What are the adverse effects of methotrexate and how should they be monitored and managed?

Methotrexate Side Effects and Management

Major Life-Threatening Toxicities

The most serious adverse effects of methotrexate are acute bone marrow suppression and hepatic fibrosis/cirrhosis, both of which can be fatal if not detected early. 1 Myelosuppression accounts for 67 of 164 reported methotrexate-associated fatalities, making hematologic toxicity the most lethal complication, while pulmonary fibrosis accounts for 30 deaths. 2

Hematologic Toxicity

• Bone marrow suppression typically occurs early in treatment (first 4-6 weeks) and is reversible with cessation. 2
• Pancytopenia can result after even a single dose and can occur at any time during treatment, typically in patients with at least one risk factor. 2
• Risk factors include renal insufficiency, advanced age (>50-70 years), lack of folate supplementation, hypoalbuminemia, and drug interactions (NSAIDs, trimethoprim-sulfamethoxazole, penicillins). 2, 3
• Manifestations include leukopenia, neutropenia, thrombocytopenia, and aplastic anemia. 4

Hepatotoxicity

• Long-term use carries a cumulative dose-dependent risk of hepatic fibrosis and cirrhosis. 1
• Transient liver enzyme elevations are common (typically within 3-4 days after dosing) and usually do not require modification of therapy. 2
• Persistent elevations of transaminases and/or depression of serum albumin indicate serious liver toxicity requiring evaluation. 4
• Liver function test monitoring is recommended every 3-6 months in stable patients. 1

Pulmonary Toxicity

• Methotrexate-induced pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression. 2
• Presents with dry nonproductive cough, dyspnea, fever, and reduced diffusion capacity on pulmonary function tests. 2, 3
• A baseline chest X-ray should be obtained for all patients starting methotrexate. 2, 3
• Pulmonary symptoms usually resolve with discontinuation of methotrexate. 3

Common Non-Life-Threatening Side Effects

Gastrointestinal Effects

• GI symptoms occur in approximately 30-32% of patients, making this one of the most common adverse effects. 3
• Include ulcerative stomatitis, nausea, vomiting, abdominal distress, diarrhea, anorexia, and GI ulceration. 2, 4
• Symptoms typically occur within 12-24 hours of medication consumption and are dose-dependent. 3
• Mucocutaneous effects such as stomatitis and mouth ulcers are very common early toxicities. 2

Other Common Effects

• Malaise, undue fatigue, chills, fever, dizziness, and decreased resistance to infection. 4
• Hair loss (rare), photosensitivity (rare), and various dermatologic reactions. 1, 4
• Headaches, drowsiness, transient cognitive dysfunction, mood alteration. 4

Critical Drug Interactions

The following medications significantly increase methotrexate toxicity and require extreme caution or avoidance:

• Trimethoprim-sulfamethoxazole is absolutely contraindicated due to severe bone marrow suppression risk from dual folic acid antagonism. 1, 2
• NSAIDs reduce renal elimination of methotrexate, particularly dangerous with any dose. 1, 2, 4
• Salicylates, phenylbutazone, phenytoin, and sulfonamides displace methotrexate from serum albumin, increasing toxicity. 1, 4
• Probenecid diminishes renal tubular transport. 1, 4
• Alcohol, retinoids, pyrimethamine, and furosemide increase methotrexate activity. 1

Monitoring Protocol

Initial Phase (First 3 Months)

• Complete blood count with differential, liver function tests, renal function tests (serum urea, electrolytes, creatinine), and baseline chest X-ray. 1, 2
• Weekly monitoring initially, then monthly for the first 3 months. 3
• Labs should be performed at least 4-6 days after dosing to avoid misinterpreting transient elevations. 2

Maintenance Phase

• Complete blood count and liver function tests every 3-6 months in stable patients without risk factors. 1, 3
• Every 1-2 months for patients with risk factors for hepatotoxicity. 1
• More frequent monitoring during periods of increased risk (dehydration, dose changes, renal impairment). 4

Specific Thresholds for Action

• Withhold methotrexate if: WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L. 3
• Stop methotrexate if: transaminases exceed 2× upper limit of normal on repeat testing. 2, 3
• For persistent elevations, GI/hepatology referral is recommended. 1

