Methotrexate

Introduction

  • Methotrexate is a medication used to treat a variety of autoimmune conditions and certain cancers.
  • It works by inhibiting dihydrofolate reductase, interfering with DNA synthesis and cellular replication.
  • Commonly prescribed for rheumatoid arthritis, psoriasis, and certain types of leukemia.
  • Requires careful monitoring due to its potential toxicity.

Uses of Methotrexate

  1. Autoimmune Conditions
    • Rheumatoid Arthritis (RA): Reduces joint inflammation and slows disease progression.
    • Psoriasis: Controls severe or refractory cases by reducing skin cell turnover.
    • Systemic Lupus Erythematosus (SLE): Used off-label in some cases.
  2. Cancer Therapy
    • Acute Lymphoblastic Leukemia (ALL): High-dose therapy as part of chemotherapy regimens.
    • Non-Hodgkin’s Lymphoma: Used in specific chemotherapy protocols.
    • Choriocarcinoma: Effective in treating this rare cancer.
  3. Ectopic Pregnancy
    • Used to terminate ectopic pregnancies by stopping the growth of embryonic cells.
  4. Other Off-Label Uses
    • Crohn’s disease, sarcoidosis, and uveitis.

Mechanism of Action

  • Methotrexate inhibits dihydrofolate reductase, blocking the conversion of dihydrofolate to tetrahydrofolate.
  • This disrupts DNA synthesis, primarily affecting rapidly dividing cells such as immune cells and cancer cells.

Forms, Brand Names, and Costs

  1. Available Forms
    • Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg.
    • Injectable: 25 mg/mL (subcutaneous, intramuscular, or intravenous).
  2. Brand Names
    • USA: Rheumatrex, Trexall, Otrexup, Rasuvo.
    • Manufacturers: Pfizer, Amgen, Teva Pharmaceuticals.
  3. Cost
    • Tablets: $10–$50 per month (depending on dosage).
    • Injections: $100–$500 per dose (brand-specific).

Dosing and Administration

  1. For Autoimmune Conditions
    • Start with 7.5–15 mg orally or subcutaneously once weekly.
    • Increase to a maximum of 25 mg weekly, if tolerated.
  2. For Cancer
    • High-dose regimens (variable dosing) administered in cycles.
  3. For Ectopic Pregnancy
    • Single-dose protocol: 50 mg/m² intramuscularly.
  4. Folic Acid Supplementation
    • 1 mg daily to reduce methotrexate toxicity.

Contraindications

  • Hypersensitivity to methotrexate.
  • Severe renal or hepatic impairment.
  • Active infections, including tuberculosis.
  • Pregnancy and breastfeeding (teratogenic).

Precautions

  • Monitor liver function and renal function regularly.
  • Use contraception during treatment and for 6 months after discontinuation.
  • Avoid alcohol to minimize liver toxicity.
  • Increased risk of infection; counsel patients to report fever or signs of infection immediately.

Common Side Effects

  1. Gastrointestinal
    • Nausea, vomiting, diarrhea, and mouth sores.
  2. Hematological
    • Anemia, leukopenia, thrombocytopenia.
  3. Liver Toxicity
    • Elevated liver enzymes, long-term fibrosis, or cirrhosis.
  4. Other
    • Fatigue, hair thinning, and skin rash.

Serious Side Effects

  • Pulmonary toxicity (pneumonitis).
  • Hepatotoxicity (irreversible liver damage).
  • Bone marrow suppression (life-threatening pancytopenia).
  • Severe infections, including opportunistic infections.

Drug Interactions

  1. Increased Toxicity
    • NSAIDs (e.g., ibuprofen, naproxen): Reduce methotrexate clearance.
    • Antibiotics (e.g., trimethoprim, sulfonamides): Additive bone marrow suppression.
  2. Reduced Effectiveness
    • Proton pump inhibitors (PPIs): Delay methotrexate elimination.
  3. Folic Acid Antagonism
    • Avoid excessive folate supplementation, as it may reduce methotrexate efficacy.

Monitoring Parameters

  • Blood Tests: CBC, liver function tests (LFTs), and renal function every 4–8 weeks.
  • Chest X-Ray: Baseline and periodic checks for pneumonitis.
  • Pregnancy Tests: For women of childbearing potential before initiating therapy.

Patient Counseling Points

  • Take methotrexate exactly as prescribed; do not exceed the weekly dose.
  • Use contraception during treatment and for 6 months afterward.
  • Avoid alcohol and stay hydrated to protect the liver and kidneys.
  • Report symptoms of infection, unusual bruising, or persistent fatigue immediately.
  • Folic acid supplementation can help reduce side effects but must be taken as directed.

Use in Children

  • Dosing is weight- or surface area-based, especially in juvenile idiopathic arthritis (JIA) or leukemia.
  • Monitor growth and development during treatment.

Use in Pregnancy

  • Contraindicated due to teratogenic effects.
  • Consult a healthcare provider for alternative treatments.

Use in Elderly

  • Start with a lower dose due to increased sensitivity to side effects, especially renal impairment.

FAQs About Methotrexate

Q1: What conditions is methotrexate used to treat?

  • Rheumatoid arthritis, psoriasis, certain cancers, ectopic pregnancy, and off-label for Crohn’s disease.

Q2: How long does methotrexate take to work for autoimmune diseases?

  • 4–6 weeks for symptom improvement, with full effects in 12 weeks.

Q3: Can methotrexate cause hair loss?

  • Yes, mild hair thinning is a possible side effect.

Q4: Is alcohol allowed during methotrexate treatment?

  • No, alcohol increases the risk of liver damage.

Q5: Can methotrexate be stopped suddenly?

  • Discontinuation should be done under medical supervision to prevent disease flare-ups.

Q6: What should I do if I miss a dose?

  • Take it as soon as possible unless it’s close to the next dose. Never double-dose.

Q7: Can methotrexate interact with over-the-counter medications?

  • Yes, avoid NSAIDs without consulting your doctor.

Q8: How is methotrexate toxicity treated?

  • Administer leucovorin rescue (folinic acid) to counteract toxicity.

Q9: Does methotrexate weaken the immune system?

  • Yes, it suppresses the immune system, increasing infection risk.

Q10: What are the signs of methotrexate toxicity?

  • Severe fatigue, mouth ulcers, shortness of breath, or dark urine.

Q11: Can methotrexate be used long-term?

  • Yes, with regular monitoring to manage side effects and toxicity.

Q12: Is methotrexate safe for children?

  • Yes, in conditions like juvenile idiopathic arthritis (JIA), with dose adjustments and monitoring.