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

Adverse events

All adverse events (irrespective of relationship to study treatment)

Pivotal study

Analysis of TEAEs that occurred “during the study” showed that in total 20142 TEAEs were reported in 4862 patients (74.9%, 41.0%PY³²) with similar frequencies in each treatment group (75.5% [2439/ 3232] and 74.3% [2423/ 3260], in the ivabradine and placebo groups, respectively). The most frequently reported TEAEs by System Organ Classification (SOC) in the ivabradine group were Cardiac disorders (43.0%, 23.4%PY versus 43.0%, 23.7%PY, in the ivabradine and placebo groups, respectively), Infections and infestations (22.1%, 12.0%PY versus 24.6%, 13.6%PY, respectively), Metabolism and nutrition disorders (15.5%, 8.5%PY versus 16.2%, 9.0%PY, respectively), Investigations (14.9%, 8.1%PY versus 10.9%, 6.0%PY, respectively) and Vascular disorders (14.8%, 8.0%PY versus 14.3%, 7.9%PY, respectively). The principal SOCs reported at higher incidence rates in the ivabradine group than in the placebo group where the difference was > 1% were Investigations (14.9%, 8.1%PY versus 10.9%, 6.0%PY, respectively) and Eye disorders (6.3%, 3.4%PY versus 3.4%, 1.9%PY, respectively).

Analysis of TEAEs that occurred “on treatment” showed that in total, 17496 TEAEs were reported in 4806 patients (74.0%, 44.1%PY) with similar frequencies in each treatment group (74.7% [2414/ 3232] and 73.4% [2392/ 3260], in the ivabradine and placebo groups, respectively). The most frequently reported TEAEs by SOC in the ivabradine group were similar to those in the “during study” analysis and were Cardiac disorders (41.2%, 24.7%PY versus 41.6%, 24.7%PY, in the ivabradine and placebo groups, respectively), Infections and infestations (19.6%, 11.7%PY versus 22.4%, 13.3%PY, respectively), Investigations (14.0%, 8.4%PY versus 10.0%, 5.9%PY, respectively), Metabolism and nutrition disorders (13.9%, 8.3%PY versus 14.7%, 8.7%PY, respectively) and Vascular disorders (13.5%, 8.1%PY versus 13.0%, 7.7%PY, respectively). The principal SOCs reported at higher incidence rates in the ivabradine group than in the placebo group where the difference was > 1% were Investigations (14.0%, 8.4%PY versus 10.0%, 5.9%PY, respectively), Eye disorders (6.1%, 3.7%PY versus 3.2%, 1.9%PY, respectively) and General disorders and administration site conditions (9.7%, 5.8%PY versus 8.8%, 5.2%PY, respectively).

Analysis of TEAEs that occurred “on treatment” showed that the most frequently reported TEAEs in both groups by preferred term were cardiac failure (21.7%, 13.0%PY versus 26.0%, 15.4%PY, in the ivabradine and placebo groups, respectively), atrial fibrillation (8.3%, 4.9%PY versus 6.7%, 4.0%PY, respectively) and blood pressure inadequately controlled (7.1%, 4.2%PY versus 6.1%, 3.6%PY, respectively). A plot of the 20 most frequent on-treatment TEAEs by preferred term in the ivabradine and placebo groups showedg that the principal TEAEs occurring more frequently in the ivabradine group than in the placebo group were atrial fibrillation (8.3%, 4.9%PY versus 6.7%, 4.0%PY, respectively), blood pressure inadequately controlled (7.1%, 4.2%PY versus 6.1%, 3.6%PY, respectively), asymptomatic bradycardia³³ (HR decreased) (5.6%, 3.4%PY versus 1.4%, 0.8%PY, respectively), symptomatic bradycardia (4.6%, 2.7%PY versus 0.9%, 0.5%PY, respectively) and phosphenes (2.8%, 1.7%PY versus 0.5%, 0.3%PY, respectively).

Other studies

Not applicable.

