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Rheumatrex

Generic Name: Methotrexate
Drug Category: Antimetabolite
Litigation Alert Level: Medium
This drug has been approved for use by males and females over the age of 2 years old for a maximum duration of 2 years.

Approved Uses

Indicated for:

Neoplastic Diseases:

• Treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole.

• Maintenance therapy in combination with other chemotherapeutic agents.

• Use alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.

Psoriasis:

• Symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune responses.

Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis:

• The management of selected adults with severe, active, rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). 

Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.

Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.

Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.

Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

Methotrexate should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy because of the possibility of serious toxic reactions (which can be fatal).

Methotrexate should be used only in life threatening neoplastic diseases, or in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy.

Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis.

Patients should be closely monitored for bone marrow, liver, lung and kidney toxicities.

The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.

Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually  recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.

Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.

Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.

Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.

Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.

Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Methotrexate is contraindicated in:

  • pregnant women with psoriasis or rheumatoid arthritis
  • nursing mothers
  • patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease 
  • patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes 
  • patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia

Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.

Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.

Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 20 mg/wk) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.

Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.

Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Use of methotrexate with penicillins should be carefully monitored.

The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (eg, azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate.

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.

The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increased toxicity such as stomatitis, myelosuppression, and neurotoxicity. Avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate. Use caution when administering methotrexate after a recent history of nitrous oxide administration.

Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate.

Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.

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Off-label Uses

• Crohn’s disease. GoToSource 

• Soft tissue sarcoma. GoToSource

• Bladder cancer. GoToSource

• Central nervous system lymphoma. GoToSource

• Prevention of graft-versus-host disease. GoToSource

• Dermatomyositis. GoToSource

• Ectopic pregnancy. GoToSource 

• Asthma, systemic lupus erythematosus, myositis and vasculitis. GoToSource 

• Atypical non-arteritic ischemic optic neuropathy. GoToSource 

• Generalized myasthenia gravis. GoToSource

Adverse Events

Stomatitis (inflammation of the mouth and lips), alopecia (hair loss) and liver damage. GoToSource

Pneumonitis (inflammation of lung tissue). GoToSource

Severe leukopenia (low white blood cell count). GoToSource

Ulcerative oral lesions. GoToSource

Haematemesis (vomiting of blood). GoToSource

Gastrointestinal mucosal necrosis (tissue death of gastrointestinal tract), bleeding, peptic ulcers, toxic epidermal necrolysis (life-threatening skin disorder) and bone marrow aplasia (bone marrow decreases or stops production of blood cells). GoToSource 

Severe megaloblastic anemia (bone marrow produces larger than normal red blood cells). GoToSource

Pancytopenia (deficiency of blood cells). GoToSource

Thrombocytopenia (deficiency of blood platelets). GoToSource

Lymphoproliferative disorders (diffuse large B-cell lymphoma and hodgkin lymphoma). GoToSource

Pericarditis (inflammation of lining around the heart) and pericardial effusion (fluid around the heart). GoToSource

Pneumocystis carinii pneumonia (infection causing lung inflammation and fluid buildup). GoToSource 

Interstitial pulmonary inflammation and fibrosis (lung scarring and inflammation). GoToSource 

Disseminated histoplasmosis (fungal infection). GoToSource

Cryptococcosis (fungal infection). GoToSource 

Herpes zoster (shingles). GoToSource 

Opportunistic infections. GoToSource 

Neutropenic enterocolitis (life-threatening disease involving lower intestinal tract). GoToSource

Stroke-like neurotoxicity. GoToSource

Paraparesis (partial paralysis of lower limbs). GoToSource

Portal hypertension (increased pressure in portal venous system). GoToSource

Development of fatty liver disease. GoToSource

Stevens-johnson syndrome (life-threatening skin disorder). GoToSource

Litigation

Lawsuits filed for lymphomas, skin disorders, infections, bone damage, liver, lung and kidney disorders. 

The material contained in GoToPills is for informational purposes only and not intended to replace the judgment, evaluation and treatment of physicians, pharmacists and other healthcare providers. GoToPills does not provide medical advice, diagnoses or treatment. Always seek the advice of your physician or other qualified health provider regarding a medical condition or treatment.

 

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Site Last Updated March 28, 2024