Regulatory Decision Summary for Aripiprazole Oral Solution

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Aripiprazole Oral Solution. Orimed Pharma Inc. filed this submission as an NDS rather than an Abbreviated NDS (ANDS) as this is a new formulation of the innovator product, