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What is methotrexate?

Methotrexate interferes with the growth of certain cells of the body, especially cells that reproduce quickly, such as cancer cells, bone marrow cells, and skin cells.

Methotrexate is used to treat certain types of cancer of the breast, skin, head and neck, or lung. It is also used to treat severe psoriasis and rheumatoid arthritis.

Methotrexate is usually given after other medications have been tried without successful treatment of symptoms.

Methotrexate may also be used for purposes not listed in this medication guide.

Important information about methotrexate

Methotrexate is usually taken once or twice per week and not every day. You must use the correct dose for your condition. Some people have died after taking methotrexate every day by accident.

Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have liver disease (especially if caused by alcoholism), or a blood cell or bone marrow disorder.

Do not use methotrexate if you are pregnant or breast-feeding a baby.

Methotrexate can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches).

Methotrexate can cause serious or life-threatening side effects on your liver, lungs, or kidneys. Tell your doctor if you have upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes), dry cough, shortness of breath, blood in your urine, or little or no urinating.

Before taking methotrexate

You should not use this medicine if you are allergic to methotrexate. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you have:

  • alcoholism, cirrhosis, or other liver disease;

  • a blood cell disorder such as anemia (lack of red blood cells) or leukopenia (lack of white blood cells);

  • a bone marrow disorder; or

  • if you are breast-feeding a baby.

Methotrexate is sometimes used to treat cancer even when patients do have one of the conditions listed above. Your doctor will decide if this treatment is right for you.

To make sure methotrexate is safe for you, tell your doctor if you have:

  • kidney disease;

  • a folate deficiency;

  • pneumonia or lung disease;

  • stomach ulcers;

  • any type of infection; or

  • if you are receiving radiation treatments.

FDA pregnancy category X. Methotrexate can cause birth defects in an unborn baby. Do not use methotrexate to treat psoriasis or rheumatoid arthritis if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

You may need to have a negative pregnancy test before starting this treatment.

Use birth control to prevent pregnancy while you are using methotrexate, whether you are a man or a woman. Methotrexate use by either parent may cause birth defects.

If you are a man, use a condom to keep from causing a pregnancy while you are using methotrexate. Continue using condoms for at least 90 days after your treatment ends.

If you are a woman, use an effective form of birth control while you are taking methotrexate, and for at least one cycle of ovulation after your treatment ends.

Do not give this medicine to a child without the advice of a doctor.

Older adults may be more likely to have side effects from this medication.

How should I take methotrexate?

Take methotrexate exactly as it was prescribed for you. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You must use the correct dose of methotrexate for your condition. Methotrexate is sometimes taken once or twice per week and not every day. Follow the directions on your prescription label. Some people have died after taking methotrexate every day by accident. Ask your doctor or pharmacist if you have questions about your dosage or how often to take this medicine.

Use methotrexate regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Methotrexate can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often, and you may need an occasional liver biopsy. Your cancer treatments may be delayed based on the results of these tests.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Call your doctor for instructions if you miss a dose of methotrexate.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of methotrexate can be fatal.

What should I avoid while taking methotrexate?

Methotrexate can pass into body fluids (including urine, feces, vomit, semen, vaginal fluid). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Patients and caregivers should wear rubber gloves while cleaning up body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Body fluids should not be handled by a woman who is pregnant or who may become pregnant. Use condoms during sexual activity to avoid exposure to body fluids.

Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds), especially if you are being treated for psoriasis. Methotrexate can make your skin more sensitive to sunlight and your psoriasis may worsen.

Avoid drinking alcohol while taking methotrexate.

Methotrexate side effects

Get emergency medical help if you have any of these signs of an allergic reaction to methotrexate: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using methotrexate and call your doctor at once if you have:

  • dry cough, shortness of breath;

  • diarrhea, vomiting, white patches or sores inside your mouth or on your lips;

  • blood in your urine or stools;

  • swelling, rapid weight gain, little or no urinating;

  • seizure (convulsions);

  • fever, chills, body aches, flu symptoms;

  • pale skin, easy bruising, unusual bleeding, weakness, feeling light-headed or short of breath;

  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  • severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common methotrexate side effects may include:

  • vomiting, upset stomach;

  • headache, dizziness, tired feeling; or

  • blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Methotrexate Dosing Information

Usual Adult Dose of Methotrexate for Acute Lymphoblastic Leukemia:

Induction: 3.3 mg/m2/day orally or IM (in combination with prednisone 60 mg/m2).

Maintenance (during remission): 15 mg/m2 IM or orally twice a week.
Alternate remission dosing: 2.5 mg/kg IV every 14 days.

Usual Adult Dose of Methotrexate for Choriocarcinoma:

15 to 30 mg IM or orally daily for 5 days. Repeat courses 3 to 5 times with a rest period of greater than or equal to 1 week between courses, until any manifesting toxic symptoms subside.

Effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which generally will return to normal or less than 50 intl units/24 hours usually after the third or fourth course and usually followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended.

Usual Adult Dose of Methotrexate for Trophoblastic Disease:

15 to 30 mg IM or orally daily for 5 days. Repeat courses 3 to 5 times with a rest period of greater than or equal to 1 week between courses, until any manifesting toxic symptoms subside.

Effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which generally will return to normal or less than 50 intl units/24 hours usually after the third or fourth course and usually followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalization of hCG is usually recommended.

Usual Adult Dose of Methotrexate for Lymphoma:

For Burkitt's tumor in Stages I-II: 10 to 25 mg orally once a day for 4 to 8 days

Malignant lymphoma in Stage III: 0.625 to 2.5 mg/kg orally daily as a part of combination chemotherapy.

Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.

Usual Adult Dose for Meningeal Leukemia:

12 mg/m2 intrathecally every 2 to 5 days until the cell count of the CSF returns to normal. At this point, one additional dose is advisable. Administration at intervals of less than 1 week may result in increased subacute toxicity.

Usual Adult Dose for Mycosis Fungoides:

2.5 to 10 mg PO daily or 50 mg IM once a week or 25 mg IM twice a week.

Usual Adult Dose for Osteosarcoma:

Initial Dose: 12 g/m2 intravenously as a 4 hour infusion (in combination with other chemotherapeutic agents). If this dose is not adequate to achieve a peak serum concentration of 1000 micromolar at the end of the infusion, the dose may be increased to 15 g/m2.

Treatments may occur at 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 weeks after surgery.

If the patient is vomiting or unable to tolerate oral medication, leucovorin should be added to this regimen at the same dose and schedule as the methotrexate.

Usual Adult Dose for Psoriasis:

Single Dose: 10 to 25 mg/week orally, IM, or IV until adequate response is achieved.
Divided Dose: 2.5 mg orally, IM, or IV every 12 hours for 3 doses once a week.
Maximum weekly dose: 30 mg.

Usual Adult Dose for Rheumatoid Arthritis:

Single dose: 7.5 mg orally weekly.
Divided dose: 2.5 mg orally every 12 hours for 3 doses once a week.
Maximum weekly dose: 20 mg.

Usual Adult Dose for Neoplastic Diseases:

I.V.: Range is wide from 30-40 mg/m2/week to 100-12,000 mg/m2 with leucovorin rescue

Usual Pediatric Dose for Acute Lymphocytic Leukemia:

100 mg/m2 over 1 hour followed by a 35 hour infusion delivering 900 mg/m2/day.

Usual Pediatric Dose for Dermatomyositis:

15 to 20 mg/m2 orally once weekly.

Usual Pediatric Dose for Meningeal Leukemia:

less than 4 months: 3 mg/dose intrathecally.
greater than or equal to 4 months less than 1 year: 6 mg/dose intrathecally.
greater than or equal to 1 year less than 2 years: 8 mg/dose intrathecally.
greater than or equal to 2 years less than 3 years: 10 mg/dose intrathecally.
greater than or equal to 3 years: 12 mg/dose intrathecally.

The dose may be administered every 2 to 5 days until CSF counts return to normal followed by a dose administered once weekly for 2 weeks and monthly thereafter. Administration at intervals of less than 1 week may result in increased subacute toxicity.

Usual Pediatric Dose for Neoplastic Diseases:

7.5 to 30 mg/m2 IM or orally every 2 weeks.
Alternate dosing: 10 to 18,000 mg/m2 IV bolus or continuous infusion over 6 to 42 hours.

Usual Pediatric Dose for Rheumatoid Arthritis:

5 to 15 mg/m2 IM or orally once weekly.

Usual Pediatric Dose for Solid Tumors:

less than 12 years: 12000 mg/m2 IV.
greater than or equal to 12 years: 8000 mg/m2 IV.
Maximum dose: 18 grams.

What other drugs will affect methotrexate?

Many drugs can interact with methotrexate. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with methotrexate, especially:

  • azathioprine;

  • leucovorin;

  • phenytoin;

  • probenecid;

  • theophylline;

  • an antibiotic or sulfa drugs;

  • isotretinoin, retinol, tretinoin;

  • NSAIDs (non-steroidal anti-inflammatory drugs)--ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others; or

  • salicylates such as aspirin, Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others.

This list is not complete and many other drugs can interact with methotrexate. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

For the Consumer

Applies to methotrexate: injectable, powder for solution, solution, tablet

Along with their needed effects, medicines like methotrexate can sometimes cause unwanted effects such as blood problems, kidney problems, stomach or liver problems, loss of hair, and other side effects. These and others are described below. Also, because of the way these medicines act on the body, there is a chance that they might cause other unwanted effects that may not occur until months or years after the medicine is used. These delayed effects may include certain types of cancer, such as leukemia. Discuss these possible effects with your doctor.

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
  • blood in urine or stools
  • bloody vomit
  • diarrhea
  • joint pain
  • reddening of skin
  • stomach pain
  • swelling of feet or lower legs
Less common
  • Blurred vision
  • confusion
  • convulsions (seizures)
  • cough
  • pinpoint red spots on skin
  • shortness of breath
  • unusual bleeding or bruising

Check with your doctor as soon as possible if any of the following side effects occur while taking methotrexate:

More common
  • Sores in mouth and on lips
Less common
  • Back pain
  • cough or hoarseness accompanied by fever or chills
  • dark urine
  • dizziness
  • drowsiness
  • fever or chills
  • headache
  • lower back or side pain accompanied by fever or chills
  • painful or difficult urination accompanied by fever or chills
  • unusual tiredness or weakness
  • yellow eyes or skin

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
  • Loss of appetite
  • nausea or vomiting
Less common
  • Acne
  • boils
  • pale skin
  • skin rash or itching

This medicine may cause a temporary loss of hair in some people. After treatment with methotrexate has ended, normal hair growth should return.

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

  • Back pain
  • blurred vision
  • confusion
  • convulsions (seizures)
  • dizziness
  • drowsiness
  • fever
  • headache
  • unusual tiredness or weakness

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Applies to methotrexate: compounding powder, injectable powder for injection, injectable solution, oral tablet

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.