Methotrexate Side Effects and Management

Introduction to Methotrexate Toxicity

The American Academy of Dermatology reports that methotrexate can cause gastrointestinal toxicity, including ulcerative stomatitis, nausea, vomiting, abdominal distress, diarrhea, anorexia, and GI ulceration 1
The American Academy of Dermatology also notes that mucocutaneous effects, such as stomatitis and mouth ulcers, are very common early toxicities 1
Altering the dose, route, or frequency of administration, or taking the medication with food, can often mitigate these common toxicities 1

Bone marrow suppression generally occurs early in treatment (first 4-6 weeks) and is reversible with cessation, according to the American Academy of Dermatology 2
The American Academy of Dermatology and the British Journal of Dermatology report that risk of bone marrow suppression is increased by medications that interfere with folic acid metabolism and NSAIDs that decrease renal clearance 2, 3
Liver enzyme elevations are common, especially transient increases within 3-4 days after dosing, as reported by the American Academy of Dermatology 1, 2
Long-term use can induce liver fibrosis or cirrhosis, though this is dose- and duration-dependent, according to the Journal of Microbiology, Immunology and Infection and the American Academy of Dermatology 4, 1
The American Academy of Dermatology notes that immunosuppression increases susceptibility to infections and reactivation of latent tuberculosis and hepatitis 1
The Journal of Microbiology, Immunology and Infection reports that methotrexate can cause reproductive side effects, including defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects 4
The American Academy of Dermatology notes that lymphoproliferative disorders, including Epstein-Barr virus-associated B-cell lymphoma, are a potential side effect of methotrexate 1

The American Academy of Dermatology recommends folic acid supplementation (1 mg daily or 5 mg weekly) to reduce hepatic abnormalities and GI adverse effects without compromising efficacy 1
The British Journal of Dermatology suggests that for overdose or severe toxicity, leucovorin (folinic acid) rescue, maintenance of hydration, and consideration of urine alkalinization may be necessary 3
The British Journal of Dermatology also notes that filgrastim can be used for toxic bone marrow suppression 3
The American Academy of Dermatology reports that timing of labs is important, and recommends performing labs at least 4-6 days after dosing to avoid misinterpreting transient elevations 2

Methotrexate-induced pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression 5
Drug interactions with methotrexate usually occur due to altered pharmacokinetic effects, such as displacement of protein binding and reduced renal elimination 6
Concomitant use of NSAIDs can reduce renal elimination of methotrexate, leading to toxicity 6
Renal impairment significantly increases the risk of methotrexate toxicity, including pulmonary manifestations 5
Advanced age is a risk factor for increased toxicity 5
Pre-existing pulmonary disease increases the risk of pulmonary toxicity 5

Common toxicities include fatigue, anorexia, nausea, and stomatitis 7
Dry, nonproductive cough is a common presenting symptom 5
Reduced diffusion capacity on pulmonary function tests is a diagnostic finding 5
Regular laboratory monitoring is essential to detect early signs of toxicity 8
Baseline chest x-ray should be obtained for all patients starting methotrexate 5
Folate supplementation may reduce some methotrexate toxicities 5
Methotrexate toxicity should be suspected in any patient on this medication who develops new mucocutaneous lesions or respiratory symptoms 5

Pancytopenia can result after even a single dose of methotrexate and can occur at any time during treatment, typically in patients with at least one risk factor, according to the American Academy of Dermatology 9, 10
Obtain urgent complete blood count with differential to confirm neutropenia, as recommended by the American Academy of Dermatology 9, 10, 11

Renal insufficiency is a major modifiable risk factor for methotrexate-induced myelosuppression, as noted by the American Academy of Dermatology 10
Advanced age is a risk factor for methotrexate-induced myelosuppression, according to the American Academy of Dermatology 11
Methotrexate dosing errors, such as daily instead of weekly dosing, can increase the risk of myelosuppression, as reported by the American Academy of Dermatology 11
Drug interactions, including NSAIDs, trimethoprim-sulfamethoxazole, and penicillins, can increase the risk of methotrexate-induced myelosuppression, as noted by the American Academy of Dermatology 11
Hypoalbuminemia is a risk factor for methotrexate-induced myelosuppression, according to the American Academy of Dermatology 10
Folic acid deficiency is a risk factor for methotrexate-induced myelosuppression, as reported by the American Academy of Dermatology 11
The concurrent use of trimethoprim-sulfamethoxazole with methotrexate can be associated with severe toxicity due to both drugs being folic acid antagonists, as noted by the American Academy of Dermatology 12

Reduced renal elimination of methotrexate by trimethoprim occurs within hours of Bactrim administration, leading to elevated methotrexate levels, as noted by the Thorax journal 13

For urinary tract infections or other bacterial infections, select antibiotics that do not interfere with methotrexate metabolism or renal elimination, as suggested by the Thorax journal 13

GI symptoms typically occur within 12-24 hours of medication consumption and are dose-dependent, according to the British Journal of Dermatology 14
Taking methotrexate with food or at bedtime can minimize GI symptoms, as recommended by the British Journal of Dermatology 14
Switching to parenteral administration may reduce nausea and other GI symptoms, as suggested by the British Journal of Dermatology 14

Diabetes mellitus is listed as a relative contraindication for methotrexate use, requiring careful monitoring, as stated by the Journal of the American Academy of Dermatology 15
Methotrexate is 85% renally excreted, so any diabetes-related renal impairment increases toxicity risk, according to the Journal of the American Academy of Dermatology 15 and the British Journal of Dermatology 14
Dose reduction is required if creatinine clearance falls between 20-50 mL/min, and methotrexate should be avoided if <20 mL/min, as recommended by the British Journal of Dermatology 14

Symptoms appearing 6-23 days after dosing may indicate methotrexate overdose, as reported by the British Journal of Dermatology 16