Ivabradine

The concomitant use of ivabradine with moderate CYP3A4 inhibitors (e.g. fluconazole), other than diltiazem or verapamil, may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is above 70 bpm, with monitoring of heart rate.

The use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided. If the combination appears necessary, close cardiac monitoring is needed.

Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.

QT prolonging medicinal products:

• Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).
• Non cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).

The concomitant use of cardiovascular and non cardiovascular QT prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction.

CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St John’s Wort]) may decrease ivabradine exposure and activity. The concomitant use of CYP3A4 inducing medicinal products may require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St John’s Wort was shown to reduce ivabradine AUC by half. The intake of St John’s Wort should be restricted during the treatment with ivabradine.

Ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore the intake of grapefruit juice should be avoided.

No data are available in patients with creatinine clearance below 15 ml/min. Ivabradine should therefore be used with precaution in this population.

Caution should be exercised when using ivabradine in patients with moderate hepatic impairment.

Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.

Ivabradine is not recommended in patients with AV-block of 2nd degree.

The use of ivabradine is not recommended immediately after a stroke since no data is available in these situations.

Ivabradine influences retinal function. Caution should be exercised in patients with retinitis pigmentosa.

Heart failure must be stable before considering ivabradine treatment. Ivabradine should be used with caution in heart failure patients with NYHA functional classification IV due to limited amount of data in this population.

Limited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients.

There are no or limited amount of data from the use of ivabradine in pregnant women. Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects. The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.

Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during breast-feeding.

Women that need treatment with ivabradine should stop breast-feeding, and choose for another way of feeding their child.

Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment.

Fertility

Studies in rats have shown no effect on fertility in males and females.

Ivabradine has no or negligible influence on the ability to use machines. A specific study to assess the possible influence of ivabradine on driving performance has been performed in healthy volunteers where no alteration of the driving performance was evidenced. However, in post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported. Ivabradine may cause transient luminous phenomena consisting mainly of phosphenes. The possible occurrence of such luminous phenomena should be taken into account when driving or using machines in situations where sudden variations in light intensity may occur, especially when driving at night.

Summary of the safety profile

The most common adverse reactions with ivabradine are luminous phenomena (phosphenes) (14.5%) and bradycardia (3.3%). They are dose dependent and related to the pharmacological effect of the medicinal product.

Tabulated list of adverse reactions

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

^* Frequency calculated from clinical trials for adverse events detected from spontaneous report.

Description of selected adverse reactions

Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency). The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.

Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.

In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to a hazard ratio of 1.26, 95% CI [1.15-1.39].

In the SHIFT trial more patients experienced episodes of increased blood pressure while treated with ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient, and did not affect the treatment effect of ivabradine.