Methotrexate Side Effects

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.

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.

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

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 tablet, subcutaneous solution

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).[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

Hepatic

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.[Ref]

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

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.[Ref]

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).[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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).[Ref]

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.[Ref]

Hypersensitivity

Hypersensitivity side effects including anaphylaxis have been reported rarely.[Ref]

Oncologic

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.[Ref]

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

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.[Ref]

Endocrine

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

Ocular

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

Other

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

References

1. Mccambridge MM, Vogelgesang SA, Ockenhouse CF "Listeria monocytogenes infection in a patient treated with methotrexate for rheumatoid arthritis." J Rheumatol 22 (1995): 786-7

2. Aboguddah A, Stein HB, Phillips P, et al "Herpes simplex hepatitis in a patient with psoriatic arthritis taking prednisone and methotrexate. Report and review of the literature." J Rheumatol 18 (1991): 1406-12

3. Gispen JG, Alarcon GS, Johnson JJ, et al "Toxicity to methotrexate in rheumatoid arthritis." J Rheumatol 14 (1987): 74-9

4. Tung JP, Maibach HI "The practical use of methotrexate in psoriasis." Drugs 40 (1990): 697-712

5. Bannwarth B, Labat L, Moride Y, Schaeverbeke T "Methotrexate in rheumatoid arthritis - an update." Drugs 47 (1994): 25-50

6. Casserly CM, Stange KC, Chren MM "Severe megaloblastic anemia in a patient receiving low-dose methotrexate for psoriasis." J Am Acad Dermatol 29 (1993): 477-80

7. Kane GC, Troshinsky MB, Peters SP, Israel HL "Pneumocystis carinii pneumonia associated with weekly methotrexate: cumulative dose of methotrexate and low CD4 cell count may predict this complication." Respir Med 87 (1993): 153-5

8. Shupack JL, Webster GF "Pancytopenia following low-dose oral methotrexate therapy for psoriasis." JAMA 259 (1988): 3594-6

9. Flynn JA, Hellmann DB "Methotrexate in rheumatoid arthritis: when NSAIDs fail." Cleve Clin J Med 62 (1995): 351-9

10. Hassell A, Dawes P "Serious problems with methotrexate?" Br J Rheumatol 33 (1994): 1001-2

11. Shiroky JB, Frost A, Skelton JD, et al "Complications of immunosuppression associated with weekly low dose methotrexate." J Rheumatol 18 (1991): 1172-5

12. Kremer JM, Phelps CT "Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months." Arthritis Rheum 35 (1992): 138-45

13. Mielants H, Veys EM, van der Straeten C, et al "The efficacy and toxicity of a constant low dose of methotrexate as a treatment for intractable rheumatoid arthritis: an open prospective study." J Rheumatol 18 (1991): 978-83

14. al-Awadhi A, Dale P, McKendry RJ "Pancytopenia associated with low dose methotrexate therapy. A regional survey." J Rheumatol 20 (1993): 1121-5

15. Aglas F, Rainer F, Hermann J, Gretler J, Huttl E, Domej W, Krejs GJ "Interstitial pneumonia due to cytomegalovirus following low-dose methotrexate treatment for rheumatoid arthritis." Arthritis Rheum 38 (1995): 291-2

16. Lemense GP, Sahn SA "Opportunistic infection during treatment with low dose methotrexate." Am J Respir Crit Care Med 150 (1994): 258-60

17. Lang B, Riegel W, Peters T, Peter H-H "Low dose methotrexate therapy for rheumatoid arthritis complicated by pancytopenia and pneumocystis carini pneumonia." J Rheumatol 18 (1991): 1257-9

18. Schnabel A, Gross WL "Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects." Semin Arthritis Rheum 23 (1994): 310-27

19. Brown M, Corrigan B "Pancytopenia after accidental overdose of methotrexate." Med J Aust 155 (1991): 493-4

20. "Product Information. Methotrexate and Methotrexate LPF (methotrexate)." Lederle Laboratories, Wayne, NJ.

