Fluvoxamine × Pimozide

The liver breaks down pimozide mainly through the enzymes CYP3A4 and CYP2D6, and to a lesser extent CYP1A2 (pimozide label). Fluvoxamine inhibits all three: CYP1A2 strongly, CYP3A4 and CYP2D6 to a lesser degree (fluvoxamine label). The US fluvoxamine label considers it a likely potent CYP3A4 inhibitor because fluvoxamine 100 mg daily roughly doubled the plasma concentrations of alprazolam, a CYP3A4 substrate (fluvoxamine label, US Food and Drug Administration, FDA). The Spanish fluvoxamine label explains the contraindication by the narrow therapeutic index of pimozide and its known ability to prolong the QT interval. According to the US label, raised pimozide levels prolong QT and have been linked to torsade de pointes, sometimes fatal. The labels give no study of pimozide levels with fluvoxamine.

QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). The danger is ventricular arrhythmia: torsade de pointes, ventricular tachycardia and ventricular fibrillation, up to cardiac arrest and sudden death (pimozide and fluvoxamine labels). An episode presents as palpitations, dizziness or fainting. Excess pimozide also strengthens its usual effects, above all extrapyramidal ones: tremor, muscle rigidity and akathisia, an inability to sit still (pimozide label). The risk of arrhythmia is higher with low potassium or magnesium and with a slow heart rate (pimozide label).

The combination is contraindicated. The Spanish fluvoxamine summary of product characteristics (SmPC) bans it in both the contraindications and the interactions sections (fluvoxamine SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The US label lists it under contraindications (fluvoxamine label, US Food and Drug Administration, FDA). The US pimozide label places fluvoxamine among the less potent inhibitors of the enzyme CYP3A4 that should also be avoided (pimozide label, FDA). The Spanish pimozide SmPC contraindicates pimozide with any inhibitor of CYP3A4 or CYP2D6 (pimozide SmPC, AEMPS). If a patient taking pimozide needs an antidepressant, do not prescribe fluvoxamine. If a patient already takes both drugs, stop one of them. Many other antidepressants are also ruled out with pimozide: sertraline, paroxetine, citalopram and escitalopram by name, fluoxetine as a CYP2D6 inhibitor and tricyclic antidepressants as drugs that prolong the QT interval (pimozide SmPC, AEMPS). Choose the replacement outside those lists. For any pimozide treatment, record an electrocardiogram (ECG) before the start and repeat it during treatment. Keep potassium and magnesium in the normal range, and stop pimozide if the QT or corrected QT (QTc) interval exceeds 500 ms (pimozide labels, AEMPS and FDA).