Regulatory Decision Summary for Blexten

Upon review, the evidence submitted in this Supplemental New Drug Submission (SNDS) was found to support the efficacy and safety of Blexten (bilastine) 10 milligram (mg) for the symptomatic treatment of seasonal allergic rhinitis (SAR) and chronic spontaneous urticaria (CSU) in patients 4 years of age and above with a body weight of at least 16 kilogram (kg).

The Blexten pediatric clinical development program included a safety trial (BILA 3312/PED) and a pharmacokinetics (PK) trial (BILA 3009/PED). The BILA 3009/PED PK trial was used to extrapolate adult efficacy data to children, as per the International Council for Harmonisation (ICH) E11 guidance for clinical trials in pediatric populations, with the premise of similar blood levels in the pediatric dose as compared to those observed in adults.

In the BILA 3009/PED PK trial, the uncertainty around the relationship between weight/age and PK parameters such as clearance, led to uncertainties when extrapolating beyond the observed data. No clinical PK data was collected in patients below the age of four years. A weight limit of 16 kg and an age limit of 4 years of age was implemented to revise the proposed indication. Based on the available data, pediatric patients, with an age greater than 4 years and a weight greater than 16.9 kg (the lowest weight within trial), taking the 10 mg Blexten dose would have an exposure comparable to adults. The 16 kg weight limit is approximate to lowest weight within the trial and the median weight according to the weight distribution as reported by the World Health Organization (WHO) and the Canadian pediatric endocrine group. The combined adult and child population pharmacokinetics model performed reasonably well using standard diagnostic tools such as Goodness-of-Fit (GOF), Visual Predictive Check (VPC) and ETA plots, which evaluated the performance of this model. The simulation of the exposure, derived from the combined Population-PK model, indicated comparable exposure between adolescent and adults following oral intake of Blexten at 20 mg daily. Comparable effect-time profiles were observed between pediatric and adult patients using an indirect PK/pharmacodynamics (PD) model.

The pediatric safety trial (BILA 3312/PED) included subjects (260 and 249 treated with Blexten 10 mg daily or placebo, respectively) with either allergic rhinoconjunctivitis or urticaria aged 2 to 11 years. The overall incidence of treatment emergent adverse events (TEAEs) were similar between patients treated with Blexten and the placebo. In the Blexten treatment group, 178 (68.5%) patients reported at least one TEAE, while 168 (67.5%) patients in the placebo group reported at least one TEAE. The primary hypothesis of non-inferiority of Blexten 10 mg with respect to placebo was demonstrated. Overall, 31.5% and 32.5% of Blexten and placebo treated patients were without TEAEs during the course of the study for a treatment difference of 0.99% (95% confidence interval (CI): -9.10, 7.10). Comparing the proportion of patients without TEAEs may not fully capture clinically relevant safety differences between the Blexten and placebo groups, however the primary analysis was supported by all secondary safety variables which included the proportion of children with related TEAEs during the course of the study.

A Risk Management Plan (RMP) was submitted for review by the Marketed Health Products Directorate and was considered acceptable. The sponsor was requested to amend the safety specification section of the RMP to replace missing information of “use in children under 2 years of age” with “use in children under 4 years of age” and “use in children aged 4 to 11 years with a body weight below 16 kg” and to include appropriate pharmacovigilance and risk minimization activities for the new safety concerns.

The Product Monograph for Blexten was revised to accurately reflect the efficacy, safety, and uncertainties identified.

Overall, the benefit-harm-uncertainty profile of Blexten for the recommended indications and dosage is favourable.