Methotrexate: A Comprehensive Guide for Patients

Methotrexate is a powerful medication used to treat a variety of conditions, including rheumatoid arthritis (RA), other inflammatory conditions, certain types of cancer, and severe psoriasis. It's crucial for patients to have a thorough understanding of this drug to ensure its safe and effective use. This guide provides detailed information about methotrexate, covering its uses, how to take it, potential side effects, and important precautions.

What is Methotrexate and What is it Used For?

Methotrexate (MTX) is classified as an antimetabolite and a folic acid antagonist. It works differently depending on the condition it's treating.

Rheumatoid Arthritis (RA) and other inflammatory conditions: Methotrexate acts as an immunosuppressant, reducing inflammation and alleviating symptoms.
Cancer: Methotrexate slows down the growth of cancer cells. It is one of the primary chemotherapeutic choices for various types of cancer. It is used in combination with other chemotherapy medications to treat acute lymphoblastic leukemia (ALL; also called acute lymphoblastic leukemia and acute lymphatic leukemia; a type of cancer that begins in the white blood cells) and non-Hodgkin's lymphoma (NHL; a type of cancer that begins in a type of white blood cells that normally fights infection) that has returned or did not respond to other medications. Methotrexate is also used alone or in combination with other chemotherapy medications to treat mycosis fungoides, a type of cutaneous T-cell lymphoma ([CTCL], a group of cancers of the immune system that first appear as skin rashes).
Psoriasis: Methotrexate slows down the growth of skin cells, preventing the formation of scales. Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body).
Other conditions: Methotrexate is also sometimes used to treat Crohn's disease (condition in which the immune system attacks the lining of the digestive tract, causing pain, diarrhea, weight loss and fever), multiple sclerosis (MS; condition in which the immune system attacks the nerves, causing weakness, numbness, loss of muscle coordination, and problems with vision, speech, and bladder control), and other autoimmune diseases (conditions that develop when the immune system attacks healthy cells in the body by mistake). Methotrexate is also used sometimes to treat gestational trophoblastic tumors (a type of tumor that forms inside a woman's uterus while she is pregnant).

How to Take Methotrexate

Dosage and Administration

Methotrexate is typically taken ONCE A WEEK. It is very important to adhere to this schedule to avoid serious side effects.

Choosing a Day: Select a specific day of the week (e.g., Saturday) and consistently take your methotrexate on that day.
Dosage: The usual dose is 3 to 10 pills, with each pill containing 2.5mg of methotrexate. Always follow your rheumatologist’s or doctor's directions. Do not take more or less medicine than ordered.
With or Without Food: Methotrexate can be taken with or without food.
If you are taking methotrexate liquid, use the bottle adapter and oral syringe (measuring device) provided by the manufacturer to accurately measure and take your dose of methotrexate solution. Do not use a household teaspoon to measure the solution. You should wear disposable gloves to prevent contact with the medication. Follow the manufacturer's instructions about how to use and clean the oral syringe. Ask your doctor or pharmacist if you if you have any questions.

Important Considerations:

Some people who mistakenly took methotrexate once daily instead of once weekly experienced very severe side effects or died.
If you are taking methotrexate to treat psoriasis, rheumatoid arthritis, or polyarticular juvenile idiopathic arthritis, your doctor may start you on a low dose of the medication and gradually increase your dose. Follow these directions carefully.
If you are taking methotrexate to treat rheumatoid arthritis or polyarticular juvenile idiopathic arthritis, it may take 3 to 6 weeks for your symptoms to begin to improve, and 12 weeks or longer for you to feel the full benefit of methotrexate. Continue to take methotrexate even if you feel well. Do not stop taking methotrexate without talking to your doctor.
Your doctor may decrease your dose of methotrexate or permanently or temporarily stop your treatment. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with methotrexate.
If you miss a dose of methotrexate, call your doctor right away. Do not take a double dose to make up for a missed one.

Folic Acid Supplementation

You should also take 1mg of folate (folic acid) each day. Your rheumatologist will prescribe the folic acid.
If you are taking methotrexate to treat psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, acute lymphoblastic leukemia, or mycosis fungoids, your doctor may tell you to take the medication once a week. Pay close attention to your doctor's directions.
Your doctor will probably tell you to take another medication, folic acid (a vitamin), to decrease some of the side effects of this medication. Take this medication exactly as directed.
The coadministration of folic acid or its derivatives may reduce methotrexate's effectiveness in treating neoplastic diseases by competing for active transport across cell membranes. Patients should follow their healthcare provider's guidance regarding folic or folinic acid use to ensure optimal treatment outcomes.

