Ivabradine × Verapamil

CYP3A4 is the only enzyme that clears ivabradine. Verapamil is a moderate CYP3A4 inhibitor and also slows the sinus rhythm on its own. In interaction studies verapamil or diltiazem raised ivabradine exposure 2- to 3-fold (AUC) and lowered the heart rate by a further 5 beats per minute (ivabradine SmPC, EMA, section 4.5). The two effects add up: more ivabradine in the blood plus a second rate-lowering drug on top.

Marked bradycardia: resting heart rate below 50 beats per minute, dizziness, fatigue, hypotension (ivabradine SmPC, EMA, section 4.4). Conduction disturbances: sinoatrial or atrioventricular block, sinus arrest (ivabradine FDA label, section 5.3). A slow rate prolongs the QT interval and may end in ventricular arrhythmia, including torsade de pointes, especially when the patient also takes QT-prolonging drugs (ivabradine SmPC, EMA, section 4.4; FDA label, section 5.3).

The combination is contraindicated in both labels: the ivabradine SmPC (EMA, section 4.3) names verapamil and diltiazem, and the verapamil SmPC (AEMPS, 4.3) names ivabradine. The contraindication in the ivabradine SmPC has no dose condition, and the FDA label of prolonged-release verapamil also says to avoid the combination (verapamil ER label, FDA). If the patient needs ivabradine, replace verapamil: the ivabradine SmPC reports no safety problems with nitrates, dihydropyridine calcium antagonists such as amlodipine, or beta-blockers (EMA, 4.4 and 4.5); with beta-blockers monitor the heart rate (ivabradine FDA label, 7.2). If verapamil itself is needed, for example for supraventricular tachycardia, stop ivabradine. Before starting ivabradine measure the resting heart rate repeatedly, by ECG or 24-hour monitoring, and do not start it below 70 beats per minute (EMA, 4.3 and 4.4). If the patient has already taken the two drugs together, reduce the ivabradine dose or stop it when the resting rate falls below 50 or bradycardia symptoms appear (EMA, 4.4). The US labels are softer but point the same way: both the ivabradine label (FDA, 5.3 and 7.1) and the verapamil label (FDA, Drug Interactions) say to avoid coadministration.