Summary

Itraconazole significantly increases oxycodone plasma concentrations by inhibiting CYP3A4 metabolism, potentially leading to enhanced opioid effects and increased risk of respiratory depression. This interaction requires careful monitoring and possible dose adjustments when these medications are used concurrently.

Introduction

Itraconazole is a triazole antifungal medication commonly prescribed for systemic fungal infections, including aspergillosis, blastomycosis, and histoplasmosis. It works by inhibiting fungal cytochrome P450 enzymes, particularly CYP3A4. Oxycodone is a semi-synthetic opioid analgesic used for moderate to severe pain management. It belongs to the phenanthrene class of opioids and is metabolized primarily through the CYP3A4 and CYP2D6 pathways in the liver.

Mechanism of Interaction

The interaction between itraconazole and oxycodone occurs through competitive inhibition of the CYP3A4 enzyme system. Itraconazole is a potent CYP3A4 inhibitor that significantly reduces the hepatic metabolism of oxycodone. Since CYP3A4 is responsible for the N-demethylation of oxycodone to noroxycodone (an inactive metabolite), inhibition of this pathway leads to increased plasma concentrations and prolonged half-life of the parent drug. This results in enhanced and prolonged opioid effects, including analgesia, sedation, and respiratory depression.

Risks and Symptoms

The primary clinical risk of this interaction is oxycodone toxicity, manifesting as excessive sedation, respiratory depression, and potentially life-threatening central nervous system depression. Studies have shown that itraconazole can increase oxycodone AUC by up to 240% and peak plasma concentrations by approximately 170%. Patients may experience prolonged and intensified opioid effects, including dizziness, confusion, constipation, and in severe cases, respiratory failure. The risk is particularly elevated in elderly patients, those with compromised respiratory function, or individuals taking other CNS depressants concurrently.

Management and Precautions

When concurrent use is necessary, consider reducing the initial oxycodone dose by 50-75% and titrate carefully based on clinical response. Monitor patients closely for signs of opioid toxicity, including respiratory rate, oxygen saturation, level of consciousness, and pain control. Extend monitoring periods as the interaction may persist for several days after discontinuing itraconazole due to its long half-life. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (though it also has some inhibitory effects) or non-azole antifungals when clinically appropriate. Educate patients and caregivers about signs of opioid overdose and ensure naloxone availability when indicated.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

Oxycodone interactions with food and lifestyle

Alcohol: Concurrent use of oxycodone with alcohol significantly increases the risk of respiratory depression, sedation, and potentially fatal overdose. Patients should avoid alcohol consumption while taking oxycodone. Grapefruit juice: May increase oxycodone blood levels by inhibiting CYP3A4 metabolism, potentially leading to increased side effects and toxicity. Patients should avoid grapefruit and grapefruit juice during oxycodone therapy.