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Methotrexate Side Effects

In Summary

Commonly reported side effects of methotrexate include: increased liver enzymes. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to methotrexate: oral tablet

In addition to its needed effects, some unwanted effects may be caused by methotrexate. In the event that any of these side effects do occur, they may require medical attention.

Major Side Effects

You should check with your doctor immediately if any of these side effects occur when 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
  • blurred vision
  • confusion
  • convulsions (seizures)
  • 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
  • shortness of breath
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • yellow eyes or skin

Minor Side Effects

Some of the side effects that can occur with methotrexate may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

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, oral solution, oral tablet, subcutaneous solution

Cardiovascular

Uncommon (0.1% to 1%): Vasculitis
Rare (less than 0.1%): Pericarditis, pericardial effusion, pericardial tamponade, hypotension, thromboembolic events (e.g., arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism), myocardial ischemia
Frequency not reported: Cerebral edema[Ref]

Dermatologic

Common (1% to 10%): Exanthema, erythema, itching
Uncommon (0.1% to 1%): Urticaria, photosensitivity, depigmentation or hyperpigmentation of the skin, alopecia, increase of rheumatic nodules, painful lesions of psoriatic plaque, herpetiform eruption of the skin, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)
Rare (0.01% to 0.1%): Increased pigmentary changes of nails, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions
Very rare (less than 0.01%): Furunculosis, telangiectasia
Frequency not reported: Exfoliative dermatitis, skin necrosis, skin ulceration, folliculitis, hidradenitis, allergic vasculitis[Ref]

Endocrine

Uncommon (0.1% to 1%): Inflammation and ulceration of the vagina
Very rare (less than 0.01%): Loss of libido (males and females), impotence, impaired menstruation, vaginal discharge, infertility, abortion, fetal death, fetal defects, gynecomastia, defective oogenesis or spermatogenesis, transient oligospermia, vaginal bleeding[Ref]

Gastrointestinal

Very common (10% or more): Anorexia, nausea, vomiting, abdominal pain, inflammation, ulcerations of the mucous membrane of mouth and throat (especially during the first 24 to 48 hours after administration), stomatitis, dyspepsia, dehydration
Common (1% to 10%): Diarrhea (especially during the first 24 to 48 hours after administration)
Uncommon (0.1% to 1%): GI bleeding and ulcers, pancreatitis
Rare (0.01% to 0.1%): Gingivitis, enteritis, melena, malabsorption
Very rare (less than 0.01%): Hematemesis, toxic megacolon
Frequency not reported: Glossitis[Ref]

General

Generally, the incidence and severity of acute side effects are related to dose and frequency of administration. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue fatigue, chills and fever, dizziness, and decreased resistance to infection.[Ref]

Genitourinary

Uncommon (0.1% to 1%): Dysuria
Rare (0.01% to 0.1%): Oliguria, anuria, azotemia
Very rare (less than 0.01%): Proteinuria
Frequency not reported: Cystitis, hematuria[Ref]

Hematologic

Common (1% to 10%): Leukocytopenia, thrombocytopenia, anemia
Uncommon (0.1% to 1%): Pancytopenia, agranulocytosis, hematopoietic disorders
Rare (0.01% to 0.1%): Megaloblastic anemia
Very rare (less than 0.01%): Severe bone marrow depression, aplastic anemia, lymphadenopathy, lymphoproliferative disorders (partly reversible), eosinophilia, neutropenia
Frequency not reported: Hemorrhage, hematoma, myelosuppression[Ref]

Hepatic

Very common (10% or more): Increase in liver related enzymes (ALAT, ASAT, alkaline phosphatase, bilirubin, and LDH levels) is commonly reported but usually resolves within one month after cessation of therapy
Uncommon (0.1% to 1%): Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes), drop of serum albumin
Rare (0.01% to 0.1%): Acute hepatitis, hepatotoxicity
Very rare (less than 0.01%): Reactivation of chronic hepatitis, acute liver degeneration, liver insufficiency, liver failure, liver atrophy, necrosis[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Allergic vasculitis, severe allergic reactions progressing to anaphylactic shock[Ref]

