What is the appropriate use and dosage of methotrexate in patients with a history of cancer, autoimmune diseases, or inflammatory conditions?

Methotrexate: Appropriate Use and Dosing

For inflammatory conditions (psoriasis, atopic dermatitis, rheumatoid arthritis), start methotrexate at 7.5-15 mg orally once weekly and rapidly escalate to at least 15 mg weekly within 4-6 weeks, while for oncologic indications, dosing varies dramatically by cancer type and ranges from 15-30 mg daily for choriocarcinoma to 12 grams/m² IV for osteosarcoma. 1, 2

Critical Safety Requirement: Weekly Dosing Only

• Methotrexate must be taken ONCE WEEKLY, not daily—this is the most common and potentially fatal error. 3
• The treatment day should be chosen with the patient when prescribing, specified on the prescription, and written on the medication box. 3
• Accidental daily administration of weekly doses causes life-threatening toxicity including pancytopenia, mucositis, and multi-organ failure. 3

Mandatory Folic Acid Supplementation

• All patients on methotrexate must receive folic acid supplementation: either 5 mg once weekly (on a different day than methotrexate) or 1 mg daily except on methotrexate day. 1, 4, 5
• This reduces nausea, myelosuppression, mucositis, and hepatotoxicity without compromising efficacy. 1
• For doses ≥12.5 mg weekly, at least 5 mg weekly folic acid is recommended. 5

Dosing by Indication

Inflammatory/Autoimmune Diseases

Rheumatoid Arthritis:

• Start at 7.5-15 mg orally once weekly. 1
• Rapidly escalate by 5 mg every 2-4 weeks to reach at least 15 mg weekly within 4-6 weeks. 1, 5
• Target dose range is 20-25 mg weekly for optimal efficacy. 5
• Oral administration is preferred initially due to ease of use and similar bioavailability at typical starting doses. 1

Psoriasis and Atopic Dermatitis:

• Typical dosing range is 7.5-25 mg weekly. 1, 4
• Average time to maximum effect is 10 weeks, with minimal additional benefit after 12-16 weeks of dose escalation. 1
• Consider discontinuing if no response after 12-16 weeks on ≥15 mg weekly. 1

Oncologic Indications

Choriocarcinoma:

• 15-30 mg orally or intramuscularly daily for 5 days. 2
• Repeat courses 3-5 times with 1+ week rest periods between courses. 2

Acute Lymphoblastic Leukemia (Maintenance):

• 30 mg/m² weekly, divided into 2 doses per week, given orally or intramuscularly. 2

Meningeal Leukemia (Intrathecal):

• Dosing must be age-based, not BSA-based, to avoid neurotoxicity in adults and underdosing in children. 2
• Age <1 year: 6 mg; Age 1 year: 8 mg; Age 2 years: 10 mg; Age ≥3 years: 12 mg. 2
• Administer every 2-5 days until CSF normalizes, then one additional dose. 2
• Only use preservative-free formulations for intrathecal administration. 2

Osteosarcoma:

• Starting dose: 12 grams/m² IV as 4-hour infusion. 2
• May escalate to 15 grams/m² if peak serum concentration doesn't reach 1,000 micromolar. 2
• Requires leucovorin rescue: 15 mg orally every 6 hours for 10 doses starting 24 hours after methotrexate infusion. 2

Route of Administration Decision Algorithm

1. Start with oral administration for inflammatory conditions. 1
2. Switch to subcutaneous/intramuscular if:
   • Inadequate response at 15-20 mg oral weekly (before further dose escalation). 1, 5
   • Gastrointestinal intolerance (nausea, vomiting) develops. 1
   • Doses ≥15 mg/m² in pediatric patients (to ensure adequate absorption). 4
3. Parenteral administration has higher bioavailability and may increase efficacy. 1, 4
4. Conversion: 0.1 mL of 25 mg/mL injection = 2.5 mg oral tablet. 1, 4

Renal Impairment Dosing

This is critical—methotrexate is renally eliminated and accumulates dangerously in renal dysfunction. 1

