Amitriptyline × Fluconazole

Fluconazole moderately inhibits CYP2C9 and CYP3A4 and strongly inhibits CYP2C19 (fluconazole SmPC). The liver breaks down amitriptyline mainly through CYP2D6 and CYP2C19, with CYP3A4 and CYP2C9 also involved (amitriptyline SmPC). Fluconazole raises the levels of amitriptyline and its metabolite nortriptyline and increases their effect (both SmPCs). Each drug can prolong the QT interval on its own. The enzyme effect of fluconazole lasts 4–5 days after it is stopped (fluconazole SmPC).

Stronger amitriptyline side effects: dry mouth, constipation, urinary retention, drowsiness, fast heartbeat. Fainting and torsades de pointes have been reported with this combination (amitriptyline SmPC). The risk of dangerous arrhythmia is higher with low potassium and advanced heart failure (fluconazole SmPC).

The amitriptyline SmPC lists fluconazole among combinations that are not recommended: it raises the levels and toxicity of tricyclic antidepressants. If fluconazole cannot be avoided, measure nortriptyline and amitriptyline levels when co-treatment starts and after one week, and adjust the amitriptyline dose if needed (fluconazole SmPC). Use fluconazole with caution in conditions that predispose to arrhythmia (fluconazole SmPC), and amitriptyline with caution in significant bradycardia, decompensated heart failure and with other QT-prolonging drugs (amitriptyline SmPC). The fluconazole effect lasts 4–5 days after the last dose, so do not stop monitoring as soon as fluconazole is stopped (fluconazole SmPC). Terbinafine is not a substitute: the amitriptyline SmPC names it together with fluconazole, as it also raises tricyclic levels.