Methotrexate Side Effects

Medically reviewed by Philip Thornton, DipPharm. Last updated on Feb 23, 2024.

Applies to methotrexate: powder for solution, solution.

Other dosage forms:

• oral solution, oral tablet

Important warnings This medicine can cause some serious health issues

Subcutaneous route (solution)

Use only for severe rheumatoid arthritis and psoriasis unresponsive to other therapies.

Monitor for bone marrow, liver, lung, skin, and kidney toxicities.

Death, fetal death and/or congenital anomalies, and severe sometimes fatal lung disease, tumor lysis syndrome, skin reactions, and Pneumocystis jiroveci pneumonia have been reported.

Use not recommended in women of childbearing potential and is contraindicated in pregnant women.

Advise females and males of reproductive potential to use effective contraception during and after treatment.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some NSAIDs.

Hepatotoxicity, fibrosis, and cirrhosis may occur with prolonged use.

Lung disease, including acute or chronic interstitial pneumonitis may occur, and has been reported at low doses.

Diarrhea and ulcerative stomatitis require therapy interruption.

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions; dose reduction is required and discontinuation may be necessary with these conditions.

Increased risk of soft tissue necrosis and osteonecrosis with concomitant radiotherapy.

Malignant lymphoma may occur.

Injection route (powder for solution; solution)

Only use for life-threatening neoplastic disease or severe rheumatoid arthritis and psoriasis unresponsive to other therapies.

Death, fetal death and/or congenital anomalies, lung disease, tumor lysis syndrome, fatal skin reactions, and Pneumocystis carinii pneumonia have been reported.

Monitor for bone marrow, liver, lung, and kidney toxicities.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).

Hepatotoxicity, fibrosis, and cirrhosis occur with prolonged use.

Diarrhea and ulcerative stomatitis require interruption of therapy.

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions.

Increased risk of soft tissue necrosis and osteonecrosis with concomitant radiotherapy.

Malignant lymphoma may occur.

Use extreme caution with high-dose regimen for osteosarcoma.

Do not use formulations/diluents with preservatives for intrathecal or high-dose therapy.

Serious side effects of methotrexate

Along with its needed effects, methotrexate 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 or nurse immediately if any of the following side effects occur while taking methotrexate:

More common

• black, tarry stools
• blood in the urine or stools
• bloody vomit
• diarrhea
• joint pain
• reddening of the skin
• sores in the mouth or lips
• stomach pain
• swelling of the feet or lower legs

Less common

• back pain
• bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, or warmth at the injection site
• blurred vision
• confusion
• cough or hoarseness
• dark urine
• dizziness
• drowsiness
• fever or chills
• headache
• lower back or side pain
• painful or difficult urination
• pinpoint red spots on the skin
• seizures
• trouble breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

Other side effects of methotrexate

Some side effects of methotrexate 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, temporary
• loss of appetite
• nausea or vomiting

Less common

• acne
• boils on skin
• pale skin
• skin rash or itching

For healthcare professionals

Applies to methotrexate: compounding powder, injectable powder for injection, injectable solution, intramuscular solution, oral liquid, oral solution, oral tablet, subcutaneous solution.

General

Frequently observed adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. In addition, infections, malaise, fatigue, chills, fever, and dizziness are commonly reported adverse reactions.^[Ref]

Cardiovascular

• Rare (0.01% to 0.1%): Pericardial effusion, pericarditis, pericardial tamponade
• Postmarketing reports: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death^[Ref]

Dermatologic

• Common (1% to 10%): Rash, pruritus, dermatitis, alopecia, photosensitivity, burning of skin lesions
• Uncommon (0.1% to 1%): Allergic vasculitis, herpetiform eruptions of the skin, Stevens-Johnson´s syndrome, toxic epidermal necrolysis, increase in rheumatoid nodules, increased skin pigmentation, impaired wound healing
• Rare (0.01% to 0.1%): Increased nail pigment changes, photo-hypersensitivity, acne petechiae, depigmentation, urticaria, erythema multiforme, painful damage to psoriatic lesion, skin ulceration, onycholysis
• Very rare (less than 0.01%): Acute paronychia, telangiectasia, furunculosis, ecchymoses, hidradenitis
• Frequency not reported: Skin exfoliation / dermatitis exfoliative
• Postmarketing reports: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis^[Ref]

Endocrine

• Postmarketing reports: Diabetes^[Ref]

Gastrointestinal

• Very common (10% or more): Nausea/vomiting (10%), dyspepsia, abdominal pain
• Common (1% to 10%): Diarrhea, stomatitis, oral ulcers
• Uncommon (0.1% to 1%): Gastrointestinal ulcerations and bleeding
• Rare (0.01% to 0.1%): Pancreatitis, gingivitis, enteritis, melena
• Very rare (less than 0.01%): Toxic megacolon, hematemesis
• Frequency not reported: Anorexia
• Postmarketing reports: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration^[Ref]

