Itraconazole × Ivabradine

In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and itraconazole strongly inhibits this enzyme (ivabradine and itraconazole summaries of product characteristics, SmPCs). When the two are taken together, ivabradine levels in the blood rise, and high levels can lead to excessive bradycardia (ivabradine SmPC, European Medicines Agency, EMA). The documents give no figures for itraconazole itself. Ketoconazole, another azole antifungal, raised mean ivabradine plasma exposure 7- to 8-fold at 200 mg once daily (ivabradine SmPC, EMA). Itraconazole keeps acting after the last dose. Its plasma levels take 7–14 days to become almost undetectable, and even longer in liver cirrhosis or with other CYP3A4 inhibitors (itraconazole SmPC). A second risk concerns the heart itself. Itraconazole has a negative inotropic effect and has been linked to cases of congestive heart failure, while ivabradine is also used in chronic heart failure (itraconazole and ivabradine SmPCs).

Excessive bradycardia shows as a resting heart rate below 50 beats per minute, dizziness, fatigue and low blood pressure (ivabradine summary of product characteristics, European Medicines Agency, EMA). Sinus arrest and heart block can occur (Corlanor label, US Food and Drug Administration, FDA). Marked bradycardia raises the risk of QT interval prolongation and severe ventricular arrhythmia, including torsade de pointes (Corlanor label, FDA). Signs of congestive heart failure during itraconazole treatment: shortness of breath, swelling of the feet, ankles or legs, sudden weight gain, increased tiredness, coughing up white or pink mucus, fast heartbeat, waking up at night more than usual (Sporanox label, FDA).

The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists itraconazole among the strong inhibitors of the enzyme CYP3A4 (cytochrome P450 3A4) that must not be taken with ivabradine (European Medicines Agency, EMA, sections 4.3 and 4.5). The itraconazole SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US labels of both drugs also contraindicate the combination (US Food and Drug Administration, FDA). So during itraconazole treatment, pause ivabradine or choose another antifungal (this follows from the contraindication in both labels). When choosing another antifungal, note that strong CYP3A4 inhibitors are contraindicated with ivabradine (ivabradine label, FDA, 4). With moderate inhibitors, start ivabradine only at 2.5 mg twice daily, with a resting heart rate above 70 beats per minute and heart rate monitoring (ivabradine SmPC, EMA, 4.5), or avoid these inhibitors altogether (ivabradine label, FDA, 7.1). The ban covers the whole itraconazole course and two weeks after its last dose (itraconazole SmPC, AEMPS, 4.5, and FDA label). Restart ivabradine no earlier than that, and only if the resting heart rate is at least 70 beats per minute on several measurements, an electrocardiogram (ECG) or 24-hour monitoring (ivabradine SmPC, EMA, 4.3 and 4.4). Ivabradine is also used in chronic heart failure (ivabradine SmPC, EMA, 4.1). Itraconazole is contraindicated in current or past heart failure, except in life-threatening or other serious infections. Stop it if signs of heart failure appear during treatment (itraconazole SmPC, AEMPS, 4.3 and 4.4). If the drugs have already been taken together, stop one of them and monitor the heart rate and ECG. With a resting heart rate below 50 beats per minute or symptoms of bradycardia, reduce the ivabradine dose, and if bradycardia persists, stop ivabradine (ivabradine SmPC, EMA, 4.2 and 4.4). Treat severe bradycardia in a specialised unit. If it compromises the circulation, give intravenous beta-stimulants such as isoprenaline, and use temporary cardiac pacing if that is not enough (ivabradine SmPC, EMA, 4.9).