Fluconazole × Pimozide

Pimozide is cleared in the liver mainly by CYP3A4, and fluconazole inhibits this enzyme. Pimozide levels rise, and pimozide itself prolongs the QT interval, so the risk of a dangerous ventricular arrhythmia, torsades de pointes, goes up (both SmPCs). Fluconazole keeps inhibiting the enzyme for 4–5 days after it is stopped (fluconazole SmPC).

QT prolongation on the ECG and ventricular arrhythmias, including torsades de pointes: palpitations, skipped beats, dizziness, fainting. Ventricular tachycardia, ventricular fibrillation and sudden death have been reported with pimozide (pimozide SmPC).

The combination is contraindicated in the Spanish SmPCs of fluconazole and pimozide and in the FDA fluconazole label. Lowering the pimozide dose does not remove the risk, and no document allows it. For a fungal infection in a patient on pimozide, choose a drug that does not inhibit CYP3A4 or CYP2D6: the pimozide SmPC contraindicates inhibitors of both enzymes. If fluconazole has already been given, start pimozide no earlier than 4–5 days after fluconazole is stopped, when its effect on the enzyme has worn off (fluconazole SmPC). Do an ECG before starting pimozide and periodically during treatment. If QT prolongation or an arrhythmia appears, review the need for pimozide; pimozide is contraindicated with low potassium or magnesium (pimozide SmPC).