What are the potential side effects of methotrexate?

From the Guidelines

Methotrexate can cause several side effects ranging from mild to severe, including nausea, vomiting, mouth sores, stomach pain, headache, dizziness, fatigue, and hair thinning, with more concerning side effects involving the liver, lungs, bone marrow suppression, and increased risk of infections, as reported in the most recent study by 1. The most common side effects of methotrexate include:

• Nausea and vomiting
• Mouth sores
• Stomach pain
• Headache
• Dizziness
• Fatigue
• Hair thinning More concerning side effects involve:
• Liver damage, with elevated liver enzymes and potential liver damage, particularly in patients with risk factors such as obesity, diabetes, and hyperlipidemia, as noted in 1
• Lung inflammation, including pneumonitis, as reported in 1
• Bone marrow suppression, leading to low blood counts, including anemia, leukopenia, and thrombocytopenia, as discussed in 1
• Increased risk of infections, particularly in patients with compromised immune systems, as mentioned in 1 Long-term use of methotrexate may also cause kidney problems, and serious but rare side effects include severe skin reactions and neurological issues, as noted in 1. Methotrexate is also highly teratogenic, meaning it can cause birth defects, so pregnancy must be avoided during treatment, as emphasized in 1. The risk of side effects increases with higher doses, and can be reduced by taking folic acid supplements, typically 1mg daily, which helps prevent some adverse effects without reducing therapeutic benefits, as reported in 1. Regular blood monitoring is essential during methotrexate therapy to detect potential problems early, and patients should avoid alcohol while taking methotrexate, as this combination increases the risk of liver damage, as noted in 1.

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 potential side effects of methotrexate include:

• Gastrointestinal issues: nausea, vomiting, diarrhea, stomatitis, and gastrointestinal ulceration
• Hematologic disorders: anemia, aplastic anemia, pancytopenia, leukopenia, and thrombocytopenia
• Hepatotoxicity: acute hepatitis, chronic fibrosis, and cirrhosis
• Infections: opportunistic infections, pneumonia, and sepsis
• Musculoskeletal issues: stress fracture
• Ophthalmic issues: conjunctivitis and visual changes
• Pulmonary issues: respiratory fibrosis, respiratory failure, and interstitial pneumonitis
• Skin issues: rashes, pruritus, urticaria, and skin necrosis
• Urogenital issues: nephropathy, renal failure, and infertility 2 Additionally, methotrexate can cause:
• Neurotoxicity: seizures, headaches, and cognitive dysfunction
• Cardiovascular issues: pericarditis, hypotension, and thromboembolic events 2 It is essential to closely monitor patients for these potential side effects, especially in the elderly and those with preexisting medical conditions 2

From the Research

Methotrexate Side Effects

The potential side effects of methotrexate are numerous and can be severe. Some of the known side effects include:

• Bone marrow suppression
• Pulmonary toxicity
• Nephrotoxicity
• Hematologic toxicity
• Increased risk of infections
• Nausea
• Oral ulcers
• Anemia
• Pancytopenia
• Macular punctate rash
• Severe stomatitis
• Leukopenia
• Thrombocytopenia
• Liver toxicity, including elevated liver enzymes and liver dysfunction
• Renal impairment and kidney failure

Organ-Specific Side Effects

Methotrexate can affect various organs, including:

• Kidneys: nephrotoxicity, renal impairment, and kidney failure 3, 4
• Liver: liver toxicity, elevated liver enzymes, and liver dysfunction 3, 5, 4
• Bone marrow: bone marrow suppression, leukopenia, and thrombocytopenia 3, 6
• Lungs: pulmonary toxicity 3

Risk Factors and Prevention

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

• High doses of methotrexate 3
• Renal deficiency or compromised renal function 3, 4
• Concomitant use of other medications, such as non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen 4
• Prior excessive alcohol consumption or chronic hepatitis B or C infection 5 To reduce the risk of side effects, patients should be closely monitored, and dosage adjustments should be made as necessary 3, 5, 4. Leucovorin can be used to prevent or treat myelosuppression, gastric toxicity, and neurotoxic effects 3, 6.