October 2012 Australian Public Assessment Report for Ivabradine Proprietary Product Name: Coralan Sponsor: Servier Laboratories

Evaluator’s overall conclusions on clinical safety

The most commonly occurring treatment-related TEAEs in the ivabradine group were known adverse effects of ivabradine stated in the currently approved PI.

In the section on SAEs in the proposed PI, it is stated that “the most frequently reported SAEs with ivabradine were Cardiac disorders, where the only SAE reported with a 1% incidence was unstable angina (1.5%)”. Results in the SHIFT study showed that the most frequently reported treatment-related SAEs by SOC in the ivabradine group was also cardiac disorders (1.7% versus 0.6% in the ivabradine and placebo groups, respectively). All treatment-related SAEs by preferred term occurred at an incidence rate of < 0.5%, the commonest being cardiac failure (0.4% versus 0.3% in the ivabradine and placebo groups, respectively), symptomatic bradycardia (0.4% versus <0.1%, respectively), atrial fibrillation (0.2% versus <0.1%, respectively) and atrioventricular block complete (0.2% versus 0%, respectively).

The incidence of “on-treatment” TEAEs with a fatal outcome was similar between the ivabradine and placebo groups (12.4% versus 13.1%, respectively). The incidence rate TEAEs leading to study drug discontinuation was higher in the ivabradine group compared to the placebo group (14.5% versus12.8%, respectively) but the incidence of SAEs leading to study drug discontinuation was similar between the ivabradine and placebo groups (8.4% versus 8.6%, respectively). The commonest TEAEs leading to study drug discontinuation in the ivabradine group were atrial fibrillation (4.2% versus 3.5% in the ivabradine and placebo groups, respectively) and cardiac failures (2.0% versus 2.4%, respectively).

In the subgroup of patients aged  75 years, the overall incidence of TEAEs was comparable between ivabradine and placebo groups (78.8% versus 77.6%, respectively). Compared to the overall study population, the incidence of TEAEs was higher in this subgroup of patients aged  75 years, in the ivabradine group (78.8% versus 74.7% in age  75 years and overall population, respectively), as well as placebo group (77.6% versus 73.4%, respectively). There was also a higher incidence in the ivabradine treatment group of this subgroup compared to that in the overall study safety dataset of cardiac failure (28.6% versus 21.7%, respectively), atrial fibrillation (11.7% versus 8.3%, respectively) and symptomatic bradycardia (7.4% versus 4.6%, respectively) (Table 18), although for atrial fibrillation and cardiac failure the incidences were similar between ivabradine and placebo groups in this subgroup of patients aged  75 years (atrial fibrillation: 11.7% and 11.6% in the ivabradine and placebo groups respectively; cardiac failure: 28.6% and 32.3%, respectively). The incidence of asymptomatic bradycardia was comparable between the ivabradine treatment group of this subgroup of patients aged 75 years and that in the overall study safety dataset (5.7% versus 5.6%, respectively).

Overall, the safety results of the SHIFT study were consistent with the known adverse effects of ivabradine. The incidence of death in the safety analysis supported the efficacy results that there was no increased risk of overall mortality compared to placebo. However, as the proposed indication is for use in CHF patients who tend to be in an older age group, the evaluation of the safety profile in this age group was considered to be important. The sample size of patients aged  75 years was small (n=720), and safety results suggested that there could be a higher incidence of cardiac failure, atrial fibrillation and symptomatic bradycardia in this age group.

In addition, no safety data was submitted for the subgroup of patients who were on at least 50% of optimal doses of recommended beta blockers. Safety data in this subgroup would be relevant to the evaluation of whether there was an increased incidence of bradycardia (asymptomatic and symptomatic) or arrhythmias in this subgroup and hence assist in determining the profile of CHF patient population for which ivabradine should be indicated in terms of concomitant use of beta blockers.

Table 18. TEAEs in the subgroup of patients aged  75 years, compared to the overall study safety dataset.