21. Tanaka Y, Shiozawa K, Nishibayashi Y, Imura S "Methotrexate induced early onset pancytopenia in rheumatoid arthritis: drug allergy? idiosyncrasy?" J Rheumatol 19 (1992): 1320-1

22. Ellman MH, Hou S, Ginsberg D "Low-dose methotrexate and severe neutropenia in patients undergoing renal dialysis." Arthritis Rheum 33 (1990): 1060-1

23. Salaffi F, Carotti M, Sartini A, Cervini C "A prospective study of the long-term efficacy and toxicity of low-dose methotrexate in rheumatoid arthritis patients." Clin Exp Rheumatol 13 (1995): 23-8

24. Basin KS, Escalante A, Beardmore TD "Severe pancytopenia in a patient taking low dose methotrexate and probenecid." J Rheumatol 18 (1991): 609-10

25. Flood DA, Chan CK, Pruzanski W "Pneumocystis carini pneumonia associated with methotrexate therapy in rheumatoid arthritis." J Rheumatol 18 (1991): 1254-6

26. Vallerand H, Cossart C, Milosevic D, Lavaud F, Leone J "Fatal pneumocystis pneumonia in asthmatic patient treated with methotrexate." Lancet 339 (1992): 1551

27. Basin K, Escalante, Beardmore T "Severe pancytopenia in a patient taking low dose methotrexate and probenecid." J Rheumatol 18 (1991): 609-10

28. Mayall B, Poggi G, Parkin JD "Neutropenia due to low-dose methotrexate therapy for psoriasis and rheumatoid arthritis may be fatal." Med J Aust 155 (1991): 480-4

29. Goodman TA, Polisson RP "Methotrexate: adverse reactions and major toxicities." Rheum Dis Clin North Am 20 (1994): 513-28

30. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcon GS "Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial." Ann Intern Med 121 (1994): 833-41

31. Atherton LD, Leib ES, Kaye MD "Toxic megacolon associated with methotrexate therapy." Gastroenterology 86 (1984): 1583-8

32. Miller DR, Letendre PW, DeJong DJ, Fiechtner JJ "Methotrexate in rheumatoid arthritis: an update." Pharmacotherapy 6 (1986): 170-8

33. Duhra P "Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis." J Am Acad Dermatol 28 (1993): 466-9

34. Whiting-O'Keefe QE, Fye KH, Sack KD "Methotrexate and histologic hepatic abnormalities: a meta-analysis." Am J Med 90 (1991): 711-16

35. Zachariae H, Kragballe K, Sogaard H "Methotrexate induced liver cirrhosis." Br J Dermatol 102 (1980): 407-12

36. Roenigk HH, Jr "Methotrexate and liver biopsies." Arch Intern Med 150 (1990): 733-4

37. Petrazzuoli M, Rothe MJ, Grin-Jorgensen C, Ramsey WH, Grant-Kels JM "Monitoring patients taking methotrexate for hepatotoxicity. Does the standard of care match published guidelines?" J Am Acad Dermatol 31 (1994): 969-77

38. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, Alarcon GS, Lee RG, Weinblatt ME "Determinants of serious liver disease among patients receiving low- dose methotrexate for rheumatoid arthritis." Arthritis Rheum 36 (1993): 329-35

39. Shergy WJ, Polisson RP, Caldwell DS, et al "Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis." Am J Med 85 (1988): 771-4

40. Ahern MJ, Kevat S, Hill W, et al "Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings." Ann Rheum Dis 50 (1991): 477-80

41. Hanrahan PS, Scivens GA, Russell AS "Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression." Br J Rheumatol 28 (1989): 147-53

42. Fries JF, Ramey DR, Singh G "Suggested guidelines for monitoring liver toxicity in rheumatoid arthritis patients treated with methotrexate: comment on the article by Kremer et al." Arthritis Rheum 37 (1994): 1829-30

43. Zachariae H, Kragballe K, Sogaard H "Methotrexate induced liver cirrhosis." Br J Dermatol 102 (1980): 407-12

44. Kremer JM "Liver biopsies in patients with rheumatoid arthritis receiving methotrexate: where are we going?" J Rheumatol 19 (1992): 189-91

45. Kremer JM, Lee RG, Tolman KG "Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy." Arthritis Rheum 32 (1989): 121-7

