Methotrexate Injections vs. Oral Methotrexate: Benefits, Risks, and How to Save

Medications often come in different forms. This can raise questions about which one is the best. Sometimes, the choice depends on the reason you’re taking a medication. In other cases, it depends on cost or insurance coverage.

Methotrexate is a medication that’s used to treat many health conditions. It comes in different forms: an oral tablet, an oral liquid, and an injection. But when would a healthcare professional choose one over the other?

Let’s explore more about methotrexate, the conditions it treats, and which form may be a good choice for you.

Methotrexate overview

Methotrexate belongs to a group of medications called antifolates. These medications work by blocking the creation and repair of DNA — our body’s genetic building blocks. This halts the creation of new cells in the body.

Because of how methotrexate works, it can be used in many cancers, such as:

• Acute lymphocytic leukemia, a cancer that affects certain white blood cells (lymphocytes)

• Non-Hodgkin lymphoma, a cancer that affects lymphocytes and lymph nodes (small glands in the body that contain white blood cells) — especially if the cancer is aggressive or is in your brain or spinal cord

• Osteosarcoma, a cancer of the bones

• Certain types of breast cancer

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Methotrexate also has anti-inflammatory properties. These make it useful in autoimmune disorders, such as psoriasis and rheumatoid arthritis (RA).

Methotrexate has also been found to have benefits in treating certain conditions it’s not FDA approved for. So it’s sometimes prescribed off-label for other purposes. Examples include eczema, lupus, and inflammatory bowel disease.

TL;DR: Methotrexate injections vs. pills and liquid

Methotrexate is available in oral and injectable forms. But there are several differences between them. This includes their doses, side effects, and absorption in the body.

Using methotrexate as a cancer treatment is often individualized. Doses and length of treatment can change depending on different factors. If you’re taking methotrexate as part of chemotherapy, talk with your oncologist about the specifics of your treatment.

For this discussion, we’ll mainly focus on using methotrexate for psoriasis and RA.

Benefits of injectable methotrexate

Methotrexate is a first-choice treatment for moderate-to-severe psoriasis and RA. It’s available as a pill, a liquid, and an injection. So it’s common for people with these conditions to ask if one form is better than the others.

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• Methotrexate drug interactions: Check for medications that may be interfering with your chance for success with methotrexate.

Injectable methotrexate has a few advantages over the oral form:

• Bioavailability: Injectable methotrexate is more bioavailable than the oral form, meaning more medication is active in the body. This is likely because the injectable form doesn’t have to be absorbed in the digestive tract. This is especially important if you need higher doses of the medication.

• Gut issues: Injectable methotrexate may cause fewer stomach-related side effects, such as nausea, vomiting, and diarrhea. This could be because injectable methotrexate doesn’t need to be absorbed in the digestive tract. But more recent studies have scientists wondering if this is true. Some people report improved side effects with the injectable form; others don’t.

• Effectiveness for RA: Injectable methotrexate may be more effective for RA than oral methotrexate. But some experts disagree on this. When the results of four studies comparing injectable with oral methotrexate were combined, people were more likely to experience an improvement of RA symptoms when methotrexate was injected under the skin. But a more recent combination of six studies suggests that oral and injectable methotrexate have similar effectiveness. A rheumatologist may suggest that you start with oral methotrexate. You could then switch to the injectable if it’s not working, you need higher doses, or you’re having gut-related side effects.

• Effectiveness for psoriasis: Injectable methotrexate may also be more effective than oral methotrexate in psoriasis. As with RA, the studies are mixed. Some suggest that it works better and quicker than oral methotrexate; others didn’t find a difference. More studies are needed to confirm this.

How to use injectable methotrexate

Injectable methotrexate can be given in a few ways:

• IV infusion — delivered directly into a vein

• Subcutaneous injection — injected just beneath the skin

• Intramuscular (IM) injection — injected into a muscle

• Intrathecal injection — injected in the space that holds your spinal fluid

The IV and intrathecal forms of methotrexate are most often used when treating cancer. The subcutaneous and IM forms are typically used when treating autoimmune disorders.

IM injections can be given in the middle of the thigh muscle, on the outside of the upper arm, or on the upper part of the buttocks. Subcutaneous injections can be given on the outside or back of the upper arm, on the outside of the upper thigh, or on the stomach at least 2 inches from the belly button.

Injectable methotrexate comes in a vial. It can be drawn up with a syringe and as an auto-injector pen, similar in style to an EpiPen (epinephrine). The vials are available as generic products. But the auto-injector pens are available only as brand-name Otrexup and Rasuvo.

Can you take injectable methotrexate by mouth?

No, injectable methotrexate isn’t designed to be taken by mouth.

In the mid- to late 1990s, researchers wanted to find out whether they could make an oral solution from injectable methotrexate. The study concluded the injectable solution could be an alternative to the tablets. But this method isn’t an FDA-approved use for injectable methotrexate. It shouldn’t be tried without instructions from a healthcare professional. Trying this on your own could affect how the medication works. It could also increase your chance of having side effects.