Potential Side Effects

Methotrexate can cause a range of side effects, some of which can be serious. It's important to be aware of these and to contact your doctor promptly if you experience any concerning symptoms.

Common Side Effects:

Mouth Ulcers: Methotrexate can cause mouth ulcers in a few patients, especially at the beginning of treatment. This should go away with time.
Nausea and Vomiting: Some patients may experience nausea and vomiting.
Hair Thinning or Hair Loss: This is another possible side effect of methotrexate.
Mild Liver Irritation: Methotrexate can cause mild liver irritation. Blood work will be done every 4-12 weeks to check your liver function.
Dizziness
Drowsiness
Headache
Swollen, tender gums
Reddened eyes

Serious Side Effects:

Allergic Reactions: This medicine may cause serious allergic reactions, including anaphylaxis, which may be life-threatening and require immediate medical attention. Check with your doctor right away if you have a rash; itching; hives; stomach pain; difficulty breathing; shortness of breath; wheezing; fast heartbeat; swelling of your face, tongue, or throat; or feeling faint while you are using this medicine.
Blood Disorders: Methotrexate can lower the number of white blood cells in your blood, which increases the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:
- If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
- Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
- Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
- Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
- Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
- Avoid contact sports or other situations where bruising or injury could occur.
- Call your doctor immediately if you experience any of the following symptoms: sore throat, chills, fever, or other signs of infection; unusual bruising or bleeding; excessive tiredness; pale skin; or shortness of breath.
Liver Damage: Methotrexate may cause severe or life-threatening liver damage, especially when it is taken for a long period of time. Tell your doctor if you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease. Ask your doctor about the safe use of alcoholic beverages while you are taking methotrexate. Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem. Call your doctor immediately if you experience any of the following symptoms: nausea; extreme tiredness; lack of energy; loss of appetite; weight loss; swelling of your legs, feet or ankles; unusual bleeding or bruising; itching; difficulty thinking clearly; pain in the upper right part of the stomach; yellowing of the skin or eyes; or flu-like symptoms.
Lung Damage: Methotrexate may cause severe or life-threatening lung damage. Tell your doctor if you have or have ever had lung disease. Check with your doctor right away if you have cough, fever, or trouble breathing. These could be symptoms of a serious lung or breathing problems (eg, acute or chronic interstitial pneumonitis). Call your doctor immediately if you experience any of the following symptoms: dry cough, fever, difficulty breathing, or shortness of breath.
Stomach and Bowel Problems: This medicine may cause stomach and bowel problems. Check with your doctor right away if you have stomach pain, black, tarry stools, constipation, diarrhea, loss of appetite, nausea, pain in the back of the throat or chest when swallowing, or vomiting blood or material that looks like coffee grounds. Methotrexate may cause damage to the lining of your mouth, stomach, or intestines. Tell your doctor if you have or have ever had stomach ulcers or ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum). If you experience any of the following symptoms, call your doctor right away: mouth sores; new or worsening diarrhea; vomiting; fever; chills; persistent, severe stomach pain; black, tarry, or bloody stools; or vomit that is bloody or looks like coffee grounds.
Kidney Problems: Methotrexate may cause serious kidney problems, including kidney failure. Your doctor will order laboratory tests before and during your treatment to see if your kidneys are affected by this medication. Tell your doctor if you have or have ever had kidney disease or if you are being treated with dialysis (treatment to clean the blood outside the body when the kidneys are not working well). If you experience any of the following symptoms, call your doctor immediately: decreased or increased urination; swelling of the face, arms, hands, feet, ankles, or lower legs; weight gain; shortness of breath; or unusual tiredness or weakness.
Nerve Problems: This medicine may cause serious nerve problems. Check with your doctor right away if you have seizures, confusion, tingling or numbness in your hands, feet, or lips, trouble seeing, or headache. blurred vision or sudden loss of visionseizuresconfusionweakness or difficulty moving one or both sides of the bodyloss of consciousness
Skin Reactions: Serious skin reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, or erythema multiforme) can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, blue-green to black skin discoloration, cough, cracks in the skin, diarrhea, itching, joint or muscle pain, loss of heat from the body, red irritated eyes, red skin lesions, often with a purple center, sore throat, sores, ulcers, or white spots in the mouth or on the lips, fever or chills, or unusual tiredness or weakness while you are using this medicine. Methotrexate may cause serious or life-threatening skin reactions.
Increased Risk of Cancer: This medicine may increase your risk for other cancers, including blood or skin cancer. The risk for skin cancer may be increased if you take cyclosporine after receiving treatment with methotrexate for psoriasis. Methotrexate may increase the risk that you will develop other cancers, such as lymphoma (cancer that begins in the cells of the immune system) and skin cancer. Talk to your doctor about the risks of receiving this medication.
Tumor Lysis Syndrome: This medicine may cause a serious reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Tell your doctor right away if you have a change in urine amount, joint pain, stiffness, or swelling, lower back, side, or stomach pain, rapid weight gain, swelling of the feet or lower legs, or unusual tiredness or weakness.

