL vials or pre-filled syringes) for subcutaneous (under the skin) injection.

The standard dose for tablets ranges from 3 per week (7.5 mg) to 10 per week (25 mg). On the day that it is taken, tablets can be taken all at once or split up and taken twice over a 24 hour period. The standard dose for injection ranges from 0.3 mL (7.5 mg) to 1.0 mL (25 mg) per week.

Watch our video to learn how inject Methotrexate at home:

Subcutaneous injections (under the skin injections) are easy to do compared to other types of injections. A small needle pokes just under the skin to deliver medicine into the “fatty tissue” below.

Taking Methotrexate

Methotrexate is available in oral tablet form and in a liquid injectable form for subcutaneous (under the skin) injection.

Injected methotrexate has a number of benefits over oral methotrexate. It tends to have fewer side effects like nausea and it is absorbed by the body better and more consistently (85% absorption for injected vs. 20-80% variability for oral).

A few small studies have even suggested that the injected form of methotrexate may be a more effective treatment for Rheumatoid Arthritis.

When methotrexate works, most patients start to feel improvement after 6 to 8 weeks. The maximum effect can take 6 to 12 months. If a patient starting on methotrexate doesn’t feel any effects after a 3 month “trial period” then the medication is usually stopped.

Dr. John Wade, MD, FRCPC, Rheumatologist, talks about how to titrate Methotrexate to a lower dose or to stop taking it completely.

Who Should Not Take Methotrexate

Patients who should NOT be taking Methotrexate include:

  • Patients taking sulfa antibiotics, such as co-trimoxazole (Septra) or trimethoprim
  • Women who are pregnant or breastfeeding
  • Women of child bearing potential who do not use reliable contraception
  • Patients with an infection. It is often best for patients who have a fever or think they have an infection to stop taking methotrexate. Phone your doctor for advice.
  • Patients who are heavy drinkers. It is best not to drink alcohol at all while taking methotrexate.

Anyone who becomes pregnant while taking Methotrexate should notify their doctor immediately.

Dr. John Wade, MD, FRCPC, Rheumatologist, talks about how to titrate Methotrexate to a lower dose or to stop taking it completely.

When to Call a Doctor

People taking methotrexate should call their doctor if they feel sick and want to stop, or if they are concerned about any side effects.

Other reasons to call your doctor while taking methotrexate include:

  • Cough or difficulty breathing (especially shortness of breath)
  • Fever or possible infection
  • Developing severe mouth sores
  • Becoming pregnant or are planning on pregnancy
  • Planning to have surgery

Dr. John Wade, MD, FRCPC, Rheumatologist, talks about the contraindications and use of Methotrexate in pregnancy.

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