Methotrexate Side Effects
Methotrexate has numerous potential side effects ranging from common gastrointestinal symptoms to serious and potentially life-threatening complications affecting multiple organ systems, with the most concerning being bone marrow suppression, hepatotoxicity, and pulmonary toxicity.
Common Side Effects
Gastrointestinal
- Nausea and vomiting (occurs in up to 25% of patients, typically within 12-24 hours after dosing) 1
- Abdominal distress
- Diarrhea
- Stomatitis and oral ulcers
- Anorexia
General
- Fatigue and malaise
- Headache
- Dizziness
Serious Adverse Effects
Hepatotoxicity
- Transient elevation of liver enzymes (common)
- Fibrosis and cirrhosis (with long-term use) 1, 2
- Risk factors for hepatotoxicity include:
- Obesity (BMI ≥ 40 kg/m²)
- Diabetes
- Hyperlipidemia
- Greater than moderate alcohol consumption
- Pre-existing liver disease (hepatitis B/C)
- Family history of inheritable liver disease 1
Hematologic Toxicity
- Leukopenia
- Thrombocytopenia
- Pancytopenia (rare but potentially fatal)
- Anemia
- Increased risk with:
Pulmonary Toxicity
- Interstitial pneumonitis (can be acute or chronic)
- Pulmonary fibrosis
- Respiratory failure
- Symptoms include dry, nonproductive cough, dyspnea, fever, and hypoxemia 1, 2
- Risk factors include:
- Pre-existing lung disease
- Cigarette smoking
- Advanced age 3
Renal Effects
- Reduced renal function increases methotrexate toxicity
- Acute renal failure (particularly with high doses)
- Dose adjustment required for impaired renal function:
- GFR > 90 mL/min: Normal dose
- GFR 20-50 mL/min: Half dose
- GFR < 20 mL/min: Avoid methotrexate 1
Dermatologic
- Photosensitivity
- Skin ulceration
- Erythematous rashes
- Alopecia
- Severe reactions (rare): toxic epidermal necrolysis, Stevens-Johnson syndrome 2
Neurologic
- Headaches
- Drowsiness
- Blurred vision
- Cognitive dysfunction
- Leukoencephalopathy (with high doses or intrathecal administration) 2
Reproductive
- Teratogenic effects (contraindicated in pregnancy)
- Temporary oligospermia in men
- Women should wait at least 3 months after discontinuation before attempting conception
- Men should wait 3 months after discontinuation before attempting to father a child 1
Drug Interactions
Medications that may increase methotrexate toxicity include:
- NSAIDs (salicylates, naproxen, ibuprofen)
- Antibiotics (trimethoprim/sulfamethoxazole, penicillins, sulfonamides)
- Probenecid
- Certain diuretics (furosemide, thiazides) 1, 3
Monitoring Recommendations
- Complete blood count, liver function tests, and renal function should be monitored:
- Every 2-4 weeks initially
- Every 3-6 months once stable on therapy 1
- Laboratory tests should be performed 4-6 days after dosing (not immediately after) 1
- Patients with risk factors for hepatotoxicity should have annual non-invasive liver fibrosis assessment 1
Risk Mitigation
- Folic acid supplementation (1-5 mg daily except on the day of methotrexate) reduces nausea, stomatitis, and hepatic adverse effects 1
- Taking medication before bedtime or with food may reduce nausea 1
- Antiemetics (ondansetron, granisetron) can help manage nausea 1
- Parenteral (subcutaneous) administration may reduce gastrointestinal side effects 1
- Complete abstinence from alcohol is advised during therapy 3
Special Considerations
- Pediatric patients generally tolerate methotrexate well with appropriate monitoring 1
- Elderly patients and those with renal impairment require closer monitoring and potentially dose reduction
- Test dose (1.25-5 mg) may be considered in patients with risk factors for toxicity 1
By understanding these potential side effects and implementing appropriate monitoring, many adverse events can be detected early and managed effectively, allowing patients to benefit from methotrexate therapy while minimizing risks.