Pimozide × Sotalol

Sotalol is a class III antiarrhythmic: it lengthens ventricular repolarisation and the QT interval, which is both its therapeutic action and its main risk. According to the label (Sotapor, 4.4), the rate of serious proarrhythmia rises with the dose: 0.5% at 81–160 mg/day, 1.8% at 161–320 mg/day, 4.5% at 321–480 mg/day. Pimozide prolongs QT on its own: its label describes QT prolongation, ventricular arrhythmias, torsade de pointes and sudden death even in patients without risk factors (Orap, 4.4). The effects add up, and the FDA pimozide label expects an additive effect on QT with antiarrhythmic agents. The interaction is purely pharmacodynamic; the documents describe no kinetic component.

QT and QTc prolongation on the ECG, flattening or inversion of the T wave, appearance of a U wave (pimozide label), then torsade de pointes, sustained ventricular tachycardia or ventricular fibrillation, sudden death. The patient experiences palpitations, dizziness or syncope. The risk is higher with a pre-treatment QTc above 450 ms, heart rate below 60 beats per minute, hypokalaemia and hypomagnesaemia, in women, with reduced creatinine clearance, heart failure and a history of ventricular arrhythmias (sotalol labels).

The combination is contraindicated from both sides. The AEMPS sotalol label (Sotapor, 4.3) bars sotalol with QT-prolonging drugs and names pimozide; the AEMPS pimozide label (Orap, 4.3 and 4.5) bars pimozide with such drugs and names sotalol. The FDA pimozide label contraindicates use with any drug that prolongs the QT interval and names sotalol in Drug Interactions. The FDA sotalol label (Betapace, 5.1) says to avoid the combination. If a patient is on both, the torsade-inducing drug is withdrawn. If the combination cannot be avoided, QT is measured before starting and the ECG is monitored (sotalol label, 4.5). Sotalol is started in hospital with continuous ECG monitoring for at least 3 days, after a baseline ECG, normalised potassium and magnesium and a creatinine clearance to set the dosing interval; QTc is checked 2–4 hours after each dose increase (Betapace, 2.1). Sotalol is contraindicated at serum potassium below 4 mEq/L (Betapace, 4). Starting at 80 mg with gradual titration lowers the proarrhythmia risk; at QTc above 480 ms on treatment, benefit and risk are reassessed and dose reduction or withdrawal is seriously considered (Sotapor, 4.4). Pimozide needs an ECG before the start and periodically during treatment, and is stopped at QT or QTc above 500 ms (Orap, 4.4). The FDA label rules out further dose increases at QTc above 0.52 s in adults (0.47 s in children) or more than 25% above baseline. Potassium is corrected before pimozide and kept normal (FDA pimozide label); potassium-wasting diuretics are avoided with pimozide (Orap, 4.5).