Ketoconazole × Ranolazine

Ranolazine is a substrate of two proteins: the enzyme CYP3A4, which breaks it down in the gut and liver, and the transport protein P-glycoprotein (P-gp). Ketoconazole strongly inhibits both CYP3A4 and P-gp. At 200 mg twice daily, it raised the ranolazine area under the curve (AUC) 3.0–3.9-fold. In the European Union, ketoconazole tablets are used for Cushing's syndrome at 400–1200 mg a day. The European ketoconazole prescribing information warns that interactions may be stronger at doses above 200 mg. Both drugs prolong the QT interval on the electrocardiogram. The ketoconazole documents base the contraindication on the risk of serious cardiovascular events, up to life-threatening ventricular arrhythmias.

Excess ranolazine causes dizziness, nausea and vomiting, and at high concentrations double vision, lethargy, confusion and fainting. Reported effects of oral ranolazine overdose include low blood pressure, slow heart rate, QT interval prolongation on the electrocardiogram, severe tremor, unsteady gait and hallucinations. When ketoconazole is combined with QT-prolonging drugs, ventricular arrhythmias can occur, including life-threatening torsade de pointes.

The combination is contraindicated (ketoconazole summary of product characteristics, SmPC, European Medicines Agency, EMA; ranolazine SmPC, EMA; labels of both drugs, US Food and Drug Administration, FDA). Do not give ranolazine during the week after ketoconazole is stopped (ketoconazole label, FDA). Review all concomitant medicines before starting ketoconazole (ketoconazole SmPC, EMA). Ketoconazole is contraindicated in documented congenital or acquired QT interval prolongation. Record an electrocardiogram before treatment, within the first week and then as clinically indicated (ketoconazole SmPC, EMA). If the patient also takes other QT-prolonging drugs, continue electrocardiogram monitoring (ketoconazole SmPC, EMA). The contraindication concerns oral ketoconazole. After adults applied ketoconazole gel to the scalp or skin, no measurable ketoconazole was found in plasma (ketoconazole gel SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). If a patient has taken both drugs and develops dizziness, vomiting, double vision or fainting, observe the patient closely and give symptomatic and supportive care (ranolazine SmPC, EMA). Monitor the electrocardiogram continuously if needed (ranolazine label, FDA).