Methotrexate

Oral
Subcutaneous
Class
Antimetabolites
Subclass
Antifolates
Substance name
Methotrexate, amethopterin
Brand names
Trexall®, Jylamvo®, Xatmep®
Common formulations
Film-coated tablet, Solution
Dosage and administration
Adults patients
Treatment
Acute lymphoblastic leukemia • Maintenance therapy
•
20 mg/m² PO weekly
As part of a combination chemotherapy maintenance regimen. Monitor absolute neutrophil count (ANC) and platelet count and adjust dose as needed to avoid excessive myelosuppression.
Plaque psoriasis • Moderate-to-severe
•
10-25 mg PO weekly
Administer with folic acid to reduce adverse effects. Do not exceed 30 mg weekly.
Rheumatoid arthritis
•
Start at: 7.5 mg PO weekly
•
Maintenance: 7.5-20 mg PO weekly
Administer with folic acid to reduce adverse reactions.
Atopic dermatitis • Moderate-to-severe • Off-label
•
10-25 mg PO weekly
Behçet's syndrome • Off-label
•
0.3 mg/kg PO weekly
Granulomatosis with polyangiitis • Off-label
•
25 mg PO weekly
Adjunctive treatment
Adjunctive treatment for gout • Refractory to conventional therapy • Off-label
•
15 mg PO weekly
Indications for use
Labeled indications
Adults
•
Treatment of acute lymphoblastic leukemia (maintenance therapy)
•
Treatment of mycosis fungoides
•
Treatment of non-Hodgkin's lymphoma (relapsed or refractory)
•
Treatment of plaque psoriasis (moderate-to-severe)
•
Treatment of rheumatoid arthritis
Children
•
Treatment of JIA
•
Treatment of polyarticular JIA
Off-label indications
Adults
•
Treatment of Behçet's syndrome
•
Treatment of atopic dermatitis (moderate-to-severe)
•
Treatment of granulomatosis with polyangiitis
•
Adjunctive treatment for gout (refractory to conventional therapy)
Safety risks
Boxed warnings
Anaphylaxis
Drug hypersensitivity reaction
Fetal toxicity
Severe adverse reactions, death
•
Maintain a high level of suspicion For severe adverse effects, including death. Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys.
Warnings and precautions
Diarrhea, vomiting, nausea, stomatitis
•
Use extreme caution in patients with gastrointestinal disease such as peptic ulcer disease or ulcerative colitis.
Folate deficiency
•
Maintain a high level of suspicion in patients treated for non-neoplastic disease, as folate deficiency may increase adverse effects. For those treated for neoplastic conditions, concurrent folic product administration may result in decreased efficacy of methotrexate.
Hepatotoxicity
•
Maintain a high level of suspicion, as methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure. Monitor liver tests at baseline, periodically during treatment, and as clinically indicated.
Infection
•
Use caution with live vaccines. Vaccinations should be in accordance to vaccination guidelines prior to initiating methotrexate therapy.
Infertility, menstrual irregularity
•
Use caution in patients (male or female) of child-bearing age.
Liver cirrhosis, ALF
•
Use caution in patients with alcoholism, alcoholic liver disease, or other chronic hepatic disease.
Myelosuppression
•
Maintain a high level of suspicion, as methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia. Obtain a CBC at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression.
Neurotoxicity
•
Use caution especially in patients who received prior cranial radiation, for severe acute or chronic neurotoxicity.
•
Maintain a high level of suspicion, as methotrexate can cause severe acute and chronic neurotoxicity, including leukoencephalopathy, for which the risk is increased in patients who received prior cranial radiation. Monitor patients for neurotoxicity.
Osteonecrosis
•
Use caution in patients with concurrent radiation therapy.
Pulmonary toxicity
•
Maintain a high level of suspicion, as methotrexate has been associated with pulmonary toxicity, including acute or chronic interstitial pneumonitis and irreversible or fatal cases. Monitor patients for pulmonary toxicity.
Renal failure
•
Use extreme caution in patients with renal impairment or renal disease or are receiving concurrent nephrotoxic drugs.
Renal toxicity
•
Maintain a high level of suspicion, as methotrexate can cause renal toxicity, including irreversible acute renal failure. Monitor renal function at baseline, periodically during treatment, and as clinically indicated.
