What are the side effects of methotrexate (MTX)?

From the Guidelines

Methotrexate can cause numerous side effects, and it is essential to monitor patients closely, especially those with risk factors, to minimize the risk of severe side effects, as recommended by the most recent guidelines 1. Methotrexate side effects can range from mild to severe, including common side effects such as nausea, vomiting, mouth sores, stomach pain, headache, dizziness, fatigue, and hair thinning. More concerning side effects involve the liver (elevated liver enzymes, hepatotoxicity), lungs (pneumonitis, shortness of breath), bone marrow (decreased blood cell counts leading to anemia, infections, or bleeding), and kidneys (reduced kidney function). Methotrexate can also cause photosensitivity, making skin more vulnerable to sunburn. Serious but rare side effects include severe skin reactions and neurological problems. The risk of side effects increases with higher doses and longer treatment duration. Methotrexate works by inhibiting folate metabolism, which explains many of its side effects, and taking folic acid supplements (typically 1mg daily except on methotrexate days) can reduce some adverse effects without compromising treatment efficacy, as supported by previous studies 1. Some key points to consider when prescribing methotrexate include:

• Monitoring liver function tests every 4 weeks, especially in patients with risk factors for hepatotoxicity, such as obesity, diabetes, and hyperlipidemia 1.
• Assessing renal function and adjusting the dose accordingly, as patients with significant renal impairment are at risk of toxicity, even with single doses of methotrexate 1.
• Avoiding alcohol consumption to reduce the risk of liver toxicity, as moderate alcohol use can increase the risk of hepatotoxicity 1.
• Informing patients to report any new symptoms, particularly unexplained cough, shortness of breath, unusual bleeding, or yellowing of the skin, to detect potential problems early 1. Regular blood monitoring is essential during methotrexate therapy to detect potential problems early, and patients should be educated on the signs and symptoms of severe side effects to ensure prompt medical attention if needed. It is also crucial to consider the patient's individual risk factors, such as renal insufficiency, advanced age, and concomitant use of other medications, when prescribing methotrexate, as these factors can increase the risk of toxicity, as highlighted in the guidelines 1. By carefully monitoring patients and adjusting the treatment plan as needed, healthcare providers can minimize the risk of severe side effects and optimize the benefits of methotrexate therapy.

From the FDA Drug Label

ADVERSE REACTIONS IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Other adverse reactions that have been reported with methotrexate are listed below by organ system In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult. Alimentary System - gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis Blood and Lymphatic System Disorders - suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely Cardiovascular - pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus) Central Nervous System - headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders - hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, hepatic failure, decrease in serum albumin, liver enzyme elevations Infection - There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection There have also been reports of infections, pneumonia, Cytomegalovirus infection, including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex. Musculoskeletal System - stress fracture. Ophthalmic - conjunctivitis, serious visual changes of unknown etiology Pulmonary System – respiratory fibrosis, respiratory failure, alveolitis, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred Skin - erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis Urogenital System - severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal death, fetal defects

The side effects of methotrexate include:

• Gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal distress, and stomatitis
• Hematologic effects: leukopenia, anemia, thrombocytopenia, and agranulocytosis
• Infections: opportunistic infections, such as Pneumocystis carinii pneumonia, and reactivation of latent infections
• Hepatotoxicity: liver enzyme elevations, acute hepatitis, and chronic fibrosis
• Neurologic effects: headaches, drowsiness, blurred vision, and seizures
• Dermatologic reactions: rash, pruritus, and skin necrosis
• Renal effects: nephropathy, renal failure, and azotemia
• Reproductive effects: infertility, abortion, and fetal defects 2

From the Research

Methotrexate Side Effects

Methotrexate is a commonly used medication for the treatment of rheumatoid arthritis and other rheumatic diseases. However, it can cause several side effects, including:

• Gastrointestinal complications, which are the most common adverse effects of methotrexate 3
• Hepatotoxicity, which can be minimized or prevented with careful monitoring of patients' symptoms and laboratory tests 4
• Haematological toxicity, which can be reduced with folic acid supplementation 3, 5
• Pulmonary toxicity, which is a rare but serious side effect of methotrexate 3, 4
• Lymphoproliferative disorders, which can occur in patients taking methotrexate, especially those with reduced renal function 3
• Exacerbation of rheumatic nodules, which can occur in patients with rheumatoid arthritis taking methotrexate 3

Risk Factors for Methotrexate Side Effects

Several factors can increase the risk of methotrexate side effects, including:

• Poor renal function, which can lead to drug accumulation and increased risk of toxicity 3
• Age, as declining renal function with age can increase the risk of toxicity 3
• Concomitant use of other medications, such as nonsteroidal anti-inflammatory drugs, which can increase the risk of toxicity 3
• Reduced renal function, which can increase the risk of hepatotoxicity, lymphoproliferative disorders, and haematological toxicity 3

Prevention and Management of Methotrexate Side Effects

Several strategies can help prevent and manage methotrexate side effects, including:

• Regular laboratory testing, such as blood counts and liver function tests, to monitor for toxicity 3, 6
• Folic acid supplementation, which can reduce the risk of haematological toxicity and other side effects 3, 5
• Close monitoring of patients' symptoms and laboratory tests to minimize or prevent toxicity 4
• Adjustment of methotrexate dosage or discontinuation of the medication if side effects occur 3