What is the recommended dose of Methotrexate (MTX) for a patient with rheumatoid arthritis or cancer, considering factors such as age and impaired renal function?

Methotrexate Dosing Recommendations

Rheumatoid Arthritis

For healthy adults with rheumatoid arthritis, start methotrexate at 7.5-15 mg orally once weekly, with rapid escalation to at least 15 mg weekly within 4-6 weeks to optimize efficacy. 1

Initial Dosing Strategy

• Start with 7.5 mg weekly as a single oral dose or 2.5 mg at 12-hour intervals for 3 doses given once weekly 2
• Oral administration is preferred over subcutaneous for initial therapy due to ease of administration and similar bioavailability at typical starting doses 1
• Escalate by 5 mg every 2-4 weeks until achieving adequate disease control, targeting 20-25 mg weekly for optimal efficacy 3
• The plateau of efficacy is attained at approximately 10 mg/m² per week in most patients 4
• Doses greater than 20 mg weekly significantly increase the incidence and severity of serious toxic reactions, especially bone marrow suppression 2

Route Optimization

• Switch to subcutaneous methotrexate at the same dose if inadequate response occurs at 15-20 mg oral weekly or if gastrointestinal intolerance develops 1, 3
• Subcutaneous administration may provide better absorption and fewer gastrointestinal side effects at higher doses 2

Mandatory Concurrent Therapy

• Prescribe folic acid supplementation: 5 mg weekly (on a different day than methotrexate) or 1 mg daily except on methotrexate day 1, 3
• Folic acid reduces nausea, myelosuppression, and gastric toxicity without compromising efficacy 1, 5

Psoriasis

For psoriasis, start with 10-25 mg weekly as a single oral, intramuscular, or intravenous dose, or use a divided oral schedule of 2.5 mg at 12-hour intervals for three doses 2

• Gradually adjust dosage to achieve optimal clinical response; 30 mg weekly should not ordinarily be exceeded 2
• In healthy adults, consider starting at 5-15 mg weekly 1
• Once remission is achieved, reduce to the lowest maintenance dose that controls the condition 1

Dosing in Renal Impairment

Methotrexate dosing must be reduced by 50% in patients with creatinine clearance between 20-50 mL/min, and the drug should be avoided entirely if creatinine clearance is below 20 mL/min. 1, 6

Specific Renal Adjustments

• GFR >90 mL/min: Use normal dose 1
• GFR 20-50 mL/min: Reduce dose by 50% 1, 6
• GFR <20 mL/min: Avoid methotrexate entirely 1, 6
• End-stage kidney disease (stage 5): Methotrexate is contraindicated 5, 7

Critical Considerations in Renal Impairment

• Myelosuppression is the most important cause of methotrexate-associated death and is significantly increased in renal dysfunction 1, 6
• Calculate actual creatinine clearance using the Cockcroft-Gault equation rather than relying on estimated GFR alone, as eGFR can overestimate renal function in elderly patients 1, 6
• Consider a test dose at the reduced level to assess tolerability before establishing regular dosing 6
• Increase monitoring frequency to every 2-4 weeks initially after dose adjustment 6

Age Considerations

Elderly patients require more cautious dosing due to decreased renal function, reduced folate stores, and increased risk of toxicity. 2

• Dose selection should account for greater frequency of decreased hepatic and renal function in elderly patients 2
• Post-marketing experience suggests bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age 2
• Use more accurate methods than serum creatinine (such as creatinine clearance) to assess renal function in elderly patients 2
• Monitor closely for early signs of hepatic, bone marrow, and renal toxicity 2

Monitoring Requirements

Initial Phase (First Month)

• Check complete blood count, liver function tests, and renal function every 7-14 days for the first month 1
• After stabilization, perform assessments every 2-3 months 1

Ongoing Monitoring

• Monitor CBC, liver function tests, and creatinine every 1-1.5 months during dose escalation 3
• For patients with renal impairment, monitor complete blood count, liver function tests, and renal function more frequently 6
• Watch for downward trends in blood counts even if absolute values remain within normal range 6

Common Pitfalls to Avoid

• Never escalate doses more frequently than every 2 weeks, as insufficient time will have elapsed to assess therapeutic response or identify delayed toxicities 3
• Do not exceed 20 mg weekly in patients with risk factors for toxicity (advanced age, renal impairment, significant alcohol use) 3
• Avoid methotrexate in patients on dialysis 1
• Do not use preserved formulations for intrathecal or high-dose therapy due to benzyl alcohol content 2
• Ensure adequate hydration and avoid concurrent nephrotoxic medications in patients with borderline renal function 6
• Avoid trimethoprim-sulfamethoxazole, as it increases bone marrow suppression through decreased tubular secretion and additive antifolate effects 2, 4

Cancer Chemotherapy Dosing

For high-dose methotrexate in cancer (≥500 mg/m²), adequate renal function is mandatory: serum creatinine must be normal and creatinine clearance must exceed 60 mL/min before each course. 2

• Patients require aggressive hydration (1,000 mL/m² over 6 hours before infusion, then 125 mL/m²/hour during and for 2 days after) 2
• Urinary alkalinization to maintain pH above 7.0 is essential 2
• Leucovorin rescue dosing is guided by serum methotrexate levels measured at 24 hours and daily until levels fall below 0.05 micromolar 2, 5