What are the most common drug interactions with methotrexate?

Most Common Drug Interactions with Methotrexate

The most common drug interactions with methotrexate involve NSAIDs, trimethoprim-sulfamethoxazole, and other medications that affect renal elimination or protein binding, which can significantly increase methotrexate toxicity and lead to potentially life-threatening complications. 1

Key Drug Interaction Categories

1. Medications Affecting Renal Elimination

• NSAIDs (Non-steroidal anti-inflammatory drugs):

  • Particularly naproxen, diclofenac, ibuprofen, and indomethacin
  • Mechanism: Reduce renal elimination of methotrexate
  • Risk: Can lead to significant morbidity and mortality 1
  • Note: Not all NSAIDs interact equally; celecoxib may have less interaction

• Other agents affecting renal elimination:

  • Salicylates
  • Probenecid
  • Cyclosporine
  • Penicillins
  • Proton pump inhibitors (possible reduction) 1, 2

2. Antibiotics

• Trimethoprim-sulfamethoxazole (co-trimoxazole):

  • Highest risk antibiotic interaction
  • Mechanism: Antifolate effects and reduced renal clearance
  • Outcome: Bone marrow suppression, immunosuppression
  • Should be avoided in patients taking methotrexate 1

• Other antibiotics of concern:

  • Penicillins
  • Tetracyclines (including minocycline)
  • Ciprofloxacin and other fluoroquinolones
  • Chloramphenicol 1

3. Medications Affecting Protein Binding

• Mechanism: Displacement of methotrexate from serum albumin binding sites
• Key medications:
  • Phenytoin
  • Sulfonamides
  • Tetracyclines
  • Salicylates 1

4. Hepatotoxic Medications

• Concomitant use increases risk of liver damage:
  • Alcohol (any amount)
  • Statins
  • Azathioprine
  • Leflunomide
  • Retinoids 1

5. Medications Causing Folate Deficiency

• Mechanism: Exacerbate methotrexate's antifolate effects
• Key medications:
  • Trimethoprim
  • Sulfonamides
  • Barbiturates
  • Nitrofurantoin 1

Clinical Management Approach

Risk Assessment

1. Obtain detailed medication history before initiating methotrexate
2. Identify high-risk patients:
   • Elderly patients
   • Renal impairment (85% of methotrexate is renally excreted)
   • Hypoalbuminemia
   • History of alcohol use 1

Monitoring Recommendations

• Enhanced monitoring when potentially interacting medications must be used:
  • More frequent CBC and liver function tests
  • Monitor renal function closely
  • Consider temporary methotrexate discontinuation for severe infections requiring antibiotics 1

Managing Toxicity

• Signs of toxicity: Fever, mouth ulceration, myelosuppression, elevated liver enzymes 3, 4
• Intervention:
  • Discontinue methotrexate
  • Initiate leucovorin rescue as soon as possible (within 24 hours) 5
  • Aggressive hydration (3-4 L/m²/day)
  • Urinary alkalinization to maintain pH >7.0 5
  • Consider glucarpidase in cases of severe toxicity with renal insufficiency 5

Common Pitfalls and Caveats

1. Underestimating interaction severity: Even low-dose methotrexate can lead to severe toxicity when interacting medications are present 6

2. Overlooking renal function: Methotrexate elimination is reduced in patients with impaired renal function, making drug interactions more dangerous 6

3. Temporary antibiotic use: For severe infections requiring antibiotics that interact with methotrexate, consider temporarily stopping methotrexate until the infection resolves and antibiotic course is complete 1

4. Alcohol consumption: Complete abstinence from alcohol is advised during methotrexate therapy due to increased hepatotoxicity risk 1

5. Piperacillin-tazobactam interaction: Recent evidence shows significant interaction with high-dose methotrexate, causing neurotoxicity and renal failure 7

By understanding these common drug interactions and implementing appropriate monitoring strategies, clinicians can significantly reduce the risk of methotrexate toxicity and improve patient outcomes.