Dronedarone × Itraconazole

The liver breaks down dronedarone mainly through the enzyme CYP3A4, and itraconazole strongly inhibits this enzyme (labels of both drugs). No study has looked at this pair directly. According to the itraconazole label, itraconazole is likely to raise dronedarone levels. The dronedarone label reports a 17-fold rise in dronedarone levels with ketoconazole 200 mg a day, another strong inhibitor of the enzyme. The QT interval gets longer as dronedarone concentration rises. The itraconazole labels explain the contraindication for such drugs by the risk of ventricular tachyarrhythmias, including life-threatening torsade de pointes. Beyond the kinetics, both drugs carry a risk for the heart muscle. Itraconazole has a negative inotropic effect and has been linked to congestive heart failure. Dronedarone reduces myocardial contractility and is contraindicated in current or past heart failure (labels of both drugs).

The main risk is ventricular arrhythmia from a prolonged QT interval, up to life-threatening torsade de pointes: palpitations, skipped beats, dizziness, fainting. Both drugs list a slow heart rate (bradycardia) among their adverse effects. Both can cause new heart failure or make it worse. Signs include increasing shortness of breath, rapid weight gain and swelling of the legs.

The combination is contraindicated in the labels of both drugs: dronedarone (European Medicines Agency, EMA, and US Food and Drug Administration, FDA) and itraconazole (Spanish Agency of Medicines and Medical Devices, AEMPS, and FDA). Do not give dronedarone during itraconazole treatment or for 2 weeks after itraconazole is stopped (itraconazole labels, AEMPS and FDA). After itraconazole is stopped, its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other inhibitors of the enzyme CYP3A4 (itraconazole label, AEMPS). If itraconazole has been started during dronedarone treatment, stop dronedarone: the label requires stopping it whenever any contraindicated condition develops (dronedarone label, EMA). Correct potassium and magnesium before starting dronedarone and keep them in the normal range during treatment (dronedarone 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). If signs of heart failure appear, stop itraconazole (itraconazole labels, AEMPS and FDA) and dronedarone (dronedarone label, EMA).