Methotrexate Side Effects

Brand Names: Methotrexate Sodium, Preservative Free, Trexall

Please note - some side effects for Methotrexate may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Methotrexate - for the Consumer

Methotrexate

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Methotrexate:

Acne; chills and fever; dizziness; flushing; general body discomfort; hair loss; headache; infertility; irregular periods; itching; loss of appetite; lowered resistance to infection; miscarriage; nausea; sensitivity to sunlight; sore throat; speech impairment; stomach pain; swelling of the breast; unusual tiredness; vaginal discharge; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black or bloody stools; blood in the urine; bone pain; calf pain/swelling; change in amount of urine; chest pain; confusion; dark urine; diarrhea; dry cough; enlarged glands; fatigue; fever or chills; inflammation of the pancreas (stomach tenderness, nausea, vomiting, fever, increased pulse rate); irregular heartbeat; mental changes; mouth sores; muscle weakness; persistent sore throat; red, swollen, or blistered skin; seizures; serious infection (herpes, hepatitis, blood infection); trouble breathing; unusual bleeding or bruising; unusual pain and discoloration of the skin; vision changes; vomit that looks like coffee grounds; yellowing of skin or eyes.

Methotrexate Tablets

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Methotrexate Tablets:

Dizziness; headache; loss of appetite; mild hair loss; nausea; stomach pain or upset; tiredness; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; calf or leg pain or swelling; change in the amount of urine; chest pain; coma; confusion; coughing up blood; dark urine; diarrhea; difficult or painful urination; dry cough; fever, chills, or sore throat; menstrual changes; mental or mood changes; mouth sores; one-sided weakness; red, swollen, peeling, or blistered skin; seizures; severe or persistent nausea or vomiting; shortness of breath; speech changes; unusual bleeding or bruising; unusual pain and discoloration of the skin; unusual tiredness or weakness; vision changes or vision loss; yellowing of skin or eyes.

Methotrexate Side Effects - for the Professional

Methotrexate

IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH Methotrexate.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Other adverse reactions that have been reported with Methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to Methotrexate difficult.

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely.

Cardiovascular: Pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).

Central Nervous System: Headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of Methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations.

Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving Methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex.

Musculoskeletal System: Stress fracture.

Ophthalmic: Conjunctivitis, serious visual changes of unknown etiology.

Pulmonary System: Respiratory fibrosis, respiratory failure, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.

Skin: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.

Urogenital System: Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.

Other rarer reactions related to or attributed to the use of Methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies

The approximate incidences of Methotrexate attributed (i.e., placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n = 128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse Methotrexate are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies.

Incidence Greater Than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 100,000/mm3).

Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm3), pancytopenia, dizziness.

Two other controlled trials of patients (n = 680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.

Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.

Adverse Reactions in Psoriasis

There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n = 204, 248) of psoriasis patients treated with Methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear.

Adverse Reactions in JRA Studies

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of Methotrexate (5 to 20 mg/m2/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited to provide reliable estimates of adverse reaction rates.

Side Effects by Body System

Hematologic

Hematologic side effects have included myelosuppression which is one of the primary toxic effects of methotrexate. Methotrexate suppressed hematopoiesis has been reported to have caused anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, and lymphoproliferative disorders including reversible hypogammaglobulinemia (which has been reported rarely).

Preexisting myelosuppression or low hematologic cell counts are contraindications to the use of this drug, particularly in patients with rheumatoid arthritis or psoriasis. Close monitoring of the CBC is mandatory. Profound count nadirs may require therapy discontinuation, at least temporarily. Folate therapy and/or leucovorin rescue may be preventive or palliative. Treated patients who become febrile should be assumed to have neutropenia until proven otherwise.

Cytopenia occurs in 5% to 25% of patients with rheumatoid arthritis (RA) who receive long-term therapy. Risk factors include renal dysfunction, preexisting folate deficiency, increased mean corpuscular volume value, advanced age, concomitant use of other anti-folate medications (such as trimethoprim-sulfamethoxazole), and possibly hypoalbuminemia, concomitant infection, history of bone marrow injury, surgery, and concurrent use of NSAIDs or probenecid. Pancytopenia is rarely observed in patients with rheumatoid arthritis. Bone marrow recovery typically occurs within two weeks after the withdrawal of MTX.

