Side Effects of Methotrexate
Common Side Effects (Occur Shortly After Initiation)
The most frequently reported adverse effects of methotrexate include gastrointestinal symptoms (nausea, anorexia, stomatitis), fatigue, and malaise, which typically occur shortly after medication initiation. 1, 2
- Gastrointestinal toxicity occurs in approximately 30-32% of patients and includes ulcerative stomatitis, nausea, vomiting, abdominal distress, diarrhea, and anorexia 1, 2
- Constitutional symptoms such as fatigue, malaise, chills, fever, and dizziness are frequently reported 2
- Oral manifestations including gingivitis, pharyngitis, and mouth ulceration are common early warning signs 1, 2
- Transient hepatic transaminase elevations occur commonly, especially 3-4 days after dosing, which is why laboratory monitoring should be performed at least 4-6 days after dosing 1
Management of Common Side Effects
- Alterations in dose, route (oral to subcutaneous or intramuscular), or frequency of administration (splitting the weekly dose over 24 hours) can mitigate these effects 1
- Taking medication with food or at bedtime helps reduce gastrointestinal symptoms 1
- Mandatory folic acid supplementation (1-5 mg daily, except on methotrexate day, or 5 mg weekly) reduces gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy 1, 3
Life-Threatening Major Toxicities
Bone Marrow Suppression (Most Lethal Complication)
Myelosuppression accounts for the majority of methotrexate-associated fatalities (67 out of 164 reported deaths), making hematologic toxicity the most lethal complication. 3, 4
- Manifestations include leukopenia, neutropenia, thrombocytopenia, anemia, pancytopenia, and aplastic anemia 2
- Timing: Bone marrow suppression generally occurs early in treatment (first 4-6 weeks) and is reversible with cessation of methotrexate 1
- Risk factors: Medications that interfere with folic acid metabolism (trimethoprim-sulfamethoxazole) and NSAIDs that decrease renal clearance markedly increase bone marrow toxicity 1
- Management: Withhold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 3, 4
- For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily 3, 4
Hepatotoxicity
Long-term methotrexate use can induce liver damage, potentially leading to fibrosis or cirrhosis, though methotrexate-induced cirrhosis is not aggressive. 1, 5
- Monitoring approach: Liver function tests should be monitored every 3-6 months assuming no abnormalities 1
- For elevations <3-fold the upper limit of normal, repeat in 2-4 weeks 1
- For persistent elevations during a 12-month period or decline in serum albumin below normal range, GI consultation and/or vibration-controlled transient elastography (FibroScan) should be considered 1
- High-risk patients (BMI >28 kg/m² or alcohol intake >14 drinks/week) require baseline FibroScan screening 3
- After 3.5-4.0 g cumulative dose, consider liver biopsy based on GI consultation and/or FibroScan 1
- Baseline liver biopsy is not recommended regardless of risk factors 3
Pulmonary Toxicity
Pulmonary fibrosis accounts for 30 of 164 methotrexate-associated fatalities, though pneumonitis is more commonly seen in rheumatoid arthritis and rarely occurs in psoriasis. 1, 3
- Manifestations: Interstitial pneumonitis presenting with dyspnea, dry cough, fever, and respiratory failure 1, 2
- A systematic review found methotrexate was not associated with significant increase in respiratory infections or adverse respiratory events (RR 1.03,95% CI 0.90-1.17), with no pulmonary deaths 1
- Baseline chest x-ray should be obtained for all patients starting methotrexate 3
- Pulmonary symptoms usually resolve with discontinuation of methotrexate 3
Immunosuppression and Infection Risk
Given the immunosuppressive nature of methotrexate, treatment increases the risk of infection, reactivation of latent tuberculosis, hepatitis, and lymphoma (especially Epstein-Barr virus-associated B-cell lymphoma). 1
- Opportunistic infections reported include Pneumocystis carinii pneumonia (most common), cytomegalovirus infection, sepsis (sometimes fatal), nocardiosis, histoplasmosis, cryptococcosis, and disseminated herpes simplex 2
- Hepatitis B and C screening and baseline tuberculosis testing (PPD, T-Spot, or QuantiFERON Gold) should be considered based on individual risk factors 1
- Serious infections appear rare and may be less frequent compared with some biologic agents 1
Other Significant Adverse Effects
Dermatologic
- Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, acne, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, and exfoliative dermatitis 1, 2
- Epidermal necrolysis is a rare but potentially devastating consequence 1
Cardiovascular
- Pericarditis, pericardial effusion, hypotension, and thromboembolic events (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, pulmonary embolus) 2
Neurologic
- Headaches, drowsiness, blurred vision, transient blindness, speech impairment (dysarthria, aphasia), hemiparesis, paresis, and convulsions 2
- Transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy following low doses 2
Renal
- Severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria 2
- Nephrotoxicity results from crystallization of methotrexate in renal tubular lumen, leading to tubular toxicity 6
Reproductive
- Methotrexate is contraindicated during pregnancy (Category X drug) 1
- Fetal abnormalities reported after exposure at all gestational ages, with critical period being first 6-8 weeks of pregnancy 1
- Women should wait at least 3 months (some sources recommend 6 months) after discontinuation before attempting pregnancy 1, 3
- Men should wait 3 months after discontinuation before attempting conception 3
- Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects 2
Critical Drug Interactions
Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk. 3, 5
- NSAIDs reduce renal elimination of methotrexate, particularly dangerous at any dose 1, 3
- Proton pump inhibitors (omeprazole, esomeprazole, pantoprazole) may decrease methotrexate clearance and cause toxicity even at low doses (10 mg/week) 7
- Other high-risk interactions include salicylates, sulfonamides, phenylbutazone, phenytoin, penicillins, probenecid, and colchicine 3, 5
Risk Factors for Increased Toxicity
- Renal insufficiency (primary risk factor due to 85% renal excretion) 1, 3, 6
- Advanced age (>50-70 years) significantly increases toxicity risk 1, 3
- Lack of folate supplementation (common preventable risk factor) 1, 3
- Hypoalbuminemia 1
- Volume depletion and acidic urine 6
- Dosing errors (mistakenly taking weekly dose daily) 8, 9
Monitoring Requirements
Regular laboratory monitoring is essential, including complete blood count, hepatic transaminases, and creatinine, with timing at least 4-6 days after dosing to avoid making adjustments based on transient elevations. 1