Immunologic

Common (1% to 10%): Disseminated herpes zoster, pneumocystis carinii pneumonia
Very rare (less than 0.01%): Immunosuppression, hypogammaglobulinemia, sepsis, opportunistic infections (may be fatal in some cases), infections caused by the cytomegalic virus, acute paronychia
Frequency not reported: Nocardiosis, cryptococcus mycosis, disseminated herpes simplex, listeria meningitis, mycobacterium avium, intracellular pneumonia, systemic fungal infections (e.g., cryptococcosis, nocardiosis, aspergillosis, histoplasmosis), sepsis, decreased resistance to infection, pneumocystis jiroveci, pneumonia (most common infection), respiratory tract infection, cutaneous bacterial infections, pneumonia, reactivation of hepatitis B infection, worsening of hepatitis C infection[Ref]

Musculoskeletal

Uncommon (0.1% to 1%): Osteoporosis, arthralgia, myalgia
Rare (0.01% to 0.1%): Stress fracture, nodulosis
Very rare (less than 0.01%): Pain, muscular asthenia or paresthesia of the extremities
Frequency not reported: Osteoporosis, osteonecrosis (aseptic necrosis of the femoral head), soft tissue necrosis, abnormal tissue cell changes, arthralgia/myalgia, back pain[Ref]

Nervous system

Common (1% to 10%): Headache, fatigue, drowsiness
Uncommon (0.1% to 1%): Vertigo, confusion, seizures, convulsion, encephalopathy
Very rare (less than 0.01%): Paresis, effect on speech including dysarthria and aphasia, myelopathy, changes in sense of taste (metallic taste), meningism, acute aseptic meningitis[Ref]

Ocular

Rare (0.01% to 0.1%): Severely impaired vision, visual disturbances, blurred vision
Very rare (less than 0.01%): Conjunctivitis, retinopathy, transient blindness/loss of vision, periorbital edema, blepharitis, epiphora, photophobia, eye discomfort[Ref]

Oncologic

Frequency not reported: Lymphomas and leukemias have been associated with this drug[Ref]

Other

Very rare (less than 0.01%): Fever, impaired wound healing
Frequency not reported: Fetal death, fetal damage, abortion, tinnitus, chills, malaise, fatigue[Ref]

Renal

Uncommon (0.1% to 1%): Inflammation and ulceration of the urinary bladder (possibly with hematuria)
Rare (0.01% to 0.1%): Renal failure, elevated serum creatinine and urea level
Frequency not reported: Renal insufficiency (usually with high doses), severe nephropathy[Ref]

Respiratory

Common (1% to 10%): Pulmonary complications due to interstitial alveolitis pneumonitis (e.g., general illness, dry/nonproductive cough, shortness of breath progressing to rest dyspnea, chest pain, fever)
Uncommon (0.1% to 1%): Pulmonary fibrosis
Rare (0.01% to 0.1%): Pharyngitis, apnea, bronchial asthma
Very rare (less than 0.01%): Pneumocystis carinii pneumonia, chronic obstructive pulmonary disease, pleural effusion
Frequency not reported: Acute pulmonary edema, pleurisy, hypoxia, respiratory failure[Ref]

Metabolic

Rare (0.01% to 0.1%): Diabetes mellitus, hyperuricemia
Frequency not reported: Metabolic disorder, tumor lysis syndrome[Ref]

Psychiatric

Rare (0.01% to 0.1%): Mood alterations
Very rare (less than 0.01%): Insomnia, cognitive dysfunction
Frequency not reported: Psychosis, depression, confusion, irritability[Ref]

References

1. "Product Information. Methotrexate Sodium (methotrexate)." Teva Pharmaceuticals (formerly IVAX), Miami, FL.

2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

3. Cerner Multum, Inc. "Australian Product Information." O 0

Not all side effects for methotrexate may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

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