Can voriconazole and oxycodone be given together?

Voriconazole and Oxycodone Interaction: Clinical Management

Voriconazole significantly increases oxycodone exposure and should be used with caution, requiring substantial oxycodone dose reduction (approximately 50-75%) to prevent opioid toxicity.

Mechanism of Interaction

Voriconazole is a potent inhibitor of CYP3A4, which is the primary metabolic pathway for oxycodone. This interaction results in:

• 3.6-fold increase in oxycodone exposure (range 2.7-5.6 fold) 1
• 1.7-fold increase in peak plasma concentration of oxycodone 1
• 2.0-fold increase in elimination half-life of oxycodone 1
• 92% decrease in noroxycodone to oxycodone ratio (indicating inhibition of CYP3A4-mediated N-demethylation) 1
• 108% increase in oxymorphone (active metabolite) exposure 1

Clinical Implications and Management

Risk Assessment

This drug interaction poses significant risks:

• Opioid toxicity including excessive sedation, respiratory depression, and neurotoxicity 2
• Potentially fatal respiratory depression with repeated dosing
• Increased risk in patients with hepatic impairment, elderly, or those on multiple medications

Management Algorithm

1. Initial Assessment:

   • Determine necessity of both medications
   • Consider alternative antifungal therapy if appropriate
   • Evaluate patient risk factors (hepatic function, age, other medications)

2. If co-administration is necessary:

   • Reduce oxycodone dose by 50-75% initially
   • Monitor closely for signs of opioid toxicity (sedation, respiratory depression, confusion)
   • Consider therapeutic drug monitoring for voriconazole to maintain appropriate levels 3
   • Titrate oxycodone dose carefully based on clinical response

3. Monitoring Protocol:

   • Assess for opioid-related adverse effects every 4-6 hours during first 48 hours
   • Monitor for signs of neurotoxicity (confusion, hallucinations, myoclonus) 2
   • Evaluate pain control and adjust oxycodone dose as needed
   • Consider more frequent monitoring in high-risk patients

Special Considerations

Patient-Specific Factors

• Hepatic Impairment: Further dose reduction may be necessary as both drugs undergo hepatic metabolism 3
• Polypharmacy: Assess for other medications that may affect CYP3A4 pathway
• Cancer Patients: Particularly vulnerable due to common use of both medications and potential for multiple drug interactions 2

Common Pitfalls to Avoid

1. Failure to recognize the interaction: This is not a minor interaction and requires proactive management
2. Inadequate dose reduction: Starting with standard oxycodone doses can lead to toxicity
3. Insufficient monitoring: Close observation is essential, especially in the first 48-72 hours
4. Overlooking other drug interactions: Both medications have extensive drug interaction profiles 3

Evidence Quality Assessment

The evidence for this interaction is strong, with pharmacokinetic studies demonstrating a dramatic increase in oxycodone exposure 1 and case reports documenting neurotoxicity 2. The Infectious Diseases Society of America guidelines acknowledge the significant drug-drug interactions with azole antifungals 3, and NCCN guidelines specifically note the risk of QTc prolongation with voriconazole 3.

While methadone has been studied with voriconazole showing a 47% increase in exposure 4, the interaction with oxycodone is more pronounced (3.6-fold increase) 1, highlighting the importance of specific opioid considerations rather than generalizing across the class.