What are the side effects of Methotrexate?

From the Guidelines

Methotrexate can cause several side effects, and it's essential to be aware of them to ensure safe use.

Common Side Effects

• Nausea
• Anorexia
• Stomatitis
• Fatigue 1 that most often occur at the time of methotrexate administration.

Less Common but More Severe Side Effects

• Myelosuppression
• Hepatotoxicity
• Pulmonary fibrosis 1 To minimize risks, it's recommended to take the lowest effective dose, typically ranging from 2.5 to 25 milligrams per week, and to monitor blood counts and liver function regularly 1.

Important Considerations

Patients should also avoid taking other medications that may interact with methotrexate, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and certain antibiotics 1. Additionally, individuals with pre-existing kidney or liver disease, or those who are pregnant or breastfeeding, should use methotrexate with caution and under close medical supervision 1. Regular laboratory monitoring (CBC and liver function tests) should be performed every 3 to 6 months, assuming no abnormalities in laboratory test results 1. Periodic renal monitoring should be considered in patients with poor renal function 1. A noninvasive baseline liver fibrosis assessment is recommended before starting treatment with methotrexate 1. Annual GI/hepatology referral or vibration-controlled transient elastography, or both, should be performed if methotrexate is continued despite abnormal baseline liver fibrosis laboratory results 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 side effects of Methotrexate include:

• Gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal distress, ulcerative stomatitis
• Hematologic disorders: leukopenia, anemia, thrombocytopenia, agranulocytosis
• Infections: opportunistic infections, pneumonia, sepsis
• Hepatobiliary disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis
• Neurologic symptoms: headaches, drowsiness, blurred vision, transient blindness, speech impairment
• Pulmonary symptoms: respiratory fibrosis, respiratory failure, interstitial pneumonitis
• Skin reactions: erythematous rashes, pruritus, urticaria, photosensitivity, toxic epidermal necrolysis, Stevens-Johnson syndrome
• Urogenital symptoms: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria 2

From the Research

Side Effects of Methotrexate

The side effects of methotrexate can be significant, with up to 60% of patients discontinuing treatment due to adverse effects, most of which occur during the first year of therapy 3. Some of the common side effects include:

• Gastrointestinal complications
• Hepatotoxicity
• Haematological toxicity
• Pulmonary toxicity
• Lymphoproliferative disorders
• Exacerbation of rheumatic nodules

Toxicity and Risk Factors

Methotrexate toxicity can be increased in patients with poor renal function, as the drug is eliminated almost entirely by the kidneys 3, 4. Declining renal function with age may be an important predictor of toxicity to methotrexate 3. Other risk factors for toxicity include:

• Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or other medications that interact with methotrexate 3, 5
• Pre-existing liver or kidney disease
• Older age

Serious Toxicities

More serious toxicities, such as pancytopenia, may result when other inhibitors of folate utilization or inhibitors of renal tubular secretion are combined with methotrexate 3. High-dose methotrexate can produce toxicity and side effects such as bone marrow suppression, pulmonary toxicity, nephrotoxicity, hematologic toxicity, and an increased risk of infections 4.

Monitoring and Prevention

To minimize the risk of toxicity, patients should be monitored regularly with blood counts, liver function tests, and renal function tests 3, 6. Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity 3. Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity 3.