Gastrointestinal

Gastrointestinal side effects are usually controlled by folate supplementation (1 to 5 mg orally, given 4 hours before MTX or 1 mg orally once a day if on low dose therapy, as in rheumatoid arthritis), dosage reduction, dividing the dose over a 12 to 24 hour period, withholding the drug, or giving it parenterally.

Extremely rare cases of colitis and toxic megacolon have been associated with the use of MTX.

Gastrointestinal side effects, especially with high-dose administration, may be expected. Serious nausea, vomiting, diarrhea, or stomatitis (10% to 80% of patients followed in long-term studies) may result in symptomatic dehydration. Other frequently reported GI side effects, particularly after high-dose therapy, include gingivitis, pharyngitis, stomatitis, anorexia, hematemesis, melena, gastrointestinal ulceration and bleeding, and enteritis. GI symptoms are often eliminated by folate supplementation. Folate does not affect efficacy of MTX.

Hepatic

Hepatic side effects including hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, and liver enzyme elevations have been reported.

Methotrexate can cause acute elevations of liver function tests (elevated serum transaminases in 15% of patients with rheumatoid arthritis (RA) on low-dose therapy) or chronic hepatotoxicity (fibrosis and cirrhosis). The incidence of liver fibrosis and cirrhosis in patients with RA (low doses) averages 3% to 7% and 0.1%, respectively. Meta-analysis has revealed the incidence of progression of liver disease (worsening of 1 grade on the histologic classification of Roenigk) in patients with RA or psoriatic arthritis averages 27%, or 7% per gram of MTX (total dose) given. Chronic hepatotoxicity typically develops only after chronic use of higher doses (2 years or more of total doses of 1.5 grams or more), is more likely in patients who ingest ethanol, who are aged, who are obese, who have chronic renal insufficiency, or who have diabetes.

In general, the following serve as guidelines for patients with non-oncologic conditions:

1) Screen all patients to be treated with complete liver blood tests (transaminases, albumin, alkaline phosphatase, bilirubin), hepatitis B and C serologic studies (some experts recommend viral serology's only in patients with abnormal liver function tests), baseline serum creatinine and complete blood count (CBC);
2) Baseline liver biopsy if the patient has preexisting liver disease, persistently abnormal baseline AST (aspartate aminotransferase), history of excessive alcohol consumption (greater than 3 drinks/day), or chronic hepatitis B or C infection;
3) Monitor hepatic enzymes every 4 to 8 weeks (with the understanding that they are not necessarily predictive of fibrosis/cirrhosis), discontinuing MTX if serum transaminase levels meet or exceed 2 to 3x baseline (some guidelines recommend withholding MTX for 1 to 2 weeks if significant abnormalities persist);
4) Liver biopsy should be considered if significant hepatic enzyme abnormalities persist for 2 to 3 months. Liver biopsy should be performed if 6 of 12 monthly AST levels are above the upper limit of normal or serum albumin levels are less than normal in the setting of well controlled disease;
5) If liver biopsy shows Roenigk grade I, II, or IIIA (mild fibrosis), MTX may be resumed with monitoring as described above; if liver biopsy show Roenigk grade IIIB (moderate fibrosis) or IV (cirrhosis), MTX should be discontinued;
6) MTX should be discontinued in patients with significant liver abnormalities, as described above, who refuse liver biopsy;
7) It is still debated whether post-therapy biopsy should be performed every 2 to 3 years or after each 1.5 to 2.0 grams cumulative dose given, regardless of liver chemistries.

*Pre-biopsy coagulation studies and withholding of aspirin and other NSAIDs are recommended.

Immunologic

New and/or opportunistic infection can arise during or after therapy with methotrexate due to drug-induced immune suppression. Infections during MTX therapy may occur in up to 58% of patients during low-dose therapy (as in RA). Patients are at great risk after high-dose therapy.

MTX should be held prior to and during elective surgery to minimize the risk of infectious complications.

