Is methotrexate (MTX) a safe drug?

Is Methotrexate a Safe Drug?

Methotrexate is a safe and effective medication when prescribed with appropriate monitoring protocols, patient education, and adherence to established safety guidelines, though it carries significant risks if these safeguards are not followed. 1

Safety Profile Overview

Methotrexate has been established as safe for long-term use across multiple decades of clinical experience, provided that treatment follows strict monitoring protocols and prescribers adhere to fundamental safety rules. 2, 3 The drug's safety has been demonstrated over a quarter century of development, with its efficacy profile outweighing side effects when properly managed. 3

The key to methotrexate safety lies in regular monitoring and proper patient education rather than inherent drug toxicity. 1, 2

Critical Safety Requirements

Mandatory Patient Education

Before prescribing methotrexate, you must ensure patients understand:

• Weekly dosing schedule - prescribe only 2.5 mg tablet strength to prevent potentially life-threatening daily dosing errors 1, 2
• Therapeutic benefit may not appear for 3-12 weeks 1
• Absolute contraindication to pregnancy and need for effective contraception (women must avoid pregnancy during treatment and for 3 months after; men should wait 3 months after last dose before fathering children) 1
• Immediate medical attention required for: fever/flu-like illness, mouth ulceration, tiredness, unexplained bruising/bleeding, nausea/vomiting/abdominal pain/dark urine, or breathlessness/cough 1
• Limit alcohol intake to well below national guidelines 1

Essential Monitoring Protocol

Blood monitoring schedule: 1

• FBC, LFTs, and U&E every 7-14 days for the first month
• Once stabilized, every 2-3 months thereafter
• For psoriasis patients: PIIINP monitoring every 3 months 1

Liver toxicity surveillance: 1

• Refer for specialist assessment if PIIINP >8 mg/L on two occasions, or three measurements >4.2 mg/L in 12 months, or >10 mg/L on one occasion
• Routine liver biopsy is NOT recommended for monitoring 1

Pre-Treatment Screening Requirements

Mandatory baseline investigations include: 1

• FBC, U&E, LFTs
• Hepatitis B and C serology
• VZV serology if no history of chickenpox
• HIV serology in at-risk populations
• Tuberculosis screening if history of TB or exposure 1

Common vs. Serious Adverse Events

Common Side Effects (Manageable)

While side effects occur frequently, they are seldom life-threatening and rarely necessitate drug withdrawal. 4 The most common toxicity is gastrointestinal (nausea, vomiting, stomatitis), which can be mitigated with folic acid supplementation. 1, 3, 5

Folic acid supplementation is strongly recommended to reduce toxicity. 1

Serious Toxicities (Rare but Important)

The three major serious toxicities are: 6, 7, 4

1. Hepatotoxicity - chronic fibrosis/cirrhosis occurs after prolonged use (generally ≥2 years) and cumulative doses ≥1.5 grams; enhanced by alcoholism, obesity, diabetes, and advanced age 6

2. Hematologic toxicity - bone marrow suppression can cause anemia, pancytopenia, leukopenia, neutropenia, and thrombocytopenia; stop immediately if significant drop in blood counts 6

3. Pulmonary toxicity - methotrexate-induced lung disease requires immediate discontinuation; inquire about respiratory symptoms at each visit 1

These serious toxicities can be minimized or prevented with careful symptom monitoring and laboratory surveillance. 4

Absolute Contraindications

Methotrexate must NOT be used in: 1, 6

• Pregnancy or breastfeeding (Pregnancy Category X)
• Active hepatitis B infection
• Active tuberculosis
• Severe renal impairment (eGFR <30 mL/min for RA; creatinine clearance <20 mL/min generally) 7
• Concurrent trimethoprim therapy 1
• Patients unable to comply with monitoring 1

Special Populations Requiring Caution

Elderly Patients

Elderly patients require more cautious dosing and closer monitoring due to: 6

• Decreased hepatic and renal function
• Decreased folate stores
• Higher risk of bone marrow suppression, thrombocytopenia, and pneumonitis with age
• Serum creatinine may overestimate renal function; use creatinine clearance calculations instead 6

Renal Impairment

For eGFR 30-59 mL/min: start with lower doses (2.5-5 mg weekly), monitor more frequently, and use lower maximum weekly doses 7

For eGFR <30 mL/min: methotrexate is contraindicated in RA patients 7

Infection Risk Management

Methotrexate increases infection risk, particularly pneumonia, skin/soft tissue infections, and urinary tract infections, with most occurring within the first 18 months. 8, 9

Vaccination Requirements

• Pneumococcal vaccine before starting treatment 1
• Annual influenza vaccination 1, 8
• VZV vaccination for seronegative patients (stop immunosuppressants 6 months before administering live vaccine) 8

Infection Management Algorithm

During active infection: 9

• Temporarily discontinue methotrexate for severe infection or infection not responding to standard treatment
• Permanently discontinue if opportunistic infection develops
• Restart when infection has cleared

Prophylaxis for High-Risk Patients

For non-vaccinated individuals or those with low CD4 counts: 8

• Prophylactic antiviral medication (acyclovir or valacyclovir) for herpes prevention
• Pneumocystis pneumonia prophylaxis when CD4 counts are low or receiving high-dose corticosteroids

Critical Drug Interactions

Avoid or use extreme caution with: 6

• NSAIDs with high-dose methotrexate (can elevate and prolong methotrexate levels, causing deaths from hematologic/GI toxicity)
• Trimethoprim/sulfamethoxazole (increases bone marrow suppression) 1, 9, 6
• Penicillins (reduce renal clearance, increase toxicity) 6
• Nitrous oxide anesthesia (potentiates toxicity; avoid concomitant use) 6
• Other hepatotoxic agents (azathioprine, retinoids, sulfasalazine) - monitor closely 6

Perioperative Management

For most elective surgeries, methotrexate can be safely continued perioperatively without increased infection risk. 10 However, consider temporary discontinuation for: 10

• Major surgery with significant comorbidities
• Patients requiring postoperative antibiotics for severe infection
• Patients with eGFR <20 mL/min

Hospital Admission Considerations

Temporarily discontinue methotrexate during hospitalization when patients have: 10

• Acute illness or infection requiring antibiotics
• Medications that interact with methotrexate (antibiotics, NSAIDs)
• Abnormal liver function (transaminases >2× upper limit of normal)
• Bone marrow suppression (WBC <3.5×10⁹/L or neutrophils <2×10⁹/L)

Resume after acute illness resolves, liver function normalizes, blood counts are adequate, and interacting medications are discontinued. 10

Common Pitfalls to Avoid

1. Daily dosing error - the most dangerous mistake; prescribe only 2.5 mg tablets and emphasize weekly dosing 1, 2

2. Inadequate monitoring - patients unable to comply with blood tests should not receive methotrexate 1

3. Ignoring renal function - always calculate creatinine clearance, especially in elderly patients 6

4. Concurrent antifolate drugs - avoid trimethoprim/sulfamethoxazole due to additive bone marrow suppression 1, 9, 6

5. Inadequate patient education - failure to warn about infection symptoms leads to delayed recognition of serious toxicity 1

Risk-Benefit Context

Methotrexate remains the cornerstone of therapy for rheumatoid arthritis and has superior efficacy in placebo-controlled trials. 3 At one year, one-third of patients show no radiographic progression, with even greater effects when combined with biological therapies. 3 The drug is well-tolerated overall, with serious toxicities being rare when monitoring protocols are followed. 3, 4

The safety of methotrexate is not determined by the drug itself, but by the rigor of the monitoring system and patient education surrounding its use. 1, 2