What are the common side effects of Methotrexate (MTX)?

Methotrexate Side Effects

Most Common Side Effects

Gastrointestinal toxicity is the most frequently encountered side effect of methotrexate, including ulcerative stomatitis, nausea, vomiting, abdominal distress, diarrhea, and anorexia. 1

• Mucocutaneous effects such as stomatitis and mouth ulcers are very common early toxicities that can often be mitigated by altering the dose, route, or frequency of administration, or taking the medication with food 2
• Malaise, undue fatigue, chills, fever, and dizziness are also frequently reported 1
• Folic acid supplementation (1 mg daily or 5 mg weekly) is recommended to reduce gastrointestinal and hepatic adverse effects without compromising efficacy 3, 2

Serious and Potentially Life-Threatening Side Effects

Hematologic Toxicity

Bone marrow suppression is the leading cause of methotrexate-related death and generally occurs early in treatment (first 4-6 weeks), but is reversible with cessation. 2

• Pancytopenia can occur after even a single dose of methotrexate at any time during treatment, typically in patients with at least one risk factor 3, 2
• Major risk factors for hematologic toxicity include: 3, 2
  • Renal insufficiency (most important modifiable risk factor)
  • Advanced age
  • Lack of folate supplementation
  • Methotrexate dosing errors (daily instead of weekly dosing)
  • Drug interactions (NSAIDs, trimethoprim-sulfamethoxazole, penicillins)
  • Hypoalbuminemia
• Concurrent use of trimethoprim-sulfamethoxazole with methotrexate can be associated with severe toxicity due to both drugs being folic acid antagonists 2

Hepatotoxicity

Hepatotoxicity is a well-known side effect, though hepatic fibrosis and cirrhosis are considerably less common than initially reported. 3

• Transient liver enzyme elevations are common, especially within 3-4 days after dosing 2
• Long-term use can induce liver fibrosis or cirrhosis in a dose- and duration-dependent manner 2
• Risk factors for hepatotoxicity include: 3
  • History of or current greater than moderate alcohol consumption
  • Persistent abnormal liver chemistry findings
  • History of liver disease including chronic hepatitis B or C
  • Diabetes mellitus
  • Obesity
  • History of significant exposure to hepatotoxic drugs
  • Hyperlipidemia
• For patients without risk factors, liver biopsy should be considered after 3.5-4.0 g cumulative dose rather than 1.0-1.5 g 3
• For patients with risk factors, repeated liver biopsies should be performed after approximately 1.0-1.5 g of methotrexate 3

Pulmonary Toxicity

Pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression, with 30 of 164 reported methotrexate-associated fatalities caused by pulmonary fibrosis. 2, 4

• Dry, nonproductive cough is a common presenting symptom that requires interruption of treatment and careful investigation 4, 1
• The typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray 1
• Reduced diffusion capacity on pulmonary function tests is a diagnostic finding 4
• Risk factors include: 4
  • Renal impairment
  • Advanced age
  • Pre-existing pulmonary disease
• Patients with pulmonary diseases (asthma, chronic cough) may not be candidates for methotrexate and should undergo pulmonary function studies in consultation with a pulmonologist prior to drug initiation 3, 4
• This lesion can occur at all dosages 1

Renal Toxicity

Methotrexate may cause renal damage that may lead to acute renal failure, primarily due to precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. 1

• Nephrotoxicity occurs in 2-12% of patients receiving high-dose methotrexate 5
• Risk factors include history of renal dysfunction, volume depletion, acidic urine, and drug interactions 5
• Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and creatinine levels are essential 1

Infectious Complications

Immunosuppression increases susceptibility to infections and reactivation of latent tuberculosis and hepatitis. 2

• Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy 1
• Other reported infections include cytomegalovirus infection, sepsis (including fatal sepsis), nocardiosis, histoplasmosis, cryptococcosis, and Herpes zoster 1
• Immunization may be ineffective during methotrexate therapy, and immunization with live virus vaccines is generally not recommended 1

Neurologic Toxicity

Leukoencephalopathy has been reported following methotrexate administration, particularly in patients who have had craniospinal irradiation. 1

• Chronic leukoencephalopathy can manifest as confusion, irritability, somnolence, ataxia, dementia, seizures, and coma, and can be progressive and even fatal 1
• A transient acute neurologic syndrome (stroke-like encephalopathy) may include confusion, hemiparesis, transient blindness, seizures, and coma 1
• Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations 1

Dermatologic Toxicity

Severe, occasionally fatal, dermatologic reactions including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme have been reported within days of methotrexate administration. 1

• Reactions were noted after single or multiple low, intermediate, or high doses in patients with neoplastic and non-neoplastic diseases 1
• Other skin reactions include erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, and telangiectasia 1

Reproductive Toxicity

Methotrexate use is contraindicated during pregnancy and can cause defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects. 2, 1

• Fetal abnormalities have been reported after exposure at all gestational ages, but the critical period appears to be within the first 6-8 weeks of pregnancy 3
• Women of child-bearing age must be on contraception while taking methotrexate and should wait at least 3 months after discontinuation before attempting pregnancy 3

Lymphoproliferative Disorders

Lymphoproliferative disorders, including Epstein-Barr virus-associated B-cell lymphoma, are a potential side effect of methotrexate. 2

• Risk for skin cancer and lymphoma has been reported, though some cases of lymphoma have regressed on drug discontinuation 3

Critical Monitoring and Prevention Strategies

Laboratory Monitoring

Timing of labs is important—perform labs at least 4-6 days after dosing to avoid misinterpreting transient elevations. 2

• Monitor complete blood count and liver function tests monthly for the first 6 months, then every 1-3 months thereafter 3
• For liver function test elevations ≥2-fold but <3-fold upper limit of normal, closely monitor, repeat in 2-4 weeks, and decrease dose as needed 3
• For persistent elevations in 5/9 AST levels during a 12-month period or decline in serum albumin below normal range with normal nutritional status, liver biopsy should be performed 3

Management of Toxicity

For overdose or severe toxicity, leucovorin (folinic acid) rescue is the preferred antidote, along with maintenance of hydration and consideration of urine alkalinization. 2

• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects 6
• Glucarpidase has been licensed for treatment of high plasma methotrexate levels >1 μmol/L in patients with compromised renal function who have delayed methotrexate elimination 6
• Filgrastim can be used for toxic bone marrow suppression 2

Special Precautions

Methotrexate exits slowly from third space compartments (pleural effusions or ascites), resulting in prolonged terminal plasma half-life and unexpected toxicity. 1

• In patients with significant third space accumulations, evacuate the fluid before treatment and monitor plasma methotrexate levels 1
• Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation 1
• Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate 1