Dronedarone × Voriconazole

The liver breaks down dronedarone mainly through the enzyme CYP3A4, and voriconazole strongly inhibits this enzyme (labels of both drugs). The labels give no study of this exact pair. The dronedarone label reports a 17-fold rise in dronedarone levels with ketoconazole 200 mg a day, another strong inhibitor of the enzyme. For this reason, it contraindicates voriconazole and other strong inhibitors. The QT interval gets longer as dronedarone concentration rises, and voriconazole prolongs the QT interval on its own. Dronedarone itself moderately inhibits CYP3A4, and the liver clears voriconazole partly through this enzyme. The documents give no figures for the rise in voriconazole levels.

The main risk of the pair is arrhythmia from a prolonged QT interval, up to torsade de pointes: palpitations, skipped beats, dizziness, fainting. As dronedarone levels rise, the QT and PR intervals on the electrocardiogram (ECG) get longer. A slow pulse is common with dronedarone even without other drugs. With voriconazole, rare cases of torsade de pointes have occurred in people with risk factors such as cardiomyopathy, low potassium, past cardiotoxic chemotherapy or other drugs taken at the same time.

The combination is contraindicated (dronedarone labels, European Medicines Agency, EMA, and US Food and Drug Administration, FDA). Both labels name voriconazole among the strong inhibitors of the enzyme CYP3A4. Stop a strong CYP3A4 inhibitor before starting dronedarone (dronedarone label, FDA). If voriconazole has been started during dronedarone treatment, stop dronedarone: the label requires stopping it whenever any contraindicated condition develops (dronedarone label, EMA). After stopping 400 mg twice daily, dronedarone and its metabolite are fully cleared from plasma within 2 weeks (dronedarone label, EMA). The documents set no specific interval before starting voriconazole. Correct potassium and magnesium before starting dronedarone and keep them in the normal range during treatment (dronedarone labels, EMA and FDA). Correct low potassium, magnesium and calcium before and during voriconazole treatment (voriconazole labels, EMA and FDA). Monitor the electrocardiogram (ECG) during dronedarone treatment and stop dronedarone if the QTc interval (QT corrected for heart rate) reaches 500 milliseconds or more (dronedarone label, EMA). In dronedarone overdose, monitor heart rhythm and blood pressure and give supportive treatment. There is no specific antidote (dronedarone labels, EMA and FDA).