Methotrexate

Methotrexate is a chemotherapy medication that’s used to treat many different types of cancer, including leukemia, osteosarcoma, and head and neck cancer, among others. This medication is also used to treat some non-cancer conditions, such as psoriasis and rheumatoid arthritis. Methotrexate is given as an injection. For low doses, you can sometimes get injections at a brief visit to the provider’s office. But for higher doses, you might need to stay in the hospital for a couple days. Methotrexate side effects include low white blood cells, mouth sores, and nervous system problems.

What is Methotrexate used for?

Cancer:

• Acute lymphoblastic leukemia (ALL); given with other chemotherapy
• Treatment and prevention of meningeal leukemia
• Non-Hodgkin lymphoma (NHL)
• Osteosarcoma; given with other chemotherapy
• Breast cancer; given with other chemotherapy
• Head and neck cancer
• Gestational trophoblastic neoplasia (GTN); given with other chemotherapy

Non-cancer conditions:

• Rheumatoid arthritis (RA)
• Polyarticular juvenile idiopathic arthritis (pJIA)
• Psoriasis

How Methotrexate works

Methotrexate is an antimetabolite medication that treats many types of cancers and non-cancer conditions (like arthritis and psoriasis).

• For cancer: Methotrexate works by blocking dihydrofolate reductase, a protein in your body that’s important for making DNA in cells and for cell growth. Since cancer cells grow much more quickly than healthy cells, the medication helps slow down cancer growth so the cancer can’t spread as well.
• For non-cancer conditions: We don’t know exactly how methotrexate works to treat non-cancer conditions such as rheumatoid arthritis and psoriasis. But research suggests that, at lower doses, it blocks the immune system from becoming too active. For psoriasis, the medication might also help slow down the growth of skin cells.

Pros and cons of Methotrexate

• The dose of methotrexate for treating cancer and non-cancer conditions is very different. Lower doses are more common for non-cancer conditions (like rheumatoid arthritis and psoriasis), whereas higher doses are typically used to treat cancers. Your provider will make sure you’re taking the right methotrexate dose for your specific medical condition.
• Be sure to get any lab tests or scans that your provider orders. These tests help your provider check that methotrexate is safe for you.
• If you’re taking methotrexate for a non-cancer condition (such as psoriasis or rheumatoid arthritis), your provider might recommend taking folic acid supplements to help prevent side effects from methotrexate. Make sure that you take only the dose that your provider recommends and carefully follow your provider's instructions.
• If you’re taking methotrexate to treat cancer, check your temperature on a regular basis. Call your provider as soon as you can if you have a fever (a temperature that’s 100.4 degrees Fahrenheit or higher). A fever could be the only sign that you’re sick, and it’s important for your provider to know if you get sick.
• Before you get any vaccines, let your provider or pharmacist know that you’re taking methotrexate. Some vaccines might work less well for you during treatment. But you should avoid getting live vaccines because of the risk of infection from the vaccine itself. Your provider can make sure you can get the vaccine that you’re interested in.
• Don’t start or stop any new medications without first talking to your provider. There are many medications you shouldn’t take with methotrexate because they can raise your risk for side effects. Your care team can make sure all your medications are safe to take together.
• You shouldn’t breastfeed while you’re taking methotrexate and for 1 week after your last dose. We don’t know whether the medication passes into human milk. But because of the way methotrexate works, it could harm a breastfeeding infant.

What are the risks and warnings for Methotrexate?

Methotrexate can cause some serious health issues. This risk may be even higher for certain groups. If this worries you, talk to your doctor or pharmacist about other options.

Harm to unborn baby

Methotrexate can cause harm to an unborn baby and pregnancy loss (miscarriage) when it’s taken during pregnancy. For this reason, you can’t take this medication for non-cancer conditions if you’re pregnant.

In general, it’s best to avoid becoming pregnant while you’re taking methotrexate. If you or your partner can become pregnant, you should use reliable birth control while you’re taking methotrexate. Keep using birth control for 6 months after the last dose (for females) or for 3 months after the last dose (for males). Contact your provider right away if you or your partner gets pregnant during treatment.

