Fluconazole × Methadone

Fluconazole moderately inhibits CYP3A4 and CYP2C9 and strongly inhibits CYP2C19 (fluconazole SmPC). All of them take part in methadone metabolism, so methadone blood levels can rise (fluconazole and methadone labels). Both drugs prolong the QT interval: fluconazole blocks cardiac potassium channels directly, and methadone prolongs QT especially at high doses, above 100 mg a day according to the Spanish methadone SmPC.

Methadone excess: drowsiness, slow shallow breathing, pinpoint pupils; in severe cases life-threatening respiratory depression. QT prolongation on the ECG, palpitations, fainting, torsades de pointes.

The combination is not contraindicated but needs monitoring. Fluconazole can raise methadone levels, and the methadone dose may need adjustment (fluconazole SmPC). The US methadone label (FDA) advises considering a methadone dose reduction until the effect is stable when an inhibitor is added, and frequent checks for respiratory depression and sedation; after fluconazole is stopped, methadone levels fall and withdrawal signs can appear. Use fluconazole with caution in conditions that predispose to arrhythmia; low potassium and advanced heart failure raise the risk (fluconazole SmPC). The Spanish methadone SmPC lists CYP3A4 inhibitors, fluconazole among them, as a QT risk factor and advises an ECG before methadone starts, two weeks later and before a dose increase (methadone SmPC).