Management of Toxicity

Immediate Management of Overdose or Severe Toxicity

Leucovorin (folinic acid) is the life-saving antidote and must be administered immediately upon suspicion of methotrexate toxicity. 2, 3

• Initial dosing: 10-15 mg/m² (approximately 15 mg for average adult) IV or PO immediately. 3
• Subsequent doses: 15 mg every 6 hours until toxicity resolves or methotrexate levels fall below 0.05 µmol/L. 2, 3
• Efficacy diminishes dramatically after 24 hours; treatment is doubtful if initiated >24 hours after last methotrexate dose. 2, 3

Additional Acute Interventions

• For recent ingestion (≥1 mg/kg within 1 hour): administer activated charcoal immediately. 2, 3
• Aggressive IV hydration to enhance renal elimination. 2, 3
• Urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules. 2, 3
• For severe neutropenia (<1×10⁹/L): filgrastim (G-CSF) 5 µg/kg subcutaneously daily. 2, 3

Management of Specific Toxicities

Hematologic:

• Monitor complete blood counts closely. 3
• Warn patients with severe neutropenia to present for antibiotics ± G-CSF if febrile. 3

Hepatic:

• Repeat liver function tests in 2-4 weeks for abnormal elevations. 1, 3
• Many liver function abnormalities are transitory and normalize without stopping methotrexate (only 5% require permanent discontinuation). 3
• For patients with BMI >28 kg/m² or alcohol intake >14 drinks/week, screen using transient elastography (FibroScan). 3

Pulmonary:

• Obtain chest X-ray immediately if dyspnea, dry cough, or fever develop. 3
• Discontinue methotrexate; symptoms usually resolve with cessation. 3

Essential Prevention Strategies

Mandatory Folic Acid Supplementation

All patients on methotrexate must receive folic acid supplementation to reduce gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy. 1, 2, 3

• Dosing options: 1 mg daily (except on methotrexate day) OR 5 mg weekly on a different day than methotrexate. 1, 2, 3
• Large doses may reduce methotrexate efficacy. 1

Correct Dosing to Prevent Fatal Errors

Methotrexate must be administered once weekly; mistaken daily use of the recommended dose has led to fatal toxicity. 4, 5

• Weekly dosing typically ranges from 7.5 to 25 mg. 1
• The dose can be given as a single dose or divided into 2-3 doses over 24 hours. 1, 3
• Daily dosing is contraindicated because it markedly increases hepatotoxicity risk. 3
• Prescriptions should not be written on a PRN basis. 4
• Write dose in full uppercase letters and specify the treatment day on the prescription. 3, 5
• Prescribe only 2.5 mg tablets to make daily dosing physically impossible. 3

Strategies to Minimize Common Toxicities

For gastrointestinal intolerance:

• Take methotrexate with food or at bedtime. 2, 3
• Switch to subcutaneous or intramuscular administration (may reduce nausea). 1, 3
• Split the weekly dose into 2-3 administrations over 24 hours. 2, 3
• Ensure adequate folic acid supplementation. 2, 3

Absolute Contraindications

Methotrexate is contraindicated in:

• Pregnancy and lactation (teratogenic at all gestational ages). 1, 4
• Cirrhosis or significant hepatic impairment. 1
• Significant thrombocytopenia, leukopenia, or anemia. 1
• Creatinine clearance <20 mL/min. 2

Reproductive Precautions

• Women must avoid conception during treatment and for at least 3 months (preferably 6 months) after discontinuation. 1, 3
• Men should wait 3 months after discontinuation before attempting conception. 3
• Methotrexate causes defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects. 2, 4

Common Pitfalls to Avoid

• Do not confuse folic acid with folinic acid (leucovorin): only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote for acute toxicity. 3
• Do not assume low serum methotrexate levels exclude toxicity: treat based on clinical presentation. 3
• Do not delay leucovorin administration: efficacy is doubtful if initiated >24 hours after last methotrexate dose. 2, 3
• Do not perform labs immediately after dosing: wait at least 4-6 days to avoid misinterpreting transient elevations. 2
• Do not overlook renal function: methotrexate is 85% renally excreted, and any renal impairment dramatically increases toxicity risk. 2, 3