What are the potential side effects of Methotrexate (methotrexate) in patients with various demographics and medical histories, including those with pre-existing liver or kidney disease?

Methotrexate Side Effects

Most Common Side Effects

The most frequently reported adverse reactions to methotrexate include ulcerative stomatitis, leukopenia, nausea, and abdominal distress, with gastrointestinal symptoms occurring in approximately 30-32% of patients. 1, 2

Other common side effects include:

• Malaise and undue fatigue 1
• Chills and fever 1
• Dizziness 1
• Decreased resistance to infection 1
• Stomatitis and oral ulcers 3, 1
• Alopecia (hair loss, though rare) 3

Life-Threatening Toxicities

Hematologic Toxicity

Myelosuppression accounts for the majority (67 out of 164) of methotrexate-associated fatalities, making hematologic toxicity the most lethal complication. 2

• Pancytopenia, leukopenia, neutropenia, thrombocytopenia, and aplastic anemia can occur even after single doses 3, 1
• Risk is highest in patients with renal impairment, advanced age (>70 years), lack of folate supplementation, and concurrent use of trimethoprim-sulfamethoxazole or NSAIDs 4, 2
• Pancytopenia may occur 4-6 weeks after dose increases 3

Hepatotoxicity

Hepatotoxicity ranges from asymptomatic transaminase elevations (most common) to fibrosis, cirrhosis, and fatal hepatic necrosis, though severe liver disease is considerably less common than initially reported. 3, 1

Risk factors for hepatotoxicity include:

• Alcohol consumption (>1 drink/day for women, >2 drinks/day for men) 3, 5
• Obesity 3
• Diabetes mellitus 3
• Pre-existing liver disease 3
• Hyperlipidemia 3
• History of hepatotoxic drug exposure 3

Modern studies show hepatic fibrosis and cirrhosis are considerably less common than initially reported, with hepatotoxicity being more common in psoriasis patients than rheumatoid arthritis patients. 3, 5

Pulmonary Toxicity

Pulmonary toxicity, including interstitial pneumonitis and respiratory fibrosis, accounts for 30 of 164 methotrexate-associated fatalities and typically presents with dry nonproductive cough, dyspnea, fever, and infiltrates on chest X-ray. 2, 1

• This complication can occur at all dosages 1
• Infection (including Pneumocystis carinii pneumonia) must be excluded 1
• Pulmonary symptoms require immediate interruption of treatment and careful investigation 1

Renal Toxicity

Methotrexate can cause severe nephropathy, acute renal failure, and azotemia, particularly with high doses due to precipitation of methotrexate and 7-hydroxymethotrexate in renal tubules. 1, 6

Organ System-Specific Side Effects

Gastrointestinal

• Gingivitis, pharyngitis, anorexia, vomiting, diarrhea 1
• Gastrointestinal ulceration and bleeding, enteritis 1
• Pancreatitis 1
• Hematemesis and melena 1

Cardiovascular

• Pericarditis and pericardial effusion 1
• Thromboembolic events including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, pulmonary embolus 1

Neurologic

• Headaches, drowsiness, blurred vision, transient blindness 1
• Speech impairment (dysarthria and aphasia), hemiparesis, seizures 1
• Leukoencephalopathy or encephalopathy (particularly after craniospinal irradiation) 1
• Transient cognitive dysfunction, mood alteration 1

Dermatologic

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 administration. 1

• Photosensitivity and "radiation recall" 3, 1
• Erythematous rashes, pruritus, urticaria 1
• Pigmentary changes, acne, telangiectasia 1

Infectious Complications

Potentially fatal opportunistic infections may occur, with Pneumocystis carinii pneumonia being the most common. 1

Other reported infections include:

• Cytomegalovirus infection and pneumonia 1
• Fatal sepsis 1
• Nocardiosis, histoplasmosis, cryptococcosis 1
• Herpes zoster and disseminated herpes simplex 1

Reproductive System

• Defective oogenesis or spermatogenesis 1
• Transient oligospermia 1
• Menstrual dysfunction 1
• Infertility, abortion, fetal death, and fetal defects 1