Allergic reaction

Some people have experienced allergic reactions to methotrexate. Let your nurse or provider know right away if you have any symptoms of a reaction such as itching, fever, nausea, trouble breathing, or a fast heartbeat. Get medical help as soon as possible if you have an anaphylactic reaction, such as hives, swelling in the face or lips, or throat tightness.

Contains potentially harmful preservative

• Risk factors: Newborns and low birth weight infants | Intrathecal injections of methotrexate

Some methotrexate products for injection have a preservative called benzyl alcohol. This preservative can be dangerous for very young babies, people taking high-dose methotrexate, and people getting the medication as an intrathecal injection (into the fluid of the spinal cord). These people shouldn’t use methotrexate products containing benzyl alcohol because of the risk of nervous system problems from the preservative. Talk to your provider if you have concerns.

Low blood cell counts

Methotrexate can cause low blood cell counts, particularly in people taking the medication at doses for cancer treatment. When your red blood cells are low, you might feel more tired. And when your platelets are low, you’re at risk for bleeding. In addition, low white blood cells put you at risk for serious and life-threatening infections.

Your provider will check your blood cell counts before you start methotrexate and every so often during treatment. Your provider will pay close attention to your white blood cell counts. If your counts are too low, your provider might make adjustments to your treatment to give your body time to make new blood cells.

It’s important to lower your risk of getting sick by washing your hands often and avoiding crowds. Check your temperature regularly, and call your provider right away if your temperature is 100.4 degrees Fahrenheit or higher.

Serious infections

People who take Methotrexate have a higher risk of getting sick, particularly from opportunistic infections (infections that usually only happen when the immune system is weak). Sometimes, providers prescribe additional medications, such as antibiotics and antiviral medications, to prevent infections. This typically depends on what condition you’re taking methotrexate for and what other medications you’re taking. Contact your provider right away if you feel sick, such as having a fever, muscle aches, severe tiredness, cough, or trouble breathing.

Kidney damage

• Risk factors: High-dose methotrexate

Methotrexate can cause kidney damage, sometimes leading to problems like permanent kidney failure. People who already have kidney problems or who are taking high-dose methotrexate are at higher risk for kidney damage. Your provider will monitor your kidney health closely during treatment. Your provider will also follow certain recommendations (such as extra intravenous hydration) to protect your kidneys if you take high-dose methotrexate.

Liver damage

• Risk factors: Heavy alcohol use | Liver problems

Though uncommon, some people taking methotrexate have developed liver problems, including cirrhosis or liver failure. Talk to your provider about the benefits and risks of taking this medication if you have liver problems.

Your provider will check your liver health with lab tests. High liver enzyme levels on your test results can suggest liver damage. Also tell your provider if you have symptoms of liver damage, like nausea, stomach pain, or yellowing of the skin or whites of the eyes. You might need to pause methotrexate while your provider examines your liver health.

Serious nervous system problems

• Risk factors: High-dose methotrexate | Intrathecal injections of methotrexate | Previous radiation to the brain

Some people taking methotrexate have had serious nervous system problems including headache, confusion, seizures, difficulty moving one side of the body, vision changes, and coma. The risks of nervous system problems appear highest in people taking high-dose methotrexate or getting intrathecal injections of methotrexate.

Sometimes, these symptoms are temporary and completely go away. Other times, they can be permanent. Your provider will regularly perform exams to check your nervous system while you’re taking methotrexate. But contact your provider right away if you have any symptoms between office visits.

Damage to the digestive tract

• Risk factors: Peptic ulcer disease | Ulcerative colitis

Sometimes, methotrexate causes vomiting, diarrhea, mouth sores, stomach bleeding, or tears in the gut. Your provider might recommend antiemetics such as ondansetron (Zofran) to help with nausea or loperamide (Imodium A-D) to treat diarrhea. Seek medical help right away if you have sudden stomach pain or bloody stool.

Lung problems

Some people who’ve taken methotrexate have had a serious lung problem called interstitial lung disease (ILD). These lung problems can sometimes be permanent or life-threatening. Talk to your provider right away if you have a sudden or worsening cough, trouble breathing, and fever. You might need to pause or stop methotrexate while your provider examines your lungs.