Important Note:

This is not an exhaustive list of all possible side effects. It is crucial to discuss any concerns or unusual symptoms with your doctor.

Precautions and Contraindications

Pregnancy and Birth Control

Methotrexate is known to cause birth defects in the children of both men and women taking this drug.

Pregnancy: Using this medicine while you are pregnant can harm your unborn baby. The medicine may also cause birth defects if it is used by the father when his sexual partner becomes pregnant. If you are pregnant, considering having a child, or nursing, discuss this with your rheumatologist before beginning this medication. Methotrexate may cause life-threatening birth defects or death of the unborn baby. Tell your doctor if you or your partner is pregnant or plan to become pregnant.
Birth Control: If you are a woman who can bear children, your doctor may give you a pregnancy test before you start using this medicine to make sure you are not pregnant. Female patients should use an effective form of birth control during treatment and for at least 3 or 6 months after the last dose. Male patients who have female partners should use an effective form of birth control during treatment and for at least 3 months after the last dose. Talk to your doctor about birth control methods that will work for you. You or your partner should not become pregnant while you are taking methotrexate. If you can become pregnant, you will need to take a pregnancy test before you begin taking methotrexate and use birth control to prevent pregnancy during your treatment and for 6 months after your final dose. If your partner can become pregnant, you should use birth control during your treatment and for 3 months after you stop taking methotrexate.
If pregnancy occurs: Tell your doctor right away if pregnancy occurs while you are using this medicine.
Breastfeeding: Breastfeeding is generally contraindicated during maternal high-dose methotrexate therapy due to potential risks to the infant. Mothers should be advised to wait at least 1 week after receiving high-dose methotrexate before breastfeeding. To minimize potential exposure, withholding breastfeeding for 24 hours after a low-dose methotrexate administration may reduce the infant's exposure by approximately 40%.
Infertility: Talk with your doctor before using this medicine if you plan to have children. Some men and women who use this medicine have become infertile (unable to have children). you should know that methotrexate may cause permanent infertility in men and women, stop sperm production in men, and interfere with the normal menstrual cycle (period) in women. Talk to your doctor about the risks of taking this medication.

Alcohol Consumption

While on methotrexate you must limit yourself to 2 alcoholic beverages per week. Limit alcohol use with this medicine. Alcohol may increase the risk for liver problems. Please tell your doctor if you have a history of any alcohol abuse, hepatitis, yellow jaundice, or liver disease.

Drug Interactions

When you are taking methotrexate, it is very important that your doctors know if you are taking any other medicine. This includes prescription and non-prescription medicines as well as birth control pills, vitamins, and herbal supplements. Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Methotrexate can be taken with other medications. You should not take methotrexate while taking antibiotics containing trimethoprim-sulfa (Bactrim®, Sulfatrim®, etc…).
the following nonprescription products may interact with methotrexate: Proton pump inhibitors such as esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec® OTC, in Zegerid® OTC). Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking methotrexate. Do not start any of these medications while taking methotrexate without discussing with your healthcare provider.
Any drug affecting renal clearance may cause an increase in methotrexate levels. Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporin, and cisplatin increase the risk of MTX toxicity in the blood; aminoglycosides, neomycin, probenecid reduces the absorption of MTX.
Coadministration of methotrexate with certain medications can alter its plasma concentrations, increasing the risk of severe adverse reactions and potentially reducing the formation of active metabolites, which may decrease its clinical effectiveness. This includes oral antibiotics like neomycin and penicillin, antifolate drugs such as dapsone and pyrimethamine, NSAIDs, and hepatotoxic or nephrotoxic products. Caution is advised when using nitrous oxide in patients receiving methotrexate, as it may exacerbate methotrexate's effects on folate metabolism, increasing the risk of severe adverse reactions. Alternative therapies should be considered.
For patients with immune-mediated inflammatory diseases, methotrexate may adversely affect humoral and cellular immune responses to COVID-19 mRNA vaccines.

