How should oral methotrexate be dosed and administered weekly in adults (e.g., for rheumatoid arthritis or psoriasis), and what monitoring is required?

Oral Methotrexate Administration for Rheumatoid Arthritis and Psoriasis

Administer oral methotrexate as a single weekly dose of 7.5-15 mg for rheumatoid arthritis or 10-25 mg for psoriasis, taken on the same day each week, with mandatory folic acid supplementation of 5 mg weekly (on a different day) or 1 mg daily (except on methotrexate day). 1, 2

Initial Dosing Strategy

For rheumatoid arthritis:

• Start at 7.5-15 mg orally once weekly 2
• Escalate by 5 mg every 2-4 weeks until adequate disease control is achieved 3
• Target dose range is 20-25 mg weekly for optimal efficacy 3
• Maximum dose should not ordinarily exceed 30 mg/week 1, 2

For psoriasis:

• Start with a test dose of 2.5-5 mg to detect extreme sensitivity 1
• Begin regular dosing at 10-25 mg per week as a single oral dose 1, 2
• Gradually increase until optimal response is achieved, not exceeding 30 mg/week 1, 2

Critical Administration Instructions

Weekly dosing schedule:

• Choose a specific day of the week with the patient and document it on the prescription 4
• Write the dosing day on the medication box when dispensed 4
• Provide a patient-held treatment record documenting the weekly schedule 5
• Common pitfall: Daily administration of a weekly dose is a potentially fatal error that accounts for most methotrexate overdoses 4

Alternative divided dosing:

• May give 2.5 mg at 12-hour intervals for 3 doses as a weekly course 2
• This schedule may improve absorption and reduce gastrointestinal side effects, particularly in children receiving 20-30 mg/m²/week 2

Mandatory Concurrent Folic Acid Supplementation

All patients must receive folate supplementation: 1, 5, 3

• Preferred regimen: 5 mg folic acid once weekly on a different day than methotrexate 3
• Alternative regimen: 1 mg daily except on the day of methotrexate administration 1, 3
• This reduces gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy 1, 5

Route of Administration Considerations

When to switch from oral to parenteral:

• If inadequate response at 15-20 mg oral weekly, switch to subcutaneous administration at the same dose before further escalation 3
• If gastrointestinal intolerance develops (nausea, vomiting), switch to intramuscular or subcutaneous route 1
• Bioavailability is better with injection; 0.1 mL of 25 mg/mL injection solution equals one 2.5 mg oral tablet 1

Baseline Testing Requirements

Before initiating methotrexate: 6, 2

• Complete blood count with differential
• Liver function tests (ALT or AST, alkaline phosphatase, albumin)
• Serum creatinine and calculate creatinine clearance
• Chest x-ray (baseline for all patients) 5, 6
• For patients with hepatotoxicity risk factors: GI/hepatology consultation or FibroScan at baseline 6

Monitoring Schedule

During first 6 months and dose escalation: 6

• CBC, liver function tests, and creatinine every 1-1.5 months 6
• Clinical assessment for toxicity at each visit 6

Maintenance phase (stable dose): 6

• CBC, liver function tests, and creatinine every 1-3 months 6
• Continue clinical assessment at each visit 6

Hepatotoxicity monitoring: 1, 6

• If ALT/AST <2× upper limit of normal: repeat in 2-4 weeks 6
• If ALT/AST 2-3× upper limit of normal: closely monitor, repeat in 2-4 weeks, decrease dose 6
• If ALT/AST >5× upper limit of normal: discontinue methotrexate 1

Dosing Adjustments for Renal Impairment

Methotrexate is 85% renally excreted and requires dose reduction in renal dysfunction: 5, 7

• GFR >90 mL/min: Use normal dose 3
• GFR 20-50 mL/min: Reduce dose by 50% 3
• GFR <20 mL/min: Avoid methotrexate entirely 3, 7
• Patients with renal impairment are at risk even after single doses and require careful monitoring 1

Expected Timeline for Response

• Therapeutic response usually begins within 3-6 weeks 2
• Patients may continue to improve for another 12 weeks or more 2
• Average time to maximum effect is 10 weeks 1
• Minimal to no further efficacy after 12-16 weeks with dose escalation 1
• Wait at least 4 weeks after each dose increase before assessing response 3

Absolute Contraindications

1, 2

• Pregnancy
• Nursing mothers
• Alcoholism or alcoholic liver disease
• Chronic liver disease
• Immunodeficiency syndromes
• Bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
• Hypersensitivity to methotrexate

Critical Drug Interactions to Avoid

Absolutely contraindicated: 5

• Trimethoprim-sulfamethoxazole (causes severe bone marrow suppression) 5

High-risk interactions requiring caution: 1, 5

• NSAIDs reduce renal elimination of methotrexate 1, 5
• Salicylates, sulfonamides, penicillins, probenecid decrease methotrexate binding or renal excretion 5

Warning Signs Requiring Immediate Action

Instruct patients to report immediately: 1, 5

• Unusual fatigue or malaise 5
• Fever or chills 5
• Mouth ulcers or stomatitis 1, 5
• New respiratory symptoms (dry cough, dyspnea) 5
• Severe nausea, vomiting, or diarrhea 1

If toxicity suspected:

• Discontinue methotrexate immediately 5
• Administer leucovorin (folinic acid) 10-15 mg every 6 hours until toxicity resolves 1, 5
• Check CBC with differential to assess for pancytopenia 5

Common Pitfalls to Avoid

• Never prescribe methotrexate daily - this is the most common fatal error 4
• Do not escalate doses more frequently than every 2 weeks 3
• Do not confuse folic acid with folinic acid (leucovorin); only leucovorin is an antidote for acute toxicity 5
• Do not exceed 20 mg weekly in patients with risk factors (advanced age, renal impairment, alcohol use) 3
• Watch for downward trends in blood counts even if values remain within normal range 3, 6