Clarithromycin × Ivabradine

In the liver and gut, a single enzyme, CYP3A4 (cytochrome P450 3A4), breaks down ivabradine, and clarithromycin strongly inhibits this enzyme (ivabradine and clarithromycin 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 clarithromycin itself. Figures exist for other strong inhibitors: ketoconazole 200 mg once daily and the macrolide antibiotic josamycin 1 g twice daily raised mean ivabradine plasma exposure 7- to 8-fold (ivabradine SmPC, EMA). The second mechanism involves the QT interval. Clarithromycin prolongs QT on its own, and the slower heart rate caused by ivabradine can worsen this prolongation and lead to a serious arrhythmia (clarithromycin and ivabradine SmPCs, EMA).

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). The QT interval on the electrocardiogram (ECG) can lengthen, and a severe ventricular arrhythmia, including torsade de pointes, may follow (ivabradine and clarithromycin summaries of product characteristics). The risk is higher in people who also take other QT-prolonging drugs (Corlanor label, FDA).

The combination is contraindicated on both sides. The ivabradine summary of product characteristics (SmPC) lists clarithromycin 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 clarithromycin SmPC lists ivabradine among contraindicated drugs (Spanish Agency of Medicines and Medical Devices, AEMPS, 4.3 and 4.5). The US ivabradine label also contraindicates strong CYP3A4 inhibitors and gives clarithromycin as an example (US Food and Drug Administration, FDA, sections 4 and 7.1). So during a course of clarithromycin, choose another antibiotic or pause ivabradine (this follows from the contraindication in both labels). The documents give no interval after clarithromycin before ivabradine can be restarted. When choosing the antibiotic, note that oral erythromycin, josamycin and telithromycin are also contraindicated with ivabradine, and drugs that prolong the QT interval should be avoided with it (ivabradine SmPC, EMA, sections 4.3–4.5). Clarithromycin itself is contraindicated with a history of QT prolongation and with low potassium or magnesium (clarithromycin SmPC, AEMPS, 4.3). Avoid it in clinically significant bradycardia (clarithromycin label, FDA, 5.2). If the drugs have already been taken together, stop one of them and monitor the heart rate and electrocardiogram (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). Before restarting ivabradine, measure the resting heart rate several times, by ECG or 24-hour monitoring, and do not start the drug below 70 beats per minute (ivabradine SmPC, EMA, 4.3 and 4.4).