Methotrexate Side Effects

Medically reviewed by Philip Thornton, DipPharm. Last updated on Oct 9, 2023.

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

powder for solution, solution

Warning

Oral route (Solution)

Severe Toxic Reactions, Including Embryo-Fetal ToxicityMethotrexate can cause severe or fatal toxicities. Monitor closely and modify dose or discontinue for the following toxicities: bone marrow suppression, infection, renal, gastrointestinal, hepatic, pulmonary, hypersensitivity and dermatologic.Methotrexate can cause embryo-fetal toxicity and fetal death. Use in polyarticular juvenile idiopathic arthritis is contraindicated in pregnancy. Consider the benefits and risks of methotrexate and risks to the fetus when prescribing methotrexate to a pregnant patient with a neoplastic disease. Advise patients to use effective contraception during and after treatment with methotrexate.

Oral route (Solution)

Jylamvo®Warning: Embryo-Fetal Toxicity, Hypersensitivity Reactions, and Severe Adverse ReactionsMethotrexate can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate oral solution is contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception during and after treatment with methotrexate oral solution.Methotrexate oral solution is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate oral solution as appropriate.

Oral route (Tablet)

Embryo-Fetal Toxicity Hypersensitivity Reactions, and Severe Adverse ReactionsMethotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.Methotrexate tablets are contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis.Serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate.

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 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 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%): 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]