Genitourinary

• Uncommon (0.1% to 1%): Vaginal inflammation and ulceration
• Rare (0.01% to 0.1%): Impotence, menstrual disorders
• Very rare (less than 0.01%): Loss of libido, formation of defective oocytes or sperm cells, transient oligospermia, infertility, vaginal discharge, vaginal bleeding, gynecomastia
• Frequency not reported: Vaginal discharge
• Postmarketing reports: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction^[Ref]

Hematologic

• Common (1% to 10%): Thrombocytopenia (platelet count less than 100,000/mm3), leukopenia (white blood cell count less than 3000/mm3), pancytopenia, anemia
• Uncommon (0.1% to 1%): Bone marrow depression, agranulocytosis, hematopoietic disorders
• Rare (0.01% to 0.1%): Megaloblastic anemia, hypotension
• Very rare (less than 0.01%): Hypogammaglobulinemia, aplastic anemia, lympho-proliferative disorder, neutropenia, lymphadenopathy, vasculitis
• Frequency not reported: Decreased hematocrit, eosinophilia
• Postmarketing reports: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia^[Ref]

Hepatic

• Very common (10% or more): Elevated liver function tests (15%)
• Uncommon (0.1% to 1%): Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin
• Rare (0.01% to 0.1%): Hepatotoxicity, acute hepatitis
• Very rare (less than 0.01%): Reactivation of chronic hepatitis, hepatic failure
• Postmarketing reports: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis, liver failure^[Ref]

Immunologic

• Uncommon (0.1% to 1%): Anaphylactic-type reaction, allergic reactions, anaphylactic shock
• Very rare (less than 0.01%): Immuno-suppression
• Postmarketing reports: Anaphylaxis, anaphylactoid reactions, vasculitis^[Ref]

Metabolic

• Uncommon (0.1% to 1%): Diabetes mellitus
• Postmarketing reports: Hyperglycemia^[Ref]

Musculoskeletal

• Rare (0.01% to 0.1%): Osteoporosis, arthralgia, myalgia
• Very rare (less than 0.01%): Stress fracture
• Frequency not reported: Osteonecrosis of jaw (secondary to lymphoproliferative disorders)
• Postmarketing reports: Stress fracture, soft tissue necrosis, arthralgia, myalgia, osteoporosis^[Ref]

Nervous system

• Common (1% to 10%): Dizziness, headache, fatigue, drowsiness
• Uncommon (0.1% to 1%): Convulsions, vertigo
• Rare (0.01% to 0.1%): Hemiparesis, paresis
• Very rare (less than 0.01%): Cerebral edema, acute aseptic meningitis with meningism (paralysis, vomiting), irritation, dysarthria, aphasia, lethargy, transient subtle cognitive dysfunction, dysarthria, unusual cranial sensations, pain, muscular asthenia, paresthesia/ hypoesthesia, changes in sense of taste (metallic taste)
• Frequency not reported: Encephalopathy/leukoencephalopathy
• Postmarketing reports: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, leukoencephalopathy, convulsions, spinal radiculopathy (with intrathecal use)^[Ref]

Ocular

• Rare (0.01% to 0.1%): Severe visual disturbances
• Very rare (less than 0.01%): Conjunctivitis, impaired vision, retinopathy
• Frequency not reported: Eye discomfort
• Postmarketing reports: Optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia^[Ref]

Oncologic

• Uncommon (0.1% to 1%): Lymphoma^[Ref]

Other

• Uncommon (0.1% to 1%): Chills
• Frequency not reported: Fever, infection, sweating, tinnitus^[Ref]

Psychiatric

• Uncommon (0.1% to 1%): Depression, confusion
• Rare (0.01% to 0.1%): Mood swings
• Very rare (less than 0.01%): Insomnia^[Ref]

Renal

• Uncommon (0.1% to 1%): Disturbed micturition, inflammation and ulceration of the urinary bladder (possibly with hematuria), renal insufficiency, nephropathy
• Rare (0.01% to 0.1%): Oliguria, anuria, electrolyte disturbances
• Very rare (less than 0.01%): Dysuria, azotemia, cystitis, hematuria, proteinuria
• Postmarketing reports: Azotemia, hematuria, proteinuria, cystitis^[Ref]

Respiratory

• Common (1% to 10%): Interstitial pneumonitis
• Uncommon (0.1% to 1%): Nosebleed, interstitial fibrosis
• Rare (0.01% to 0.1%): Respiratory paralysis, dyspnea, pharyngitis, bronchial asthma
• Very rare (less than 0.01%): Chronic interstitial obstructive lung disease, pleuritis, dry cough, pleural effusion
• Frequency not reported: Upper respiratory infection, chest pain, coughing, epistaxis, alveolitis, pulmonary alveolar hemorrhage
• Postmarketing reports: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis^[Ref]

Frequently asked questions

• Why should I take folic acid with methotrexate?
• Does it cause weight gain?
• How long does it take to work?
• How do I know if methotrexate is working for rheumatoid arthritis?
• What are the different brands of methotrexate?
• How long does methotrexate stay in your system?
• What causes Plaque Psoriasis?
• How does methotrexate work for ectopic pregnancy?

Further information

Methotrexate side effects can vary depending on the individual. Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Medical Disclaimer