Methotrexate Side Effects: Methotrexate has long been used as an immunosuppressive medication and as a chemotherapy agent. Methotrexate functions primarily as an inhibitor of folic acid which is a necessary cofactor for cellular metabolism. Because of its effects on cell division the potential methotrexate side effects are numerous and potentially very serious. Adult dosing of methotrexate varies from 7.5to 50 mg per week depending on the indications. In general dosing for autoimmune disorders is lower than dosing for chemotherapy. The typical dose for ectopic pregnancy is 50 mg/m² with a repeat dose in seven days if beta-hCG levels have not decreased at least 25% from the date of the initial injection.

Methotrexate Black Box Warnings: The list of methotrexate black box warnings is remarkably long. Methotrexate should only be administered under the supervision of a physician with experience using this type of medication and only for life-threatening malignancies, for difficult to treat disabling psoriatic or rheumatoid arthritis that hasn’t responded to other treatments, and close monitoring for bone marrow, lung, liver, and kidney toxic effects is important. Methotrexate is not recommended to be used in women of childbearing age unless there is clear-cut medical reasoning to suggest that the benefits outweigh the risks of severe fetal congenital anomalies and fetal death. The elimination to methotrexate can be reduced in renal insufficiency, and and in patients with fluid accumulations like ascites or pleural effusions. In these cases dosage may need to be discontinued or reduced. Some NSAIDs when used with methotrexate can lead to unusually severe and even fatal bone marrow suppression, aplastic anemia, and gastrointestinal toxicity. Severe liver disease including cirrhosis and hepatocellular fibrosis can occur after prolonged use. Elevation of liver transaminases is is common and usually transient and without symptoms and is not predictive of later liver disease. Lack of elevation of liver transaminases does not give certain reassurance that hepatotoxicity is not occurring. If patients are on chronic therapy persistently abnormal liver function tests may predict cirrhosis but periodic liver biopsies may be needed even without abnormal liver function tests. Pulmonary toxicity can be severe with acute and chronic interstitial lung inflammation even at low doses it is not always reversible. This may require interruption or cessation of methotrexate treatment. Severe gastrointestinal toxicity can include diarrhea and such severe ulcerations of the gut that they may cause perforation and death. Development of lymphoma may occur with low-dose methotrexate therapy and although this may resolve with cessation of treatment it may require different chemotherapy for management. Tumor lysis syndrome can occur with rapidly growing tumors leading to the need for intervention to prevent renal failure and severe methotrexate side effects. Severe skin reactions that can even be fatal may occur as little as several days after single or multiple treatments by any route of administration. If immunosuppression occurs infections with organisms called opportunistic infections can be severe and sometimes lethal methotrexate side effects. When used in combination with radiation therapy osteonecrosis and soft tissue necrosis may complicate methotrexate therapy.

Common Methotrexate Side Effects: Many of the common methotrexate side effects are related to bone marrow suppression and the related pancytopenia that can result. Leukopenia and especially neutropenia can lead to fever, chills, and opportunistic infections. Elevated liver enzymes, nausea, vomiting, mouth inflammation, abdominal pain, and diarrhea are common methotrexate side effects of the gastrointestinal system. Generalized methotrexate side effects include malaise, fatigue, dizziness, itching, hair loss, and photosensitivity and other rashes.

Serious Methotrexate Side Effects: Methotrexate is one of the few medications where the list of serious side effects is more extensive than the list of common side effects. Many of the serious methotrexate side effects relate to its bone marrow suppression and include thrombocytopenia, severe anemia, leukopenia, agranulocytosis, immunosuppression, and opportunistic infections related to the leukopenia. Gastrointestinal severe methotrexate side effects can include severe diarrhea, severe ulcerative stomatitis, cirrhosis of the liver and hepatic fibrosis. Severe neurologic methotrexate side effects can include arachnoiditis with intrathecal use, neurotoxicity and seizures, leukoencephalopathy, and serious pulmonary methotrexate side effects can include pulmonary fibrosis and pneumonitis. As with many chemotherapy agents secondary malignancies can be serious methotrexate side effects and include lymphoproliferative disorders. Severe kidney toxicity is also potential serious methotrexate side effect.

Drug Interactions and Cautions:  Live vaccines like smallpox vaccination, life intranasal influenza vaccination, measles mumps and German measles vaccine, and Zostavax vaccine should not be used in patients on methotrexate because of the potential of opportunistic infection with the vaccine viruses. Methotrexate use is contraindicated with acitretin and streptozocin. The list of medications with cautions and contraindications for use with methotrexate is extensive and the reader should refer to the manufacturers prescribing guidelines for detailed information. Some of the more commonly used medications where caution or alternative medications need to be considered include acetaminophen containing analgesics, Cox-2 inhibitors, NSAID medications, phenytoins, sulfonamides, trimethoprim, allopurinol, ciprofloxacin, cyclosporine, all other chemotherapy agents, interferon, metformin, and penicillins. In addition many herbal medications including black cohosh, kava, and willow bark should be avoided.

Pregnancy and Lactation:  Methotrexate is pregnancy category X and is absolutely contraindicated during pregnancy except for therapy of ectopic pregnancy and medical abortions. Methotrexate considered unsafe for use during lactation.

Unusual Side Effects:   Cirrhosis and pulmonary fibrosis can be  severe and sometimes difficult to diagnose until their advanced stage, and are unusual side effects.  They none-the-less are very important methotrexate side effects to be aware of so that pulmonary symptoms can be investigated early, and advanced cirrhosis can be avoided.

Methotrexate is commonly used in combination with the newer biologic medications for treatment of severe rheumatoid arthritis. These combinations although very effective run the risk of essentially all of the common and serious methotrexate side effects.