• GFR >90 mL/min: Use normal dose. 1, 5
• GFR 20-50 mL/min: Reduce dose by 50%. 1, 5
• GFR <20 mL/min: Avoid methotrexate entirely. 1, 5
• Patients on dialysis: Contraindicated. 1

Baseline Testing Requirements

Before initiating methotrexate, obtain: 1

• Complete blood count (CBC) with differential
• Liver function tests (AST, ALT, albumin, bilirubin)
• Renal function (creatinine, calculated GFR)
• Hepatitis B and C serology
• HIV serology
• Varicella-zoster virus (VZV) serology if no history of chickenpox
• Chest X-ray if patient is >40 years old and smokes, or has respiratory symptoms or risk factors. 1

Monitoring Schedule

During dose escalation (first 3 months):

• CBC, liver function tests, creatinine every 1-1.5 months. 5, 6
• Watch for downward trends in blood counts even if values remain within normal range. 5

After stabilization:

• CBC, liver function tests, creatinine every 2-3 months. 1, 5, 6
• For psoriasis patients: Also monitor PIIINP (peptide of procollagen III) every 3 months. 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. 1

At every visit:

• Inquire about respiratory symptoms (cough, dyspnea) to detect pneumonitis early. 1
• Assess for mucositis, mouth ulcers, fever—these indicate toxicity. 3

Managing Common Adverse Effects

Nausea (occurs in up to 25% of patients): 1

• Take medication before bedtime or with food. 1
• Ensure adequate folic acid supplementation (up to 5 mg daily). 1
• Consider ondansetron 8 mg 2 hours before methotrexate dose, repeated at 12 and 24 hours if needed. 1
• Switch to subcutaneous/intramuscular administration—this often resolves nausea. 1

Oral intolerance:

• Split oral dose over 24 hours (e.g., 12.5 mg twice, 12 hours apart). 1
• Increase folic acid dose. 1
• Switch to parenteral administration. 1

Absolute Contraindications

• Pregnancy (teratogenic). 1
• Breastfeeding. 1
• Creatinine clearance <20 mL/min or dialysis. 1
• Active infection (particularly tuberculosis, HIV without treatment). 1
• Significant hepatic impairment or active liver disease. 1
• Severe immunodeficiency. 1

Special Populations

Patients with Cancer History:

• Methotrexate is both a chemotherapeutic agent and immunosuppressant. 2, 7
• The British Association of Dermatologists notes that low-dose methotrexate for inflammatory conditions does not appear to increase malignancy risk above baseline population rates, though vigilance for lymphoma is advisable. 1
• Methotrexate-associated lymphoproliferative disease (MTX-LPD) can occur, particularly in rheumatoid arthritis patients, and may reverse upon stopping methotrexate. 1

Elderly Patients:

• May require dose reduction due to decreased renal function. 1
• CSF volume and turnover decrease with age—consider dose reduction for intrathecal administration. 2

Pediatric Patients:

• For inflammatory conditions: Maximum 1 mg/kg weekly (not exceeding 25 mg/week). 4
• For Crohn's disease: 15 mg/m² once weekly (maximum 25 mg). 4
• For juvenile idiopathic arthritis: Start 10 mg/m² weekly, maximum 15 mg/m² weekly. 4

Critical Drug Interactions

• NSAIDs, aspirin, probenecid, penicillins, sulfonamides: Reduce methotrexate renal clearance and increase toxicity risk. 1
• Trimethoprim-sulfamethoxazole: Additive folate antagonism—increases bone marrow suppression risk. 1
• Alcohol: Significantly increases hepatotoxicity risk—advise strict avoidance. 1

Common Pitfalls to Avoid

1. Never escalate doses more frequently than every 2 weeks—insufficient time to assess response or identify delayed toxicities. 5
2. Do not use preserved formulations for intrathecal or high-dose therapy (contains benzyl alcohol). 2
3. Do not use BSA-based dosing for intrathecal administration—use age-based dosing. 2
4. Do not continue escalating if adequate disease control is achieved at lower doses—use minimum effective dose. 5
5. Do not exceed 20 mg weekly in patients with risk factors for toxicity (advanced age, renal impairment, alcohol use). 5
6. Routine liver biopsy for monitoring is NOT recommended. 1