Special Populations

Patients with Renal Impairment

Methotrexate is contraindicated in patients with end-stage kidney disease (eGFR <30 mL/minute) due to severe and potentially irreversible toxicity. 6, 7

• A test dose (2.5-5 mg) is mandatory in patients with decreased glomerular filtration rate 3, 4
• Lower initial doses are required with eGFR 30-59 mL/minute, with more gradual dose increases and lower weekly maximums 6
• Renal impairment is the primary risk factor for toxicity due to 85% renal excretion 2

Patients with Liver Disease

Methotrexate is absolutely contraindicated in patients with alcoholism, alcoholic liver disease, or other chronic liver disease. 3

• Baseline liver biopsy is not recommended regardless of risk factors 3, 2
• Non-invasive liver fibrosis assessment (FIB-4 Index, transient elastography) should be performed at baseline in high-risk patients 4
• For patients without risk factors, first liver biopsy should be considered after 3.5-4 g cumulative dose rather than 1-1.5 g 3
• For patients with risk factors, consider delayed baseline biopsy after 2-6 months to establish efficacy, then repeat biopsies after 1-1.5 g cumulative dose 3

Pregnancy and Lactation

Methotrexate is absolutely contraindicated during pregnancy and breastfeeding due to teratogenic effects at all gestational ages. 3

• Women must use contraception while taking methotrexate 3
• Women should wait at least 3-6 months after discontinuation before attempting conception 3, 2
• Men should wait 3 months after discontinuation before attempting conception 2
• The critical period for teratogenic effects is within the first 6-8 weeks of pregnancy 3

Critical Drug Interactions Increasing Toxicity

Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk from dual folate antagonism. 2

Other high-risk interactions include:

• NSAIDs reduce renal elimination and are particularly dangerous at any methotrexate dose 4, 2
• Penicillins interfere with renal secretion 3, 4
• Acitretin increases hepatotoxicity risk (though combination may be used with appropriate monitoring) 3
• Sulfonamide-based drugs increase pancytopenia risk 3

Prevention of Toxicity

All patients on methotrexate must receive mandatory folic acid supplementation (1-5 mg daily except on methotrexate day, or 5 mg weekly) to reduce gastrointestinal, hepatic, and hematologic toxicity. 3, 4, 2

Additional preventive measures:

• Limit alcohol consumption to well below moderate levels (women: <1 drink/day, men: <2 drinks/day) 5
• Ensure adequate hydration and urine alkalinization with high-dose methotrexate 1, 6
• Obtain baseline chest X-ray to establish pulmonary status 4, 2
• Screen for hepatitis B and C in patients with liver disease risk factors 4

Monitoring Requirements

Initial Monitoring (First 3 Months)

• Complete blood count with differential, liver function tests, and creatinine at least monthly 2
• More frequent monitoring (every 2-4 weeks) after dose increases, as pancytopenia can occur up to 6 weeks post-adjustment 3, 4

Maintenance Monitoring

After stabilization, perform complete blood count and liver function tests every 3-6 months assuming no abnormalities. 3, 2

• Avoid checking liver function tests within 2 days after methotrexate dose due to transient elevations 4
• For patients with risk factors, maintain monthly monitoring for first 6 months, then every 1-3 months 3

Management of Abnormal Results

If transaminases exceed 2× upper limit of normal on repeat testing, stop methotrexate. 2

• For persistent elevations in 5 of 9 AST levels during 12 months or decline in serum albumin below normal range, perform liver biopsy or consider gastroenterology referral 3
• Withhold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 2

Management of Acute Toxicity

Leucovorin (folinic acid) is the life-saving antidote for methotrexate toxicity and must be administered immediately upon suspicion, as efficacy diminishes dramatically after 24 hours. 4, 2

• Initial dosing: 10-15 mg/m² (approximately 15 mg for average adult) IV or orally, repeated every 6 hours until toxicity resolves 2
• For recent ingestion (≥1 mg/kg within 1 hour), administer activated charcoal immediately 2
• Initiate aggressive IV hydration and urinary alkalinization with sodium bicarbonate 2
• For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily 2

Common pitfall: Do not confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote. 2