Methotrexate: Uses, Dosage & Side Effects

10 min read

Quick Facts

What Is Methotrexate?

Methotrexate is a dihydrofolate reductase inhibitor and antimetabolite that suppresses immune responses and has anti-inflammatory properties. It is a cornerstone DMARD for rheumatoid arthritis.

How Methotrexate Works
Methotrexate inhibits dihydrofolate reductase, blocking folate-dependent nucleotide synthesis. At low doses used for RA, it accumulates in inflammatory cells and inhibits polyamine and aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, resulting in adenosine accumulation and anti-inflammatory effects.

Indications

  • Rheumatoid arthritis (first-line DMARD)
  • Psoriasis and psoriatic arthritis
  • Polyarticular juvenile idiopathic arthritis
  • Ankylosing spondylitis (off-label)
  • Systemic lupus erythematosus (off-label)
  • Acute leukemia, lymphoma, osteosarcoma
  • Ectopic pregnancy (medical management)

Dosage and Administration

CRITICAL: METHOTREXATE IS DOSED WEEKLY, NOT DAILY

Rheumatoid Arthritis:

  • Initial: 7.5 mg once weekly
  • Increase by 2.5 mg every 4-8 weeks
  • Maintenance: 15-25 mg once weekly
  • Maximum: 25 mg weekly (rarely exceeded)

Route Options:

  • Oral tablets: taken as single weekly dose or divided into 3 doses over 12 hours on one day/week
  • Subcutaneous/IM injection: preferred for better bioavailability, used if oral GI intolerance
  • Intrathecal: only for CNS malignancies (specialized administration)

Folic Acid Supplementation (MANDATORY):

  • 1 mg daily on days NOT taking methotrexate
  • OR 5 mg once weekly (taken 24 hours after methotrexate)
  • Reduces toxicity and GI side effects
Clinical Note
FATAL if given daily by mistake instead of weekly. All prescriptions and patient education must emphasize WEEKLY dosing. Baseline CBC, liver function tests, and renal function essential. Monthly monitoring required initially, then every 8-12 weeks once stable.

Side Effects

Common: Nausea, mouth ulcers, stomatitis, fatigue, headache, alopecia Serious: Hepatotoxicity/cirrhosis, myelosuppression, severe infection, pulmonary toxicity (interstitial pneumonitis), teratogenicity/abortifacient, nephrotoxicity, opportunistic infections (especially TB reactivation with concurrent biologics)

Warning
Methotrexate is highly teratogenic and contraindicated in pregnancy. Women and men of childbearing potential require effective contraception. Hepatotoxicity and cirrhosis develop with chronic use; baseline imaging and periodic monitoring essential. WEEKLY DOSING CRITICAL—daily administration is fatal. Monitor for signs of hepatotoxicity, bone marrow suppression, and infection. Concurrent NSAIDs may increase renal toxicity; monitor renal function closely.

Contraindications

  • Pregnancy (highly teratogenic)
  • Breastfeeding (excreted in breast milk)
  • Severe hepatic disease or cirrhosis
  • Severe renal impairment (CrCl <30 mL/min)
  • Severe bone marrow suppression
  • Active infection
  • Hypersensitivity to methotrexate

Drug Interactions

  • NSAIDs: increased methotrexate nephrotoxicity; monitor renal function
  • Trimethoprim-sulfamethoxazole: increased methotrexate toxicity; avoid if possible
  • Proton pump inhibitors: may increase methotrexate levels
  • Penicillins: decreased renal clearance of methotrexate; potential toxicity
  • Acetylsalicylic acid: reduced clearance of methotrexate
  • Theophylline: methotrexate decreases theophylline clearance

Key Clinical Evidence

Multiple RCTs (ATTRACT, BeSt) demonstrate methotrexate as cornerstone first-line DMARD for RA. Combination therapy with biologic agents shows superior outcomes. Toxicity is manageable with appropriate monitoring.

Monitoring Parameters

  • Baseline assessment before initiating therapy
  • Regular clinical follow-up per indication
  • Laboratory parameters as specified in sections above
  • Drug interaction screening at each visit

Special Populations

Dosing adjustments may be necessary in:

  • Renal impairment
  • Hepatic impairment
  • Elderly patients
  • Pregnancy and lactation
  • Pediatric patients

Patient Counseling

  • Take exactly as directed; do not modify dose without consulting healthcare provider
  • Report any unusual symptoms or adverse effects
  • Maintain regular follow-up appointments
  • Store at room temperature away from moisture and light
  • Keep out of reach of children

Disclaimer: This information is for educational purposes only and should not substitute for professional medical advice. Always consult with a qualified healthcare provider before starting, stopping, or modifying any medication.

Sources

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Last updated: 2024-01-01Sources: 2

The content on Medical Atlas is for informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider.