What is the proper administration and dilution of intrathecal (in the spinal canal) methotrexate?

Intrathecal Methotrexate Administration and Dilution

Intrathecal methotrexate should be diluted to a concentration of 1 mg/mL using preservative-free normal saline, with age-based dosing (not body surface area) to minimize neurotoxicity while maintaining efficacy. 1

Preparation and Dilution

Critical dilution requirements:

• Dilute preservative-free methotrexate to exactly 1 mg/mL concentration 1, 2
• Use only preservative-free normal saline as the diluent 3, 1
• Never use preserved formulations containing benzyl alcohol for intrathecal administration 1
• Preparations at 1 mg/mL maintain pH and osmolality within 10% of physiologic CSF range 4

Common pitfall: Higher concentrations (>1 mg/mL) increase risk of neurotoxicity through elevated CSF methotrexate levels and non-physiologic pH/osmolality 2, 4. The literature documents paraplegia and severe neurotoxicity associated with inappropriately concentrated solutions 2.

Dosing Strategy

Age-based dosing (NOT body surface area):

• <1 year: 6 mg 1
• 1 year: 8 mg 1
• 2 years: 10 mg 1
• ≥3 years: 12 mg 1

Rationale: CSF volume correlates with age, not body surface area. Body surface area-based dosing (12 mg/m²) results in subtherapeutic concentrations in children and toxic concentrations with neurotoxicity in adults 1. Age-based dosing produces more consistent CSF methotrexate concentrations and significantly reduces CNS relapse rates 1.

For prophylaxis in lymphoma: 12 mg is the most common dose, achieving therapeutic CSF levels (>1 μmol/L) for 24-48 hours 3. Doses of 12.5 mg and 15 mg have also been reported 3.

For leptomeningeal metastases: 10-15 mg is the usual dose range 3.

Administration Technique

Isovolumetric administration is mandatory:

• Remove CSF volume equal to the total volume being instilled (drug + diluent + flush) 3
• This prevents precipitous increases in intracranial pressure that can cause herniation 3
• Patients with neoplastic meningitis are precariously positioned on the pressure-volume curve 3

Route preference:

• Intraventricular administration via Ommaya reservoir is superior to lumbar puncture 3, 5
• Intraventricular dosing achieves 10-fold higher ventricular CSF exposure compared to lumbar administration 3
• Lumbar administration risks epidural/subdural leakage and produces highly variable ventricular concentrations 3, 5
• Survival benefit has been suggested for intraventricular versus lumbar routes 3

Frequency:

• Treatment: Twice weekly for 8 doses, then weekly for 4 doses, then monthly 3
• Prophylaxis: During each chemotherapy cycle, total of 4-8 doses 3
• Intervals <1 week may increase subacute toxicity 1

Risk Mitigation

Leucovorin rescue:

• Administer oral leucovorin 10 mg twice daily starting on treatment day, continuing for 3 days 3
• Reduces systemic myelosuppression without crossing blood-brain barrier to interfere with CSF efficacy 3

Contraindications and dose reduction:

• Renal insufficiency 3
• Large pleural effusions or ascites 3
• Abnormal CSF flow 3
• Elderly patients may require dose reduction due to decreased CSF volume and turnover 1
• Presence of CNS leukemia (lower doses needed) 2

Drug interactions to avoid:

• Aspirin, phenytoin, sulfonamides, tetracycline (increase toxicity through protein displacement) 3

Monitoring

Therapeutic concentrations: 1 μmol/L (1 × 10⁻⁶ M) in CSF persist for 48 hours after each dose 3. Periodic CSF methotrexate level monitoring may predict serious neurotoxicity 2.

Warning: Intrathecal methotrexate appears significantly in systemic circulation and can cause systemic toxicity; adjust concurrent systemic methotrexate therapy accordingly 1.