46. Felson DT, Chernoff M, Anderson JJ, Weinblatt M, Furst D, Schmid F, Williams HJ, Wilke W, Suarezalmazor M, Mckendry R, Bell M "The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis." J Rheumatol 22 (1995): 218-23

47. Willkens RF, Leonard PA, Clegg DO, et al "Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis." Ann Rheum Dis 49 (1990): 591-3

48. Themido R, Loureiro M, Pecegueiro M, et al "Methotrexate hepatotoxicity in psoriatic patients submitted to long-term therapy." Acta Derm Venereol 72 (1992): 361-4

49. Bergquist SR, Felson DT, Prashker MJ, Freedberg KA "The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate." Arthritis Rheum 38 (1995): 326-33

50. Banerjee AK, Lakhani S, Vincent M, Selby P "Dose-dependent acute hepatitis associated with administration of high dose methotrexate." Hum Toxicol 7 (1988): 561-2

51. Clegg DO, Furst DE, Tolman KG, Pogue R "Acute, reversible hepatic failure associated with methotrexate treatment of rheumatoid arthritis." J Rheumatol 16 (1989): 1123-6

52. Szanto E, Sandstedt B, Kollberg B "Hepatoxicity associated with low-dose, long-term methotrexate treatment of rheumatoid arthritis." Scand J Rheumatol 16 (1987): 229-34

53. Phillips CA, Cera PJ, Mangan TF, Newman ED "Clinical liver disease in patients with rheumatoid arthritis taking methotrexate." J Rheumatol 19 (1992): 229-33

54. Ahern MJ, Kevat S, Hill W, et al "Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings." Ann Rheum Dis 50 (1991): 477-80

55. Kremer JM, Alarcon GS, Lightfoot RW Jr, Willkens RF, Furst DE, Williams HJ, Dent PB, Weinblatt ME "Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology." Arthritis Rheum 37 (1994): 316-28

56. Gilbert SC, Klintmalm G, Menter A, Silverman A "Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis." Arch Intern Med 150 (1990): 889-91

57. Maiche AG "Acute renal insufficiency due to viral infection caused by cytomegalovirus (CMV) during treatment with methotrexate." Acta Oncol 34 (1995): 969-70

58. Ching DWT "Severe, disseminated, life threatening herpes zoster infection in a patient with rheumatoid arthritis treated with methotrexate." Ann Rheum Dis 54 (1995): 155

59. Houtman PM, Stenger AA, Bruyn GA, Mulder J "Methotrexate may affect certain T lymphocyte subsets in rheumatoid arthritis resulting in susceptibility to Pneumocystis carinii infection." J Rheumatol 21 (1994): 1168-70

60. Boogerd W, Snade JJ, Moffie D "Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate." J Neurol Neurosurg Psychiatry 51 (1988): 1277-83

61. Tuxen MK, Hansen SW "Neurotoxicity secondary to antineoplastic drugs." Cancer Treat Rev 20 (1994): 191-214

62. Walker RW, Allen JC, Rosen G, Caparros B "Transient cerebral dysfunction secondary to high-dose methotrexate." J Clin Oncol 4 (1986): 1845-50

63. Szawarski P, Chapman CS "A woman who couldn't speak: report of methotrexate neurotoxicity." Postgrad Med J 81 (2005): 194-5

64. de Waal R, Algra PR, Heimans JJ, Wolbers JG, Scheltens P "Methotrexate induced brain necrosis and severe leukoencephalopathy due to disconnection of an Ommaya device." J Neurooncol 15 (1993): 269-73

65. Allen JC, Rosen G, Mehta BM, Horten B "Leukoencephalopathy following high-dose IV methotrexate chemotherapy with leucovorin rescue." Cancer Treat Rep 64 (1980): 1261-73

66. Worthley SG, Mcneil JD "Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid arthritis." J Rheumatol 22 (1995): 335-7

67. ten Hoeve RF, Twijnstra A "A lethal neurotoxic reaction after intraventricular methotrexate administration." Cancer 62 (1988): 2111-3

68. Schweitzer DH, Edelbroek PM, de Wolff FA, Keizer HJ "Acute reversible neurotoxicity after intrathecal low-dose methotrexate." Eur J Cancer 27 (1991): 219-20

