Regulatory Decision Summary for Aptiom

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

eslicarbazepine acetate

Therapeutic area:

Antiepileptics

Type of submission:

Supplement to a New Drug Submission

Control number:

209753
What was the purpose of this submission?

 

Aptiom is an antiepileptic drug indicated as adjunctive therapy in the treatment of partial-onset seizures (POS) in adult patients with epilepsy, and which was also granted an indication for monotherapy in adults in newly diagnosed patients with partial-onset seizures.

This Supplement to a New Drug Submission (SNDS) proposed the extension of the indication for the treatment of partial-onset seizures to include monotherapy and adjunctive therapy in patients 4 years of age and older. The submission was based on extrapolation of efficacy data from adult data to the pediatric population.

 

Why was the decision issued?

 

Epilepsy is the most common serious neurological disorder in children and patients often need several antiepileptic drugs in order to control their seizures. In the absence of pediatric-specific labeling, prescribers lack critical information (e.g., dosing, tolerability/ safety, age-specific monitoring) that can facilitate the appropriate and safe use of antiepileptic drugs (AEDs) in this population.

To avoid unnecessary clinical studies and thereby expedite pediatric access to drugs, there is a consensus among regulatory agencies that extrapolation of the efficacy from adequate, well-controlled studies in adults to children is acceptable for AEDs used in the treatment of partial-onset seizures. This is based on the analysis of AED efficacy outcomes of randomized controlled trials that have shown considerable consistency for epilepsy drugs between adult and pediatric populations.

Population pharmacokinetic modelling was used to determine a pediatric dosing regimen that provides similar drug exposure at levels that have shown efficacy in adults. Safety data in pediatric patients was provided by 3 clinical studies that have been conducted for adjunctive therapy. No safety data was provided for pediatric patients treated with Aptiom only.

The efficacy of Aptiom (eslicarbazepine acetate) as adjunctive therapy in the treatment of partial-onset seizures (POS) in adolescents and children over 6 years of age was established by extrapolation using a population pharmacokinetic (PK) analysis. Adult and pediatric population PK models were used to determine a pediatric dosing regimen that provides similar drug exposure at levels that have shown efficacy in adults. Pharmacokinetic data used to perform the population PK analysis were collected from 4 adult and 2 pediatric clinical studies for adjunctive therapy.

One phase 3 clinical study (study 305) failed to demonstrate the efficacy of eslicarbazepine (ESL) when using the responder rate (decrease of 50% of seizure frequency) as the primary endpoint in pediatric patients with partial-onset seizures. The study is considered to have failed due poor design and execution features. The study results do not impact the ability to perform extrapolation of efficacy from adults to pediatric patients with partial-onset seizures.

The PK data provided does not support the proposed monotherapy pediatric indication. The Population PK analysis used extrapolated data from adjunctive therapy in adults, and not monotherapy. The modelling was also based on adjunctive pediatric PK studies accounting for the drug interactions in the model, that is, no monotherapy PK clinical study was conducted to establish ESL blood levels in children and adolescents. Furthermore, it is unclear if the dosage proposed for pediatric monotherapy is appropriate since it is the same as the dosage proposed for adjunctive therapy and population PK models that have accounted for drug-interactions have led to different ESL exposures in mono- and adjunctive therapy.

There is also considerable uncertainty regarding the efficacy and appropriate dosage for the youngest age group (2 to 6 years old) which is not considered to have been properly established by the Population PK study. The modeling showed that for the 2 to 6 years age group, both AUC24,ss and Cmax,ss presented notably lower values relative to the older age groups.

The safety of Aptiom in pediatric patients was established mainly by 3 clinical studies conducted to support adjunctive therapy. The safety profile of adjunctive Aptiom treatment in pediatric patients is in line with the established safety profile in adults.

It was concluded that the benefit harm uncertainty for the proposed monotherapy indication is considered unfavourable and the indication was not granted. In addition, the benefit harm uncertainty for the adjunctive therapy indication for children 6 years and younger is also considered unfavourable, and the indication was not granted.

However, the benefit harm uncertainty of Aptiom used as adjunctive therapy in pediatric patients above 6 years of age with partial-onset seizures is considered favourable.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.