Can Methotrexate Cause Diarrhea?
Yes, methotrexate can cause diarrhea as part of its gastrointestinal toxicity profile, and this can range from mild to life-threatening severity requiring immediate drug discontinuation.
Gastrointestinal Toxicity Overview
Methotrexate commonly causes gastrointestinal adverse effects, which are among the most frequent reasons for treatment discontinuation 1. The FDA drug label explicitly lists diarrhea as a reported adverse reaction 2. When diarrhea occurs alongside vomiting or stomatitis and results in dehydration, methotrexate must be discontinued immediately until recovery 2.
Severity Spectrum
Mild to Moderate GI Effects
- Nausea and abdominal distress are among the most frequently reported adverse reactions with methotrexate 2
- These symptoms typically occur within 12-24 hours of medication consumption and are dose-dependent 3
- Gastrointestinal adverse effects may be better tolerated when the weekly dose is divided into 3 doses given every 12 hours 3
Severe and Life-Threatening Enteropathy
- Methotrexate can cause severe apoptotic enteropathy with watery diarrhea leading to hypovolemic shock 4
- This life-threatening complication has been documented even without dose changes, including when switching from oral to intramuscular routes 4
- Severe diarrhea may be accompanied by mucositis and can indicate methotrexate toxicity requiring urgent intervention 5
Risk Factors for GI Toxicity
The following increase risk of severe gastrointestinal complications:
- Renal dysfunction - methotrexate is primarily renally excreted, and impaired clearance dramatically increases toxicity risk 2, 5
- Accidental daily dosing instead of weekly dosing 5
- Concurrent use of interacting medications (NSAIDs, antibiotics, proton pump inhibitors) 6
- Hypoalbuminemia and polypharmacy 5
- Dehydration from vomiting or diarrhea creating a vicious cycle of worsening toxicity 7
Management Strategies
Prevention
- Folic acid supplementation (1-5 mg daily on non-methotrexate days) reduces gastrointestinal adverse effects 3
- Taking medication before bedtime or with food may reduce nausea 3
- Consider subcutaneous administration, which may reduce GI side effects compared to oral dosing 3, 8
When to Stop Methotrexate
- Immediately discontinue if diarrhea causes dehydration 2
- Stop during acute illness, infection, or hospitalization when GI symptoms develop 6
- Withhold if severe mucositis or enteritis develops 6
Treatment of Toxicity
- Leucovorin (folinic acid) rescue for significant toxicity 8, 5
- Hydration and urine alkalinization 5
- Monitor complete blood count, as GI toxicity may accompany bone marrow suppression 8, 2
Critical Pitfalls
The most dangerous scenario is when diarrhea develops in the context of methotrexate toxicity - this can indicate severe enteropathy requiring immediate cessation and rescue therapy 4. Do not dismiss diarrhea as a minor side effect; assess for concurrent mucositis, fever, or signs of dehydration which suggest serious toxicity 6. Patients with renal impairment are at exponentially higher risk and require dose reduction (50% reduction for creatinine clearance 20-50 mL/min) or complete avoidance (creatinine clearance <20 mL/min) 3, 8.