69. Ojeda VJ "Necrotising leucoencephalopathy associated with intrathecal/intraventricular methotrexate therapy." Med J Aust 2 (1982): 289-93

70. Bleyer WA, Drake JC, Chabner BA "Neurotoxicity and elevated cerebrospinal-fluid methotrexate concentration in menigeal leukemia." N Engl J Med 289 (1973): 770-3

71. Necioglu Orken D, Yldrmak Y, Kenangil G, Kandraloglu N, Forta H, Celik M "Intrathecal methotrexate-induced acute chorea." J Pediatr Hematol Oncol 31 (2009): 57-8

72. Hamous JE, Guffy MM, Aschenbrener CA "Fatal acute respiratory failure following intrathecal methotrexate administration." Cancer Treat Rep 67 (1983): 1025-6

73. Even-Sapir E, Barnes DC, Llewellyn CG, Langley GR "Methotrexate-induced neurotoxicity: appearance on indium-111-white blood cells, gallium-67-citrate and thallium-201-chloride scintigraphy." J Nucl Med 34 (1993): 1377-81

74. Tsai JJ, Shin JF, Chen CH, Wang SR "Methotrexate pneumonitis in bronchial asthma." Int Arch Allergy Immunol 100 (1993): 287-90

75. Israel CW, Wegener M, Adamek RJ, Bitsch T, Weber K, Ricken D "Severe pneumonitis as complication of low-dosage methotrexate treatment of psoriasis-associated rheumatoid arthritis." Dtsch Med Wochenschr 120 (1995): 603-8

76. Bernstein ML, Sobel DB, Wimmer RS "Noncardiogenic pulmonary edema following injection of methotrexate into the cerebrospinal fluid." Cancer 50 (1982): 866-8

77. Phillips TJ, Jones DH, Baker H "Pulmonary complications following methotrexate therapy." J Am Acad Dermatol 16 (1987): 373-5

78. Jones G, Mierins E, Karsh J "Methotrexate-induced asthma." Am Rev Respir Dis 143 (1991): 179-81

79. Xavier AM, Bertken RD "Low dose methotrexate and acute respiratory insufficiency." J Rheumatol 15 (1988): 1588

80. Searles G, McKendry RJR "Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors: four case reports and a review of the literature." J Rheumatol 14 (1987): 1164-71

81. Kerstens PJ, van Loenhout JW, Boerbooms AM, van de Putte LB "Methotrexate, pneumonitis, and infection." Ann Rheum Dis 51 (1992): 1179

82. Hassan W, Carpenter M, Kelly C "Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis." Thorax 48 (1993): 191

83. de Bandt M, Rat AC, Palazzo E, Kahn MF "Delayed methotrexate pneumonitis." J Rheumatol 18 (1991): 1943

84. Dayton CS, Schwartz DA, Sprince NL, Yagla SJ, Davis CS, Koehnke RK, Furst DE, Hunninghake GW "Low-dose methotrexate may cause air trapping in patients with rheumatoid arthritis." Am J Respir Crit Care Med 151 (1995): 1189-93

85. Fleming JJ, Child JA, Cooper EH, et al "Renal tubular damage without glomebular damage after cytotoxic drugs and aminoglycosides." Biomedicine 33 (1980): 251-4

86. Ahmad S, Shen FH, Bleyer WA "Methotrexate-induced renal failure and ineffectiveness of peritoneal dialysis." Arch Intern Med 138 (1978): 1146-7

87. Seideman P, Muller-Suur R, Ekman E "Renal effects of low dose methotrexate in rheumatoid arthritis." J Rheumatol 20 (1993): 1126-8

88. Ellison NM, Servi RJ "Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration." Cancer Treat Rep 69 (1985): 342-3

89. Freeman-Narrod M, Kim JS, Ohanissian H, et al "The effect of high-dose methotrexate on renal tubules as indicated by urinary lysozyme concentration." Cancer 50 (1982): 2775-9

90. Stark AN, Jackson G, Carey PJ, et al "Severe renal toxicity due to intermediate-dose methotrexate." Cancer Chemother Pharmacol 24 (1989): 243-5

