Diltiazem × Ivabradine

Diltiazem is a moderate inhibitor of CYP3A4, the enzyme that clears ivabradine. When the two are taken together, ivabradine exposure (area under the concentration curve, AUC) rises 2–3-fold (ivabradine SmPC, EMA). Both drugs slow the heart. Ivabradine slows the sinus node; diltiazem prolongs the refractory periods of the atrioventricular node and can cause bradycardia or second- or third-degree atrioventricular block (diltiazem SmPC). Together they lower the heart rate by a further 5 beats per minute beyond the effect of ivabradine alone and worsen conduction disturbances (ivabradine SmPC, EMA; Corlanor label, FDA).

Bradycardia: resting pulse below 50 beats per minute, dizziness, fatigue, low blood pressure (ivabradine SmPC, EMA). Sinus arrest and atrioventricular block with fainting can occur (Corlanor label, FDA; diltiazem SmPC). Marked bradycardia raises the risk of QT prolongation and torsade de pointes, especially with other QT-prolonging drugs (Corlanor label, FDA).

The combination is contraindicated from both sides: the ivabradine SmPC (EMA) forbids use with diltiazem and verapamil, and the diltiazem SmPC forbids use with ivabradine (section 4.3 of both). The FDA labels require avoiding concomitant use (ivabradine and diltiazem labels, FDA). If a calcium channel blocker is needed, the ivabradine SmPC notes no safety problems with dihydropyridines such as amlodipine (ivabradine SmPC, EMA). If a patient already takes both, one of them is stopped and heart rate and ECG (electrocardiogram) are monitored. With a resting heart rate below 50 beats per minute or symptoms of bradycardia the ivabradine dose is reduced; if bradycardia persists, ivabradine is stopped (ivabradine SmPC, EMA). Ivabradine is not started with a resting heart rate below 70 beats per minute (ivabradine SmPC, EMA).