From the Guidelines
Posaconazole and methadone can be used together, but careful monitoring is required due to potential drug interactions. Posaconazole may increase methadone levels by inhibiting CYP3A4 enzymes that metabolize methadone, potentially leading to increased sedation, respiratory depression, or QT interval prolongation, as noted in the context of azole-associated drug–drug interactions 1. When initiating posaconazole in a patient on methadone, it is recommended to maintain the current methadone dose initially but monitor for signs of opioid toxicity including drowsiness, confusion, pinpoint pupils, and respiratory depression. Consider reducing the methadone dose by 25-50% if toxicity develops. Some key considerations include:
- ECG monitoring is recommended before and during co-administration to assess for QT interval prolongation, given that posaconazole, like other azoles, may cause QTc prolongation 1.
- Patients should be educated to report symptoms such as excessive drowsiness, dizziness, or irregular heartbeat.
- The interaction may persist for several days after posaconazole discontinuation due to its long half-life.
- Alternative antifungal therapy could be considered if the patient is on a stable methadone regimen for opioid use disorder to avoid disrupting treatment. Given the potential for serious drug–drug interactions, particularly through the inhibition of the cytochrome P450 3A4 isoenzyme, careful management and monitoring are essential when co-administering posaconazole and methadone 1.
From the Research
Posaconazole and Methadone Interaction
- There is no direct evidence of an interaction between posaconazole and methadone in the provided studies.
- However, a study on voriconazole, which is similar to posaconazole, found that it increased the steady-state exposure of methadone, particularly the (S)-methadone enantiomer 2.
- Posaconazole is known to inhibit cytochrome P450-dependent 14-alpha demethylase, but it is not significantly metabolized through the cytochrome P450 enzyme system and is primarily excreted in an unchanged form in the feces 3.
- Posaconazole may increase plasma concentrations of concomitantly applied drugs that undergo an extensive first-pass effect through gut and liver due to its CYP3A inhibiting potency 4.
Methadone-Associated QT Interval Prolongation
- Methadone is associated with QT interval prolongation, which can increase the risk of torsades de pointes and sudden cardiac arrest 5, 6.
- A study found that approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation, and serum (S)- and (R)-methadone concentrations contributed to this prolongation 6.
- Another study found that QTc interval prolongation was correlated with the frequency of respiratory arrest, endotracheal intubation, and mortality in acute methadone overdose 5.