Secondary lymphoproliferative disease
•
Maintain a high level of suspicion for lymphoproliferative disease in patients on low dose methotrexate. Discontinue methotrexate completely if lymphoproliferative disease is observed.
Serious infections
•
Maintain a high level of suspicion, as methotrexate increases the risk for developing life-threatening or fatal bacterial, fungal, or viral infections, including opportunistic infections. Monitor patients for infection during and after treatment.
Severe adverse reactions
•
Use extreme caution especially in patients with a weekly dosing regimen for dosing errors, as severe adverse reactions including death may occur.
Severe cutaneous adverse reactions
•
Maintain a high level of suspicion, as methotrexate has been associated with severe, including fatal dermatologic reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme. Monitor for dermatologic toxicity.
Skin cancer
•
Use extreme caution in all patients, especially in patients with psoriasis who received prior methotrexate and are on concomitant use of cyclosporine.
Tumor lysis syndrome
•
Use caution in patients with rapidly growing tumors.
Specific populations
Renal impairment
eGFR 20-50 mL/min/1.73 m²
•
Reduce dose by 50%. Monitor renal function.
eGFR 10-20 mL/min/1.73 m²
•
Reduce dose by 50%. Monitor renal function.
eGFR < 10 mL/min/1.73 m²
•
Do not use.
Renal replacement therapy
Continuous renal replacement
•
Dose as in eGFR 10-20 mL/min/1.73 m². Reduce dose by 50%. Monitor renal function.
Intermittent hemodialysis
•
Use with extreme caution. Reduce dose by 50%. Monitor renal function. Dose at least 12 hours before next dialysis.
Peritoneal dialysis
•
Do not use.
Hepatic impairment
Any severity
•
Reduce dose. Monitor serum aminotransferases. Monitor for toxicity. Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Reduce to 75% of dose. Bilirubin >5 mg/dL: Do not use.
Pregnancy and breastfeeding
Pregnancy
All trimesters • Australia Category: D
•
Avoid use. Evidence of fetal harm in humans. Methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. Discontinue methotrexate at least 6 months before conception. For non-neoplastic diseases, methotrexate is contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception.
Breastfeeding
Do not use during breastfeeding.
•
Do not breastfeed during treatment with methotrexate and for 1 week after the final dose.
Unknown drug levels in breastfed infants.
No overt adverse effects reported in breastfed infants.
Adverse reactions
Very common > 10%
•
Diarrhea, nausea, vomiting, stomatitis
Common 1-10%
•
Alopecia, anemia, ↓ WBC count, ↓ platelet count, hyperhidrosis, pancytopenia, photosensitivity of skin, pneumonitis, arthralgia, chest pain, cough, dizziness, dysuria, fever, headache, itching, loss of appetite, nosebleed, skin rash, tinnitus, vaginal discharge
Unknown frequency
•
Acne vulgaris, acute cystitis, acute pancreatitis, agranulocytosis, anaphylaxis, aphasia, aplastic anemia, ataxia, bone fracture, bradycardia, cerebral venous thrombosis, cognitive impairment, coma, conjunctivitis, ↓ blood neutrophil count, diabetes mellitus, dysarthria, ecchymosis, encephalopathy, erythema multiforme, exfoliative dermatitis, folate deficiency, gastrointestinal bleeding, gastrointestinal perforation, gingivitis, gynecomastia, hypotension, ↑ BUN, ↑ blood eosinophil count, ↑ blood glucose, ↑ urine protein, leukoencephalopathy, limb paresis, lymphadenopathy, lymphoma, ocular pain and inflammation, oligozoospermia, optic atrophy, optic neuritis, osteonecrosis, osteoporosis, pulmonary embolism, peptic ulcer disease, pericardial effusion, pericarditis, pharyngitis, phlebitis, premature ventricular contractions, pulmonary fibrosis, radiation recall reaction, renal failure, back pain, blurred vision, confusion, ↓ libido, erectile dysfunction, fatigue, hematemesis, hematuria, infertility, irritability, malaise, melena, myalgia, seizure, somnolence, visual disturbances, retinal thrombosis, skin ulceration, Stevens-Johnson syndrome, teratogenesis, thrombosis, toxic epidermal necrolysis, tumor lysis syndrome, urticaria, VT, vasculitis, vitamin B12 deficiency, vitamin B6 deficiency, xerophthalmia
Interactions
Drug(s)
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