Methotrexate Side Effects and Management

Introduction to Methotrexate Toxicity

Mucocutaneous effects such as stomatitis and mouth ulcers are very common early toxicities that can often be mitigated by altering the dose, route, or frequency of administration, or taking the medication with food 1
Folic acid supplementation (1 mg daily or 5 mg weekly) is recommended to reduce gastrointestinal and hepatic adverse effects without compromising efficacy, as suggested by the American Academy of Dermatology 2, 1

Bone marrow suppression is the leading cause of methotrexate-related death and generally occurs early in treatment (first 4-6 weeks), but is reversible with cessation, according to Praxis Medical Insights 1
Pancytopenia can occur after even a single dose of methotrexate at any time during treatment, typically in patients with at least one risk factor, as reported by the Journal of the American Academy of Dermatology 3, 4, 1
Major risk factors for hematologic toxicity include renal insufficiency, advanced age, lack of folate supplementation, methotrexate dosing errors, drug interactions, hypoalbuminemia, as identified by the Journal of the American Academy of Dermatology and Praxis Medical Insights 3, 4, 1, 5

Hepatotoxicity is a well-known side effect, though hepatic fibrosis and cirrhosis are considerably less common than initially reported, according to the Journal of the American Academy of Dermatology 3, 4
Transient liver enzyme elevations are common, especially within 3-4 days after dosing, as noted by Praxis Medical Insights 1
Long-term use can induce liver fibrosis or cirrhosis in a dose- and duration-dependent manner, as reported by Praxis Medical Insights 1
Risk factors for hepatotoxicity include history of or current greater than moderate alcohol consumption, persistent abnormal liver chemistry findings, history of liver disease, diabetes mellitus, obesity, history of significant exposure to hepatotoxic drugs, and hyperlipidemia, as identified by the Journal of the American Academy of Dermatology and Praxis Medical Insights 1, 3, 4, 5
For patients without risk factors, liver biopsy should be considered after 3.5-4.0 g cumulative dose rather than 1.0-1.5 g, as recommended by the Journal of the American Academy of Dermatology 3, 4

Pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression, with 30 of 164 reported methotrexate-associated fatalities caused by pulmonary fibrosis, according to Praxis Medical Insights 1, 5
Dry, nonproductive cough is a common presenting symptom that requires interruption of treatment and careful investigation, as noted by Praxis Medical Insights 5
Reduced diffusion capacity on pulmonary function tests is a diagnostic finding, as reported by Praxis Medical Insights 5
Risk factors include renal impairment, advanced age, pre-existing pulmonary disease, as identified by Praxis Medical Insights 5
Patients with pulmonary diseases may not be candidates for methotrexate and should undergo pulmonary function studies in consultation with a pulmonologist prior to drug initiation, as recommended by the Journal of the American Academy of Dermatology and Praxis Medical Insights 6, 5

Methotrexate use is contraindicated during pregnancy and can cause defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects, according to Praxis Medical Insights 1
Fetal abnormalities have been reported after exposure at all gestational ages, but the critical period appears to be within the first 6-8 weeks of pregnancy, as noted by the Journal of the American Academy of Dermatology 2
Women of child-bearing age must be on contraception while taking methotrexate and should wait at least 3 months after discontinuation before attempting pregnancy, as recommended by the Journal of the American Academy of Dermatology 2

Lymphoproliferative disorders, including Epstein-Barr virus-associated B-cell lymphoma, are a potential side effect of methotrexate, according to Praxis Medical Insights 1
Risk for skin cancer and lymphoma has been reported, though some cases of lymphoma have regressed on drug discontinuation, as noted by the Journal of the American Academy of Dermatology and Praxis Medical Insights 6

Timing of labs is important—perform labs at least 4-6 days after dosing to avoid misinterpreting transient elevations, as recommended by Praxis Medical Insights 1
Monitor complete blood count and liver function tests monthly for the first 6 months, then every 1-3 months thereafter, as suggested by the Journal of the American Academy of Dermatology and Praxis Medical Insights 3, 4
For liver function test elevations ≥2-fold but <3-fold upper limit of normal, closely monitor, repeat in 2-4 weeks, and decrease dose as needed, as recommended by the Journal of the American Academy of Dermatology 3, 4
For persistent elevations in 5/9 AST levels during a 12-month period or decline in serum albumin below normal range with normal nutritional status, liver biopsy should be performed, as suggested by the Journal of the American Academy of Dermatology 3, 4
For overdose or severe toxicity, leucovorin (folinic acid) rescue is the preferred antidote, along with maintenance of hydration and consideration of urine alkalinization, according to Praxis Medical Insights 1
Filgrastim can be used for toxic bone marrow suppression, as noted by Praxis Medical Insights 1