What is the interaction between oxycodone and fluconazole?

Interaction Between Oxycodone and Fluconazole

Fluconazole significantly increases oxycodone plasma concentrations by inhibiting CYP3A4 enzymes, potentially leading to opioid toxicity including respiratory depression. 1

Mechanism of Interaction

The interaction between oxycodone and fluconazole occurs primarily through the inhibition of hepatic metabolic pathways:

• Oxycodone is mainly metabolized by the cytochrome P450 (CYP) enzyme system, particularly:

  • CYP3A4 (primary pathway)
  • CYP2D6 (secondary pathway)

• Fluconazole is a potent inhibitor of:

  • CYP3A4 (moderate to strong inhibition)
  • CYP2C9 (strong inhibition)
  • CYP2C19 (moderate inhibition) 1, 2

When these medications are used concomitantly, fluconazole blocks the metabolism of oxycodone, leading to:

• Increased oxycodone plasma concentrations
• Prolonged elimination half-life
• Potentially enhanced and prolonged opioid effects

Clinical Significance

Research demonstrates that when both CYP3A4 and CYP2D6 pathways are inhibited, exposure to intravenous oxycodone increases approximately 2-fold, and the elimination half-life is prolonged from 3.8 to 6.6 hours 3. Similar effects can be expected with oral oxycodone.

This interaction can result in:

• Excessive sedation
• Respiratory depression (most concerning adverse effect)
• Hypotension
• Increased risk of opioid toxicity
• Potentially fatal outcomes in severe cases

Management Recommendations

1. Dose Adjustment:

   • Reduce oxycodone dose by 30-50% when initiating fluconazole
   • Titrate slowly based on clinical response

2. Monitoring:

   • Closely monitor for signs of opioid toxicity:
     • Excessive sedation
     • Respiratory depression (rate <12/min or shallow breathing)
     • Pinpoint pupils
     • Mental status changes

3. Alternative Options:

   • Consider using an alternative antifungal with less CYP3A4 inhibition if appropriate
   • For pain management, consider opioids less dependent on CYP3A4 metabolism

4. Patient Education:

   • Instruct patients to report increased drowsiness, confusion, or breathing difficulties
   • Advise against alcohol consumption which can compound CNS depression

Special Considerations

• Duration of Effect: The inhibitory effect of fluconazole can persist for several days after discontinuation due to its long half-life (approximately 30 hours)

• Renal Impairment: Patients with decreased renal function may experience more pronounced interactions due to decreased clearance of fluconazole 4

• Elderly Patients: More susceptible to adverse effects due to age-related changes in drug metabolism and increased sensitivity to CNS depressants

• Polypharmacy: Be aware of other medications that might inhibit CYP enzymes, as they could further compound this interaction

Common Pitfalls

1. Failure to recognize the interaction: Many clinicians underestimate the significance of this drug interaction

2. Inadequate dose adjustment: Not reducing oxycodone dose when starting fluconazole therapy

3. Insufficient monitoring: Lack of close observation for signs of opioid toxicity, especially respiratory depression

4. Abrupt discontinuation: Stopping fluconazole without adjusting oxycodone dose upward may lead to inadequate pain control

This interaction requires careful clinical management to balance effective pain control while preventing potentially serious adverse effects from opioid toxicity.