Treatment-related adverse events (adverse drug reactions)

Pivotal study

The analysis of treatment-related TEAEs that occurred “on treatment” showed that the incidence of treatment-related TEAEs was higher in the ivabradine group than in the placebo group (17.8% [574/ 3232], 10.6%PY and 8.3% [271/ 3260], 4.9%PY in the ivabradine and placebo groups, respectively). The most frequently reported treatment-related TEAEs by SOC in the ivabradine group were Cardiac disorders (6.1%, 3.6%PY versus 2.6%, 1.5%PY, in the ivabradine and placebo groups, respectively), Investigations (5.3%, 3.2%PY versus 1.6%, 1.0%PY, respectively) and Eye disorders (3.7%, 2.2%PY versus 0.8%, 0.5%PY, respectively). The most frequently reported treatment-related TEAEs by preferred term in the ivabradine group were also those that were reported at higher incidence rates in the ivabradine group than in the placebo group (where the difference was > 1%), and were asymptomatic bradycardia (HR decreased) (4.6%, 2.8%PY versus 1.0%, 0.6%PY, respectively), symptomatic bradycardia (3.7%, 2.2%PY versus 0.7%, 0.4%PY, respectively) and phosphenes (2.7%, 1.6%PY versus 0.5%, 0.3%PY, respectively).

Other studies

Not applicable.

Deaths and other serious adverse events

Pivotal study

Serious adverse events (SAEs)

Analysis of SAEs that occurred “during the study” showed that the incidence of SAEs (fatal or not) was similar between the ivabradine group and the placebo group (44.9%, 24.4%PY versus 47.6%, 26.3%PY, respectively). The most frequently reported SAEs by SOC in the ivabradine group were Cardiac disorders (28.5%, 15.5%PY versus 30.4%, 16.8%PY, in the ivabradine and placebo groups, respectively), General disorders and administration site conditions (7.4%, 4.0%PY versus 7.8%, 4.3%PY, respectively) and Infections and infestations (6.7%, 3.6%PY versus 7.2%, 4.0%PY, respectively). The SAEs by SOC reported at higher incidence rates in the ivabradine group than in the placebo group were Investigations (2.3%, 1.3%PY versus 2.2%, 1.2%PY, respectively), Neoplasms benign, malignant and unspecified (2.1%, 1.1%PY versus 1.9%, 1.0%PY, respectively) and Renal and urinary disorders (1.6%, 0.9%PY versus 1.4%, 0.8%PY, respectively).

Analysis of SAEs that occurred “on treatment” showed that the incidence of SAEs (fatal or not) was similar between the ivabradine group and the placebo group (42.4%, 25.4%PY versus 45.4%, 27.0%PY, respectively) (Table 15). The most frequently reported SAEs by SOC in both groups were the same as those in the “during study” analysis: Cardiac disorders (26.4%, 15.8%PY versus 28.8%, 17.1%PY, in the ivabradine and placebo groups, respectively), General disorders and administration site conditions (6.2%, 3.7%PY versus 6.1%, 3.6%PY, respectively), and Infections and infestations (5.5%, 3.3%PY versus 6.1%, 3.6%PY, respectively). The SAEs by SOC reported at higher incidence rates in the ivabradine group than in the placebo group were General disorders and administration site conditions (6.2 %, 3.7%PY versus 6.1 %, 3.6 %PY, respectively), Investigations (2.0 %, 1.2%PY versus 1.9%, 1.1%PY, respectively), Neoplasms benign, malignant and unspecified (2.0 %, 1.2 %PY versus 1.7%, 1.0 %PY, respectively), Renal and urinary disorders (1.2%, 0.7%PY versus 1.0%, 0.6%PY, respectively) and Eye disorders (0.5%, 0.3%PY versus 0.4%, 0.2%PY, respectively).

Table 15. Serious emergent adverse events on treatment (all clinical events) by SOC and PT in at least 5 patients in either group (Safety Set)

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