Does Zyflo (zileuton) interact with warfarin?

Zileuton (Zyflo) Causes a Significant Drug Interaction with Warfarin

Yes, zileuton (Zyflo) significantly increases warfarin levels and requires close INR monitoring and warfarin dose adjustment to prevent bleeding complications. 1

Mechanism of Interaction

Zileuton is a leukotriene synthesis inhibitor that affects warfarin metabolism through several mechanisms:

1. Direct FDA warning: The FDA label explicitly states that "zileuton increases warfarin levels" and recommends monitoring prothrombin time and adjusting warfarin dose accordingly 1

2. Cytochrome P450 interaction: Zileuton likely inhibits cytochrome P450 isoenzymes involved in warfarin metabolism, similar to other medications that interact with warfarin 2, 3

Clinical Implications

Monitoring Requirements

• INR monitoring: More frequent INR monitoring is essential when initiating zileuton in patients on warfarin therapy
• Timing: Check INR within 3-14 days of starting zileuton (early monitoring has been shown to decrease bleeding risk by 39%) 4
• Duration: Continue close monitoring throughout zileuton therapy and for a period after discontinuation

Dosage Adjustments

• Preemptive dose reduction: Consider a preventive reduction of warfarin dose when initiating zileuton therapy
• Individualized adjustment: The exact dose reduction should be based on subsequent INR results

Comparison to Other Drug Interactions with Warfarin

Zileuton's interaction with warfarin is similar to other known warfarin-interacting medications:

• Antibiotics: Trimethoprim/sulfamethoxazole (requires 25% warfarin dose reduction), fluoroquinolones, and macrolides significantly increase bleeding risk 5, 4
• Antidepressants: SSRIs double the risk of bleeding when combined with warfarin 2, 6
• NSAIDs: Double the risk of bleeding through both pharmacokinetic and pharmacodynamic mechanisms 2

Management Strategy

1. Before starting zileuton:

   • Obtain baseline INR
   • Consider a preemptive warfarin dose reduction

2. During zileuton therapy:

   • Monitor INR more frequently, especially during the first 2 weeks
   • Adjust warfarin dose based on INR results
   • Be vigilant for signs of bleeding

3. After discontinuing zileuton:

   • Continue close INR monitoring
   • Readjust warfarin dose as needed

Pitfalls to Avoid

• Delayed monitoring: Failure to check INR within the first 2 weeks of co-administration increases bleeding risk
• Ignoring minor bleeding signs: Even minor bleeding can progress to significant hemorrhage
• Abrupt discontinuation: Stopping either medication without appropriate monitoring and dose adjustment

Alternative Considerations

If the patient's clinical situation allows, consider alternatives to this drug combination when possible. However, when both medications are necessary, proper monitoring and dose adjustment can effectively manage the interaction.