Methotrexate

Approved Indications:

• Oncology:
• Acute lymphoblastic leukemia (ALL)
• Non-Hodgkin lymphoma (including CNS prophylaxis)
• Choriocarcinoma and other gestational trophoblastic neoplasms
• Head and neck cancers
• Breast cancer
• Osteosarcoma
• Lung cancer (non-small cell)
• Autoimmune and Inflammatory Disorders:
• Rheumatoid arthritis (moderate to severe, active)
• Juvenile idiopathic arthritis
• Psoriasis (severe, recalcitrant, and disabling)
• Psoriatic arthritis

Clinically Accepted Off-label Uses:

• Crohn's disease
• Systemic lupus erythematosus
• Granulomatosis with polyangiitis (Wegener’s)
• Mycosis fungoides
• Uveitis
• Dermatomyositis
• Sarcoidosis (severe cases)

Route: Oral, intramuscular (IM), subcutaneous (SC), or intravenous (IV)

Rheumatoid Arthritis:

• Adults: 7.5–25 mg once weekly (PO, IM, SC); folic acid supplementation (1–5 mg/day) is recommended.

Psoriasis:

• Adults: 10–25 mg once weekly (PO, IM, or SC); dose may be divided into 2–3 doses every 12 hours over 24 hours for improved tolerance.

Oncology (High-Dose Protocols):

• Dose varies from 100 mg/m² to 12 g/m² IV over several hours, followed by leucovorin rescue.

Pediatric Acute Lymphoblastic Leukemia (ALL):

• Induction and maintenance protocols involve doses ranging from 20–40 mg/m² IV or IT (intrathecal), based on protocol.

Renal Impairment:

• CrCl 30–50 mL/min: Reduce dose by 50%
• CrCl <30 mL/min: Avoid use

Hepatic Impairment:

• Avoid in active liver disease or significantly impaired liver function.

Elderly:

• Start with lower doses and monitor closely.

Methotrexate is a folate analog that inhibits the enzyme dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate, which is essential for purine and thymidylate synthesis. This inhibition disrupts DNA, RNA, and protein synthesis in rapidly dividing cells. At lower doses, methotrexate also exerts anti-inflammatory effects by increasing extracellular adenosine, which suppresses inflammatory cell activation and cytokine production.

• Absorption: Oral bioavailability is 70–90% at lower doses; reduced at higher doses.
• Distribution: Widely distributed; accumulates in liver, kidneys, and third-space fluids.
• Protein Binding: ~50%
• Metabolism: Partially hepatic via aldehyde oxidase; intracellular polyglutamation enhances retention.
• Half-life: 3–10 hours (longer with renal impairment)
• Elimination: Primarily renal (glomerular filtration and active tubular secretion); some biliary excretion.

• Pregnancy: Category X – Contraindicated in pregnancy due to teratogenicity, fetal death, and malformations.
• Lactation: Excreted in breast milk. Contraindicated during breastfeeding due to potential toxicity in infants.
• Contraception: Effective contraception is required for both males and females during and after therapy (6 months for females, 3 months for males).

• Class: Antimetabolite; Immunosuppressant; Disease-Modifying Antirheumatic Drug (DMARD)
• Subclass: Folate Antagonist

• Hypersensitivity to methotrexate or excipients
• Pregnancy and breastfeeding
• Severe renal or hepatic impairment
• Active infectious disease (e.g., TB, hepatitis)
• Preexisting blood dyscrasias (e.g., leukopenia, thrombocytopenia)
• Alcoholism or chronic liver disease
• Immunodeficiency syndromes

• Bone Marrow Suppression: Risk of leukopenia, anemia, thrombocytopenia; monitor CBC regularly.
• Hepatotoxicity: Elevated transaminases; fibrosis with long-term use. Regular liver function tests required.
• Pulmonary Toxicity: Interstitial pneumonitis and pulmonary fibrosis may occur.
• Infections: Increased risk due to immunosuppression.
• Renal Toxicity: Especially with high-dose regimens.
• Dermatologic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis reported.
• Gastrointestinal Ulceration: Including stomatitis and mucositis.

Common:

• Gastrointestinal: Nausea, vomiting, stomatitis, anorexia
• Hematologic: Mild anemia, leukopenia
• Dermatologic: Rash, photosensitivity, alopecia
• Neurologic: Headache, dizziness, fatigue

Serious:

• Hepatotoxicity
• Bone marrow suppression
• Pulmonary fibrosis
• Nephrotoxicity (at high doses)
• Severe cutaneous adverse reactions (SCARs)

Timing:

• Side effects may appear within days to weeks of therapy initiation; some (e.g., hepatotoxicity, fibrosis) may develop over months or years.

• NSAIDs, penicillins, proton pump inhibitors: May reduce renal clearance and increase toxicity.
• Trimethoprim/sulfamethoxazole: Additive myelosuppression.
• Live vaccines: Avoid due to immunosuppression.
• Alcohol: Increases hepatotoxicity risk.
• Enzyme Interactions: Methotrexate is not significantly metabolized via CYP450 but competes for renal tubular secretion.

• FDA Safety Update (2023): Emphasis on weekly, not daily dosing to prevent fatal overdoses.
• ACR Guidelines (2024): Methotrexate remains first-line therapy for rheumatoid arthritis; recommends folic acid supplementation and SC route for better efficacy.
• EMA Review (2023): Additional hepatotoxicity warnings; updates on patient education materials.

• Tablets: Store at 20°C to 25°C; protect from moisture and light.
• Injection (vial): Store at 15°C to 25°C; do not freeze; protect from light.
• Handling Precautions:
• Wear gloves during preparation.
• Dispose of unused medication as hazardous pharmaceutical waste.