Pimozide × Sertraline

Sertraline raises pimozide concentrations. With a single 2 mg dose of pimozide on top of sertraline 200 mg/day at steady state, pimozide AUC and Cmax rose by about 40% (pimozide label Orap, 4.5; FDA Zoloft label, 12.3). The sertraline label quotes about 35% (4.5). The mechanism is unknown (sertraline label, 4.5). The pimozide label suggests that serotonin reuptake inhibitors may inhibit its CYP2D6 metabolism and names paroxetine and fluoxetine (Orap, 4.5). Pimozide has a narrow therapeutic index, and higher concentrations raise the risk of QTc prolongation and ventricular arrhythmias (Zoloft label, 7.1). Sertraline itself prolongs QTc in a concentration-dependent way (sertraline label, 4.4; Zoloft, 5.10), so the pharmacodynamic effect on repolarisation comes on top of the kinetic interaction. Pimozide doses above 2 mg have not been studied with sertraline (Zoloft, 12.3).

QTc prolongation on the ECG, T-wave changes and U waves (pimozide label), torsade de pointes, ventricular arrhythmias, sudden death. The patient experiences palpitations, dizziness or syncope. With pimozide 2 mg the study showed no ECG change, but there are no data for higher doses (Zoloft, 12.3). The risk is higher with hypokalaemia and hypomagnesaemia, bradycardia, heart disease and a family history of QT prolongation (sertraline label, 4.4). It is also higher in CYP2D6 poor metabolisers, 5–10% of the population, whose pimozide concentrations match those seen with strong inhibitors (Orap, 4.4).

The combination is contraindicated from both sides. The AEMPS sertraline label (4.3) bars use with pimozide outright, and the AEMPS pimozide label (Orap, 4.3) bars pimozide with serotonin reuptake inhibitors and names sertraline. The FDA labels say the same: sertraline is contraindicated in patients taking pimozide (Zoloft, section 4), and pimozide is contraindicated in patients on sertraline (Contraindications). If a patient is already on both, the combination is stopped and an ECG is recorded. Another drug of the same class is not an automatic replacement. The pimozide label also contraindicates paroxetine, citalopram and escitalopram (Orap, 4.3) and names fluoxetine as a CYP2D6 inhibitor (Orap, 4.5); the FDA label says to avoid fluvoxamine as a CYP3A4 inhibitor and reports bradycardia with fluoxetine. Pimozide needs an ECG before the start and periodically during treatment, and is stopped at QT or QTc above 500 ms (Orap, 4.4). Hypokalaemia and hypomagnesaemia are contraindications for it (Orap, 4.3); potassium is corrected before the start and kept normal (FDA label). Sertraline is used with caution in patients with risk factors for QTc prolongation (sertraline label, 4.4; Zoloft, 5.10).