91. Pitman SW, Parker LM, Tattersall MH, et al "Clinical trial of high-dose methotrexate (NSC-740) with citrovorum factor (NSC-3590)-toxicologic and therapeutic observations." Cancer Chemother Rep 6 (1975): 43-9

92. Maiche AG, Lappalainen K, Teerenhovi L "Renal insufficiency in patients treated with high dose methotrexate." Acta Oncol 27 (1988): 73-4

93. Abelson HT, Fosburg MT, Beardsley P, et al "Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine." J Clin Oncol 1 (1983): 208-16

94. Schilsky RL "Renal and metabolic toxicities of cancer chemotherapy." Semin Oncol 9 (1982): 75-83

95. Halla JT, Hardin JG "Underrecognized postdosing reactions to methotrexate in patients with rheumatoid arthritis." J Rheumatol 21 (1994): 1224-6

96. Doyle LA, Berg C, Bottino G, Chabner B "Erythema and desquamation after high-dose methotrexate." Ann Intern Med 98 (1983): 611-2

97. Harrison PV "Methotrexate-induced epidermal necrosis." Br J Dermatol 116 (1987): 867-9

98. Trout S, Kemmann E "Reversible alopecia after single-dose methotrexate treatment in a patient with ectopic pregnancy." Fertil Steril 64 (1995): 866-7

99. Neiman RA, Fye KH "Methotrexate induced false photosensitivity reaction." J Rheumatol 12 (1985): 354-5

100. Preston SJ, Diamond T, Scott A, Laurent MR "Methotrexate osteopathy in rheumatic disease." Ann Rheum Dis 52 (1993): 582-5

101. Alarcon GS, Koopman WJ, McCarty MJ "Nonperipheral accelerated nodulosis in a methotrexate-treated rheumatoid arthritis patient." Arthritis Rheum 36 (1993): 132-3

102. Cohn JR, Cohn JB, Fellin F, Cantor R "Systemic anaphylaxis from low dose methotrexate." Ann Allergy 70 (1993): 384-5

103. Klimo P, Ibrahim E "Anaphylactic reaction to methotrexate used in high doses as an adjuvant treatment of osteogenic sarcoma." Cancer Treat Rep 65 (1981): 725

104. Takami MS, Kuniyoshi Y, Oomukai T, Ishida TI, Yamano YI "Severe complications after high-dose methotrexate treatment." Acta Oncol 34 (1995): 611-2

105. Kerr LD, Troy K, Isola L "Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis." J Rheumatol 22 (1995): 2356-8

106. Moder KG, Tefferi A, Cohen MD, Menke DM, Luthra HS "Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study." Am J Med 99 (1995): 276-81

107. Pointud P, Prudat M, Peron JM "Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis." J Rheumatol 20 (1993): 1215-6

108. Kingsmore SF, Hall BD, Allen NB, et al "Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review." J Rheumatol 19 (1992): 1462-5

109. Bruyn GA, Essed CE, Houtman PM, Willemse FW "Fatal cardiac nodules in a patient with rheumatoid arthritis treated with low dose methotrexate." J Rheumatol 20 (1993): 912-4

110. Kettunen R, Huikuri HV, Oikarinen A, Takkunen JT "Methotrexate-linked ventricular arrhythmias." Acta Derm Venereol 75 (1995): 391-2

111. Forbat LN, Hancock BW, Gershlick AH "Methotrexate-induced pericarditis and pericardial effusion: first reported case." Postgrad Med J 71 (1995): 244-5

112. Igawa M, Kadena H, Ohkuchi T, Ueda M, Usui T, Matsuura H "Myocardial ischemia after treatment with methotrexate, etoposide and cisplatin." Urol Int 50 (1993): 98-100

113. Urbam C, Nirenberg A, Caparros B, et al "Chemical pleuritis as the cause of acute chest pain following high-dose methotrexate treatment." Cancer 51 (1983): 34-7

114. Finger DR, Klipple GL "Gynecomastia following low dose methotrexate therapy for rheumatoid arthritis." J Rheumatol 22 (1995): 796-7

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.

Hide
(web3)