Limited data have shown that the use of low-dose MTX for patients with rheumatoid arthritis is associated with decreased CD8 and naive CD4 T lymphocytes after only 8 weeks of therapy.

Methotrexate is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.

Immunologic side effects including case reports of sometimes fatal opportunistic infections have been reported. Pneumocystis carinii pneumonia has been reported most frequently. Also of concern are infections associated with severe immunosuppression, such as disseminated herpes zoster, Listeria meningitis, Mycobacterium avium intracellulare pneumonia, and systemic fungal infections (cryptococcosis, nocardiosis, aspergillosis, and histoplasmosis).

Nervous system

Nervous system side effects include headaches, dizziness, drowsiness, blurred vision, subtle cognitive dysfunction, moodiness, tinnitus or unusual cranial sensations. After intrathecal administration, headache, back pain, fever, and even transient paraplegias have been reported. A case of acute chorea and a case of a woman who couldn't speak after receiving methotrexate by intrathecal administration have also been reported. Serious neurotoxicity has been associated with the use of high-dose MTX after intrathecal or intraventricular administration to patients who have undergone craniospinal irradiation, but has also been described in other patients who have received low-dose oral therapy.

The development of serious neurotoxicity is more likely if MTX is given in high doses to patients who have undergone craniospinal irradiation.

Significant neurotoxicity can present as an acute stroke-like encephalopathy or a chronic leukoencephalopathy. Unique features of the former include its acute onset (seizures, confusion, hemiparesis, speech problems, loss of consciousness) and reversibility within days.

The use of high-dose IV MTX has been associated with the development of chronic delayed leukoencephalopathy in patients with or without a history of craniospinal irradiation. A syndrome of subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis, and stupor may begin several months after the initiation of therapy. Affected patients often improve after discontinuation of therapy.

Intrathecal or intraventricular administration of MTX has been associated with the acute onset of headache, nausea, vomiting, fever, back pain, dizziness, and meningismus. Acute symptoms usually resolve within one to two days. In some cases, subacute neurotoxicity, with myelopathy or encephalopathy, may occur within days to weeks. Subacute neurotoxicity is usually characterized by paresis/plegia, dementia, confusion, tremor, ataxia, irritability, and somnolence.
Delayed leukoencephalopathy, as described above, has also been associated with the use of intrathecal MTX. The condition can improve but can be progressive and fatal.

Progressive dementia and leukoencephalopathy has been reported in at least one case after low-dose, oral administration of MTX for the treatment of rheumatoid arthritis.

Respiratory

Two patterns of pulmonary toxicity have been reported: a hypersensitivity reaction and a toxic reaction with diffuse alveolar damage and nonspecific lung injury. Risk factors are unknown, but may include male gender, cigarette smoking, and concomitant use of an NSAID.

The hypersensitivity reaction is characterized by interstitial pneumonitis, granuloma formation, and the development of bronchopneumonia. Some patients have asthmatic symptoms.

Interstitial pneumonitis may be associated with duration of treatment or weekly or cumulative dose. The prevalence of this complication ranges from 2.5% to 7.5% in patients with psoriatic or rheumatoid arthritis. One prospective study has shown that the cumulative dose of MTX is independently related to small, but significant, increases in residual volume and that MTX may cause mild degrees of air trapping after long-term therapy.

The differential diagnosis of MTX pneumonitis includes infectious pneumonia, hypersensitivity pneumonitis caused by other drugs and autoimmune alveolitis due to rheumatoid arthritis (RA). Pneumocystis carinii pneumonia (PCP) can resemble MTX pneumonitis, and bronchoalveolar lavage (BAL) is a useful tool to distinguish between the two. BAL is not necessarily helpful in distinguishing MTX pneumonitis from RA alveolitis, however, since an elevated lymphocyte count and an increased CD4/CD8 ratio are observed in both conditions.

Pulmonary function tests in affected patients reflect a restrictive ventilatory defect and decreased oxygen diffusing capacities. A mild peripheral eosinophilia is often present.

