What are the common adverse effects of methotrexate?

Common Adverse Effects of Methotrexate

The most common adverse effects of methotrexate include gastrointestinal symptoms (nausea, vomiting, abdominal distress), ulcerative stomatitis, leukopenia, elevated liver enzymes, fatigue, and increased risk of infections. 1

Gastrointestinal and Mucosal Effects

• Gastrointestinal effects: Nausea, vomiting, and abdominal distress occur frequently and can lead to discontinuation of therapy 1, 2
• Stomatitis/Oral ulcers: Common mucosal side effect that can be distressing for patients 1
• Other GI effects: Diarrhea, anorexia, and in rare cases, hemorrhagic enteritis 1

These GI side effects often occur shortly after initiating methotrexate and can be mitigated by:

• Changing from oral to subcutaneous or intramuscular administration 2
• Taking medication with food 2
• Folic acid supplementation (reduces incidence of GI and hepatic adverse effects) 2, 3
• Pre-emptive use of antiemetics like ondansetron for nausea/vomiting 2

Hepatotoxicity

Methotrexate commonly causes liver-related adverse effects:

• Transient liver enzyme elevations: Occur in up to 30% of patients 2
• Long-term concerns: Hepatic fibrosis and cirrhosis with prolonged use 1, 2
• Risk factors for hepatotoxicity: 4
  • Alcohol consumption
  • Obesity (BMI ≥40 kg/m²)
  • Diabetes mellitus
  • Hyperlipidemia
  • Pre-existing liver disease
  • Cumulative dose (particularly after 3.5-4.0 g)

Monitoring recommendations:

• Liver function tests every 3-6 months for low-risk patients 2
• More frequent monitoring for high-risk patients 2
• Consider non-invasive fibrosis assessment for patients on long-term therapy 2

Hematologic Effects

• Bone marrow suppression: Can manifest as leukopenia, thrombocytopenia, anemia, or pancytopenia 1
• Risk factors: Renal impairment, concomitant medications (especially trimethoprim-sulfamethoxazole), advanced age 1, 5

Pulmonary Toxicity

• Pneumonitis: Rare but potentially serious complication with acute or chronic interstitial pneumonitis 1
• Symptoms: Dry, nonproductive cough, dyspnea, fever 1
• Risk: Higher in patients with underlying lung disease 1

Infection Risk

• Increased susceptibility: Due to immunosuppressive effects 2
• Opportunistic infections: Including Pneumocystis carinii pneumonia 1
• Reactivation risk: For latent tuberculosis, hepatitis B and C 2

Other Adverse Effects

• Fatigue and malaise: Common complaints that can affect quality of life 1
• Neurological: Headache, dizziness, cognitive dysfunction with long-term use 1
• Dermatologic: Rash, photosensitivity, alopecia 1
• Reproductive: Contraindicated during pregnancy due to teratogenic effects; requires discontinuation at least 3 months before planned pregnancy 2

Monitoring and Prevention Strategies

1. Baseline screening:

   • Complete blood count
   • Liver and renal function tests
   • Hepatitis B/C screening in high-risk patients
   • Tuberculosis testing when appropriate 2

2. Ongoing monitoring:

   • Regular liver function tests every 3-6 months 2
   • Complete blood counts at similar intervals 2
   • Prompt evaluation of new respiratory symptoms 1

3. Risk reduction:

   • Folic acid supplementation (reduces GI, hepatic, and hematologic toxicity) 3
   • Alcohol limitation or avoidance 2
   • Avoiding concomitant hepatotoxic medications when possible 2
   • Consider route change (subcutaneous instead of oral) if GI side effects are problematic 2

Special Considerations

• Pregnancy: Absolutely contraindicated during pregnancy and breastfeeding; women should wait at least 3 months after discontinuation before attempting conception 2
• Male fertility: Men should also discontinue methotrexate at least 3 months before planned conception 2
• Elderly patients: May have increased risk of toxicity due to decreased renal function 1

By understanding these common adverse effects and implementing appropriate monitoring strategies, the risks associated with methotrexate therapy can be significantly reduced while maintaining its therapeutic benefits.