Methotrexate Side Effects

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

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