Respiratory side effects including toxicity can occur at any dosage in 3% to 11% of patients, and can mimic infectious pneumonia. Interstitial pneumonitis has emerged as one of the most unpredictable and potentially life-threatening side effects from low-dose MTX therapy. It presents as fever, dry/nonproductive cough, dyspnea, hypoxemia, and/or epistaxis, usually with chest X-ray infiltration. Signs or symptoms of infection must be treated seriously due to the possibility of MTX-induced neutropenia.

Renal

Renal side effects include renal insufficiency which is most commonly associated with high-dose MTX since, after these doses, the concentration of a major circulating metabolite, 7-OH MTX, can precipitate in the renal tubule. Concomitant use of other potentially nephrotoxic drugs, including NSAIDs, and preexisting renal insufficiency are risk factors. There is a higher risk of nephrotoxicity in patients with underlying renal dysfunction. Aggressive and adequate hydration and urinary alkalinization helps minimize the risk of MTX-induced nephropathy, cystitis, and hematuria. If monitoring reveals renal dysfunction, decreasing MTX doses or discontinuing the drug altogether may improve renal function.

General

General side effects which have been reported frequently include malaise, fatigue, and chills. Less commonly reported effects include arthralgias and myalgias. Leucovorin is typically given to diminish toxicity and counteract the adverse effects of high-dose therapy.

There is an increased risk of methotrexate (MTX) toxicity in patients who have "third space" accumulations of fluid, such as pleural effusions. MTX accumulates in these spaces and becomes cleared from these spaces slowly. These "deep pools" of MTX markedly increase the risk of toxicity, particularly gastrointestinal toxicity (mucositis) and should be evacuated before therapy begins.

Genitourinary

Genitourinary side effects may seriously affect either sex. Women may experience menstrual dysfunction, vaginal discharge, abortion, or infertility. Decreased libido has been described in each sex. Defective oogenesis and spermatogenesis is usually transient.

Dermatologic

Cases of severe, sometimes fatal, dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions have been observed after single or multiple, low, intermediate or high doses of methotrexate for the treatment of neoplastic and non-neoplastic diseases.

Alopecia typically resolves several months after discontinuation.

Dermatologic side effects include erythematous rashes, desquamation, epidermal necrosis, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, cutaneous vasculitis, furunculosis, and alopecia. Painful plaque erosions have rarely been reported (when MTX was used to treat psoriasis).

Musculoskeletal

Musculoskeletal side effects from low-dose MTX in patients with rheumatoid arthritis include rare instances of accelerated nodulosis. This problem is more commonly associated with MTX than other second-line agents. The use of MTX may be associated with decreased bone density in a syndrome called "MTX osteopathy" (this potential complication requires further investigation). This syndrome may be especially important in postmenopausal women.

Hypersensitivity

Hypersensitivity side effects including anaphylaxis have been reported rarely.

Oncologic

Oncologic side effects include some evidence that methotrexate may be oncogenic, particularly with respect to the development of some lymphomas and leukemias.

Large retrospective studies have shown that hematologic malignancies are uncommon in patients with RA treated with disease-modifying antirheumatic drugs, including MTX. These studies have shown that there does not appear to be a relationship between the peak or cumulative dose of the duration of MTX therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancies seen in MTX-treated patients do not appear different from those seen in patients with RA treated with other disease-modifying antirheumatic drugs. Underlying rheumatoid arthritis (RA) or Sjogren's syndrome are independent risk factors for the development of non-Hodgkin's lymphoma.

Cardiovascular

Cardiovascular side effects including pericarditis, pericardial effusion, myocardial ischemia, hypotension and ventricular arrhythmias have rarely been associated with MTX. Thromboembolic events including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus have also been reported with methotrexate use. Chemical pleuritis secondary to MTX has been identified as the cause of chest pain in some patients after high-dose therapy.

Endocrine

Endocrinologic side effects have included gynecomastia associated with the use of low-dose MTX in patients with rheumatoid arthritis.

Ocular

Ocular side effects reported with methotrexate include conjunctivitis and serious visual changes of unknown origin.

Other

Other side effects have included rare cases of bone and soft tissue necrosis following radiation therapy in patients receiving MTX.

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