Serious skin problems (including skin burns)

• Risk factors: Previous radiation | Previous sunburn

Methotrexate can cause serious skin problems, including severe and potentially life-threatening skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN). Tell your provider right away if you start having painful blisters, skin wounds, or peeling skin. These are signs of a serious skin reaction that need immediate medical attention.

Methotrexate might also cause skin burns from being out in direct sunlight or from previous radiation. You should avoid sun exposure when possible. If you’re going outdoors, wear sunscreen with an SPF of at least 30 and clothes that protect your skin. Let your provider know if you get a sunburn or have painful skin while you’re taking methotrexate.

Effect on folic acid levels in the body

Folic acid, also called folate, is a B vitamin that helps cells grow and make DNA. To treat cancer, methotrexate works by stopping your body from making folate. This lowers the amount of folate in your body, which causes cancer cells to die. Most people who take methotrexate for cancer shouldn’t take folic acid supplements because they can make methotrexate work less well to treat your cancer.

But when methotrexate is used for autoimmune conditions such as psoriasis, regularly taking folic acid is important for replenishing the important nutrient in your body and preventing certain side effects. Talk to your provider about whether or not you should take folic acid while you’re taking methotrexate.

Risk for new cancers

Some people who took methotrexate have developed new cancers. Some people reported getting cancers affecting their white blood cells (lymphoproliferative disease) even at low doses of methotrexate; the new cancer improved when they stopped the medication in these cases.

Your provider will check for signs of new cancers from your lab tests and your symptoms during treatment. Speak with your provider if you notice any new, unusual symptoms. You might need to pause your treatment while your provider examines you.

Tumor lysis syndrome

• Risk factors: Taking methotrexate to treat cancer

Tumor lysis syndrome (TLS) is a complication of treatment if you’re taking methotrexate for cancer. This happens when cancer cells are destroyed and the cells release what they have inside into the bloodstream. This complication can be dangerous because it can lead to high levels of uric acid and potassium in the blood, which can cause kidney or heart problems.

Your provider might give you extra fluids to prevent TLS. Your provider will also check your electrolyte levels often. If your lab results show signs of TLS, you might need to pause methotrexate while you get treated for this complication.

Changes to your ability to have children (infertility)

Methotrexate might cause infertility, which means you might not be able to have children in the future. People have reported low sperm count and menstrual problems. It’s unclear whether these changes are reversible. Talk to your provider about your options for fertility preservation if you’re considering having children in the future.

Risks with radiation therapy

People who are taking methotrexate with radiation treatment are at higher risk for tissue and bone damage. Talk to your provider if you’re concerned about getting radiation with methotrexate.

Higher risk for side effects if you have extra body fluid

• Risk factors: Fluid buildup in the stomach area or lungs

Methotrexate can build up in pockets of fluid in the body. The medication can stay in your body longer if you’ve been told that you have fluid buildup in your body, such as around your stomach (ascites) or your lungs. This can put you at risk for worse side effects from methotrexate. Your provider will check for any extra fluid in your body and manage or treat it before you start methotrexate.

Risk of serious side effects with dosing errors

Methotrexate is used to treat many different conditions (both cancer and non-cancer conditions). The doses for non-cancer conditions are very different from the doses for cancers. Methotrexate can cause serious side effects, especially when it’s used at higher doses (like for treating cancer).

Some people who are taking methotrexate for non-cancer conditions have taken the wrong dose and had serious, life-threatening side effects. Make sure you have a plan with your provider and you’re very clear on the dose you should be taking.

Depending on your condition, methotrexate is given as an injection into the vein (intravenously, IV); into the fluid around the spinal cord (intrathecally), into the muscle (intramuscularly, IM); or under the skin (subcutaneously, SC).

The dose of methotrexate can vary since it depends on what condition you’re taking the medication for. Sometimes, the dose depends on your body size or body surface area (BSA) in m2 units.

The manufacturer dosages for certain conditions are listed below as examples. But your dose and how often you need injections might be different depending on the specific dosing protocol that your provider uses. Your provider might adjust the dose to best fit your needs.