Instead, know that there are two FDA-approved oral methotrexate solutions: Xatmep and Jylamvo. Xatmep is approved for use in children. But Jylamvo can be taken by children or adults. These versions are better options than swallowing injectable methotrexate.

Good to know: If you switch between these oral solutions, you’ll want to pay close attention to the dose. Xatmep and Jylamvo have slightly different concentrations. Xatmep is available as a 2.5 mg/mL oral liquid, and Jylamvo is available as a 2 mg/mL liquid. This will slightly change how much liquid is needed for your dose. Xatmep can be stored and used for up to 2 months after opening, while Jylamvo can be used for up to 3 months after opening.

Benefits of oral methotrexate

One major benefit of taking oral methotrexate is not having to deal with needles. Some people are uncomfortable using needles and would rather take something by mouth.

People with vision problems may find it hard to read the small numbers on a syringe or an auto-injector pen. Taking pills may make it easier to know if you’re taking the correct dose of methotrexate.

Other people may have trouble giving themselves shots because their condition is severe. RA can cause swelling and discomfort in the hands. This can make drawing medication into a small syringe difficult. The risk of giving an incorrect dose may be higher in this situation.

Methotrexate onset time

When methotrexate is taken for RA, you may start to see improvements after 3 months. But it could take up to 6 months to see methotrexate’s full effects.

When methotrexate is used for psoriasis, you could start seeing results in 4 to 6 weeks. Expect full effects about 6 months after starting methotrexate.

What’s more, injectable methotrexate may work more quickly than the oral form. In RA and psoriasis, two studies found that more people using injectable methotrexate had an improvement in symptoms at 8 weeks compared with people using oral methotrexate. But it’s not clear whether this is beneficial in the long run.

How quickly methotrexate works for cancer varies from person to person. Ask an oncologist about your chemotherapy regimen. They can address general concerns about methotrexate’s effectiveness.

Methotrexate side effects

Methotrexate’s side effects are similar between the injectable and oral forms. The most common ones are stomach related, such as nausea and vomiting. This may happen less often with the injectable form, but it’s a common side effect either way.

Other possible side effects include headache, diarrhea, and mouth sores. Methotrexate can also put stress on the liver. Your rheumatologist may order liver function tests while you’re taking the medication. These are a group of blood tests that check your liver health.

Some people may rarely experience hair loss. This happens more frequently for people with psoriasis. Hair loss shouldn’t be excessive. So speak with a healthcare professional if you notice severe hair loss or bald patches. Normal hair growth usually resumes once you stop the medication.

What’s more, methotrexate can lower folic acid levels in the body. This may contribute to some side effects, such as nausea, vomiting, and liver problems. A healthcare professional may prescribe a folic acid supplement to take with methotrexate. Adding folic acid can relieve gut-related side effects and lower stress on the liver. But it’s important to take folic acid only if it’s prescribed to you. If you’re being treated for cancer, folic acid can lower methotrexate’s effectiveness.

Serious methotrexate side effects

Kidney damage is another risk with methotrexate, especially at high doses. If you have kidney problems, your risk of this side effect is higher. Depending on your dose and medical history, a healthcare professional may monitor your kidney health. This is done with blood tests called a kidney panel.

Methotrexate can also cause bone marrow suppression. This is a rare but life-threatening side effect: It could lower several types of blood cells in your body. It’s usually seen only with higher doses used for cancer treatments. A rheumatologist may order blood tests to make sure your blood cells stay within a safe range.

How to save on methotrexate

There are ways to save on oral and injectable methotrexate. Both are available as brand-name medications. But you can also find them as lower-cost generics. GoodRx can help you navigate many ways to save on your prescription.

• Save with GoodRx. At select pharmacies, generic oral methotrexate’s price is as low as $10.92 using a free GoodRx coupon. The price of injectable methotrexate is as low as $8.30.

• Save with a copay savings card. If you have commercial insurance and meet eligibility requirements, Otrexup’s price and Rasuvo’s price are as little as $0 using a savings card from the manufacturer. Jylamvo’s price and Xatmep’s price are as little as $5 using a savings card.

• Save with patient assistance programs. If you’re uninsured or underinsured, you may be eligible for a patient assistance program for Rasuvo, Jylamvo, or Xatmep. These programs offer their medications for free.

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Written by:

Rachel Feaster, PharmD, BCOP, BCPS

Rachel Feaster has over 10 years of professional experience in ambulatory, inpatient, pharmacogenomics, and oncology care. She is board certified in oncology and pharmacotherapy.

Edited by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

Reviewed by:

Vanessa Carranza, PharmD

Vanessa Carranza, PharmD, is a pharmacist who has dedicated her career to the advancement of medical education for healthcare providers, patients, and caregivers, most notably in the oncology space.

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