Methotrexate Side Effects: Common, Severe, Long Term (2024)

Medically reviewed by Philip Thornton, DipPharm. Last updated on Sep 2, 2023.

Applies to methotrexate: oral solution, oral tablet. Other dosage forms:

• powder for solution, solution

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 immediately if any of the following side effects occur while taking methotrexate:

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 vagin*l 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 the 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

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 or thinning

Less common

• Blemishes on the skin
• hard, red, swollen skin irritation
• pimples

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%): vagin*l 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, vagin*l discharge, vagin*l bleeding, gynecomastia

Frequency not reported: vagin*l 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 do I know if methotrexate is working for rheumatoid arthritis?
• How long does it take to work?
• 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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circ*mstances.

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

Medical Disclaimer