Cancer

• Acute lymphoblastic leukemia: The typical dose ranges from 10 mg/m2 to 5,000 mg/m2 IV. Lower doses (up to 30 mg/m2 per week) can be given IM. The typical starting tablet dose is 20 mg/m2 by mouth once a week. Methotrexate (Trexall) is taken together with other chemotherapy.
• Meningeal leukemia: The dose depends on age and ranges from 6 mg to 15 mg injected intrathecally. For treatment, methotrexate is given anywhere from every other day to twice weekly. For prevention, the medication is given once weekly.
• Osteosarcoma: The typical dose is 12 grams/m2 IV. It’s given with other chemotherapy.
• Mycosis fungoides: When taken by itself, the typical dose of methotrexate (Trexall) is 25 mg to 75 mg by mouth once a week. When it’s taken with other chemotherapy, the typical dose of methotrexate (Trexall) is 10 mg/m2 by mouth twice a week.
• Non-Hodgkin lymphoma: The typical dose is 2.5 mg by mouth 2 to 4 times per week, taken together with chemotherapy.

Non-cancer conditions

• Rheumatoid arthritis: The typical starting dose is 7.5 mg IM once weekly. For tablet, the typical starting dose is 7.5 mg by mouth once a week.
• Polyarticular juvenile idiopathic arthritis: The typical starting dose is 10 mg/m2 IM or SC once weekly. For tablets, the typical starting dose is 10 mg/m2 by mouth once per week.
• Psoriasis: The typical dose is 10 mg to 25 mg IM or IV once weekly. For tablets, the typical dose is 10 mg to 25 mg by mouth once a week.

Methotrexate may interact with certain medications or supplements. Always let your doctor and pharmacist know about any other medications or supplements (including prescribed and over-the-counter medications, vitamins, and dietary or herbal supplements) that you are currently taking. The list below does not include all possible drug interactions with Methotrexate. Please note that only the generic name of each medication is listed below:

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine, Live
• Zoster Vaccine, Live

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Acetazolamide
• Adenovirus Vaccine
• Amoxicillin
• Amtolmetin Guacil
• Asparaginase
• Aspirin
• Bacillus of Calmette and Guerin Vaccine, Live
• Beet Root
• Bentiromide
• Bromfenac
• Bufexamac
• Capecitabine
• Capmatinib
• Celecoxib
• Chloral Hydrate
• Cholera Vaccine, Live
• Choline Salicylate
• Clonixin
• Dantrolene
• Darolutamide
• Dengue Tetravalent Vaccine, Live
• Dexibuprofen
• Dexketoprofen
• Dexlansoprazole
• Diclofenac
• Dicloxacillin
• Diflunisal
• Dipyrone
• Doxifluridine
• Doxycycline
• Droxicam
• Enasidenib
• Esomeprazole
• Etodolac
• Etofenamate
• Felbinac
• Fenbufen
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Floxacillin
• Flufenamic Acid
• Fluorouracil
• Flurbiprofen
• Foscarnet
• Fosphenytoin
• Hydrochlorothiazide
• Ibuprofen
• Ibuprofen Lysine
• Indomethacin
• Influenza Virus Vaccine, Live
• Ketoprofen
• Ketorolac
• Lasmiditan
• Leflunomide
• Levetiracetam
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Mezlocillin
• Morniflumate
• Nabumetone
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nitrous Oxide
• Omeprazole
• Oxaprozin
• Oxyphenbutazone
• Pantoprazole
• Parecoxib
• Penicillin G
• Penicillin V
• Pexidartinib
• Phenylbutazone
• Phenytoin
• Piketoprofen
• Piperacillin
• Piroxicam
• Pirprofen
• Poliovirus Vaccine, Live
• Pristinamycin
• Probenecid
• Proglumetacin
• Proguanil
• Propionic Acid
• Propyphenazone
• Proquazone
• Pyrimethamine
• Rabeprazole
• Salicylic Acid
• Salsalate
• Sapropterin
• Silver Sulfadiazine
• Simeprevir
• Smallpox Vaccine
• Sodium Salicylate
• Sulfacetamide
• Sulfacytine
• Sulfadiazine
• Sulfamethizole
• Sulfamethoxazole
• Sulfapyridine
• Sulfisoxazole
• Sulindac
• Tamoxifen
• Tegafur
• Tenoxicam
• Teriflunomide
• Tiaprofenic Acid
• Ticarcillin
• Tolfenamic Acid
• Tolmetin
• Triamterene
• Trimethoprim
• Typhoid Vaccine, Live
• Valdecoxib
• Warfarin
• Yellow Fever Vaccine
• Zonisamide

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Cyclosporine
• Eltrombopag
• Etoricoxib
• Mercaptopurine
• Procarbazine
• Rofecoxib
• Theophylline

The following side effects may get better over time as your body gets used to the medication. Let your healthcare provider know immediately if you continue to experience these symptoms or if they worsen over time.