Contraindications

Methotrexate is contraindicated for patients with hypersensitivity reactions to this medication. Pregnant or breastfeeding patients should avoid using methotrexate due to the elevated risk of teratogenicity and excretion into breast milk. In cases of rheumatoid arthritis or psoriasis, it is contraindicated to use methotrexate in patients with chronic liver disease, cirrhosis, alcoholic hepatitis, or active alcohol use disorder.

Methotrexate is contraindicated in patients with a history of severe hypersensitivity reactions, including anaphylaxis.

Caution is necessary for using methotrexate for patients who have preexisting blood disorders, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.

Other Precautions

Infections: Methotrexate can lower your body's resistance to infection.
- While you are being treated with methotrexate, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Methotrexate may lower your body's resistance and the vaccine may not work as well or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live virus vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.
- Tell your doctor if you often get any type of infection or if you think you may have any type of infection now. Also tell your doctor if you have or have ever had hepatitis B (a viral infection that affects the liver), cytomegalovirus (a common virus that usually only causes serious symptoms in people who have weakened immune systems or who are infected at birth), herpes zoster (shingles; a rash that can occur in people who have had chickenpox in the past), tuberculosis, or any other condition that affects your immune system.
- Methotrexate may also cause reactivation of tuberculosis, so tests to eliminate the presence of tuberculosis are required. Also, one should monitor for bone marrow toxicity as myelosuppression can occur due to folate deficiency. A sudden dip in blood counts must alert one to that possibility.
Sun Sensitivity: This medicine may make your skin more sensitive to sunlight. Wear sunscreen, eye protection, and a hat. Do not use sunlamps or tanning beds. plan to avoid unnecessary or prolonged exposure to sunlight or ultraviolet light (tanning beds and sunlamps) and to wear protective clothing, sunglasses, and sunscreen. Methotrexate may make your skin sensitive to sunlight or ultraviolet light. If you have psoriasis, your sores may get worse if you expose your skin to sunlight while you are taking methotrexate.
Surgery: if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking methotrexate.
Medical History:
- tell your doctor and pharmacist if you are allergic to methotrexate, any other medications, or any of the ingredients in methotrexate tablets. Ask your doctor or pharmacist for a list of the ingredients.
- tell your doctor if you have or have ever had any of the conditions mentioned in the IMPORTANT WARNING section, a low level of folate in your blood, radiation therapy to the head or brain, pleural effusions (a condition when fluid collects in the lungs), or ascites (swelling of the stomach caused by liver disease).

Monitoring Your Health While Taking Methotrexate

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Blood and urine tests may be needed to check for unwanted effects.

Patients taking methotrexate should undergo laboratory testing with complete blood count, serum creatinine, and transaminase level monitoring weekly for the first 4 weeks and then at least bimonthly. A complete list of the current medications should be revised to avoid any possible drug interactions before prescribing methotrexate. Liver function tests (serum AST, ALT, and albumin levels) and liver biopsy can also be performed in cases of hepatotoxicity. Creatinine clearance requires monitoring to avoid possible nephrotoxicity; a CrCl of 50 mL/min is necessary before prescribing methotrexate. Monitoring for pulmonary toxicity is also needed as the patients may have a dry cough, fever, or dyspnea. Baseline chest radiographs are recommended to detect interstitial and alveolar infiltrates, hilar adenopathy, pleural effusions, and pulmonary fibrosis.

Key risk factors for methotrexate toxicity include drug interactions and patient-specific factors such as serum albumin and …

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before, during, and after your treatment to check your body's response to methotrexate and to treat side effects before they become severe.

Additional Information

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.
Unless your doctor tells you otherwise, continue your normal diet.
Dispose of any unused oral oral solution 90 days after opening the bottle for the first time.
Dispose of unneeded medications in a way so that pets, children, and other people cannot take them. Do not flush this medication down the toilet. Use a medicine take-back program. Talk to your pharmacist about take-back programs in your community. Always lock safety caps. Place the medication in a safe location - one that is up and away and out of their sight and reach. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
Keep a written list of all of the prescription and nonprescription (over-the-counter) medicines, vitamins, minerals, and dietary supplements you are taking. Bring this list with you each time you visit a doctor or if you are admitted to the hospital.

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