Methotrexate

Methotrexate acts as a folate antagonist by reversibly inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of DNA, RNA, and proteins. This inhibition leads to depletion of tetrahydrofolate, disrupting cell proliferation, particularly in rapidly dividing cells. At lower doses, its anti-inflammatory and immunosuppressive effects are attributed to adenosine release and inhibition of lymphocyte proliferation.

Adult

Highly variable based on indication and route of administration. For Rheumatoid Arthritis/Psoriasis: Oral, subcutaneous, or intramuscular, 7.5 to 25 mg once weekly, adjusted based on response and tolerability. For oncology indications, doses can range from low daily oral doses to high-dose intravenous infusions (e.g., 100-15000 mg/m2) with leucovorin rescue.…

Pediatric

For Acute Lymphoblastic Leukemia (ALL): Varies widely by protocol, often 15-30 mg/m2 orally once weekly, or higher doses IV. For Juvenile Idiopathic Arthritis (JIA): Oral or subcutaneous, 0.3-1 mg/kg (maximum 25 mg/week) once weekly.

Renal adjustment

Reduce dose or increase dosing interval based on creatinine clearance (CrCl). For CrCl 30-50 mL/min: Reduce dose by 50% or extend interval by 50%. Generally contraindicated if CrCl <30 mL/min due to risk of severe toxicity and prolonged elimination.

Hepatic adjustment

Use with extreme caution; generally contraindicated in patients with significant hepatic impairment (e.g., bilirubin >3-5 mg/dL or AST >3 times ULN). Dose reduction may be necessary for milder impairment, but clear guidelines are lacking.

Geriatric

Use with caution; start at lower doses and titrate slowly due to potential age-related decrease in renal and hepatic function. Increased susceptibility to myelosuppression and other toxicities.

Max dose

For Rheumatoid Arthritis/Psoriasis, typically 25 mg once weekly. For oncology, maximum doses can be much higher but are protocol-specific and require leucovorin rescue.

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl <30 mL/min)
• Significant hepatic impairment (e.g., cirrhosis, chronic active hepatitis)
• Pre-existing blood dyscrasias (e.g., significant anemia, leukopenia, thrombocytopenia)
• Immunodeficiency syndromes
• Active serious infections (e.g., tuberculosis, herpes zoster)
• Alcoholism
• Pulmonary fibrosis
• Peptic ulcer disease
• Hypersensitivity to methotrexate