Common Side Effects

• Mouth sores
• Nausea or vomiting
• Diarrhea
• Stomach pain
• Tiredness
• Dizziness
• Chills
• Fever
• Infection
• Higher liver enzyme levels in blood
• Low white blood cells
• Low platelet levels

Serious Side Effects

Contact your healthcare provider immediately if you experience any of the following.

• Serious infections (from having low white blood cell counts): temperature of 100.4 degrees Fahrenheit, with or without other symptoms, such as chills, cough, muscle aches, very fast heartbeat, confusion
• Low platelets: blood in urine or stool, nosebleeds, unexplained bruising or bleeding, bruising or bleeding that doesn’t go away
• Serious lung problems: sudden cough, fever, difficulty breathing
• Serious liver problems: nausea, vomiting, tiredness, stomach pain or swelling, pale-colored stool, dark-colored urine, yellowing of the whites of the eyes or skin
• Serious nervous system problems: headache, confusion, vision changes, difficulty talking, difficulty moving one side of the body, seizure, coma
• Serious skin reactions: painful blisters, skin wounds, peeling skin, fever, sore throat, body aches
• Allergic reaction: rash, difficulty breathing, swelling of the mouth or around the eyes

The following side effects have also been reported

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Black, tarry stools
• Bleeding gums
• Blood in the urine or stools
• Bloody vomit
• Diarrhea
• Increased heartbeat
• Itching, rash, reddening of the skin
• Joint pain
• Nausea
• Pinpoint red spots on the skin
• Sores in the mouth or lips
• Stomach pain
• Swelling of the eyelids, face, lips, hands, feet, or lower legs
• Swelling or inflammation of the mouth
• Trouble breathing
• Unusual bleeding or bruising
• Vomiting
• Yellow eyes or skin

Less common

• Back pain
• Bloody nose
• Blurred vision
• Body and muscle pain
• Burning while urinating
• Confusion
• Continuing ringing, buzzing, or other unexplained noise in the ears
• Cough or hoarseness
• Cracked, dry, scaly skin
• Dark urine
• Dizziness
• Drowsiness
• Ear congestion
• Fever or chills
• Headache
• Loss of appetite
• Loss of hearing
• Loss of voice
• Lower back or side pain
• Painful or difficult urination
• Pale skin
• Runny nose
• Seizures
• Sneezing
• Sore throat
• Stuffy or runny nose
• Unusual tiredness or weakness
• Weight loss
• White or brownish vaginal discharge

Incidence not known

• Anxiety
• Blistering, peeling, or loosening of the skin
• Bloating
• Blurred or change in vision
• Changes in skin color
• Confusion
• Constipation
• Decreased interest in sexual intercourse
• Difficulty in moving
• Dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• Dry mouth
• Dryness or soreness of throat
• Eye pain
• Fruit-like breath odor
• Heartburn
• Inability to have or keep an erection
• Increased hunger or thirst
• Indigestion
• Irritation in the mouth
• Large, flat, blue, or purplish patches in the skin
• Loss in sexual ability, desire, drive, or performance
• Loss of consciousness
• Menstrual problem
• Night blindness
• Pain in the chest or groin
• Pain, redness, swelling, or tenderness in the arm or leg
• Red skin lesions, often with a purple center
• Red, wart-like spots on the skin
• Sudden loss of coordination
• Sudden onset of slurred speech
• Swelling or soreness of the breasts
• Swollen, painful, or tender lymph glands in the neck or armpit
• Tingling or numbness in the hands, feet, or lips

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Hair loss or thinning

Less common

• Blemishes on the skin
• Hard, red, swollen skin irritation
• Pimples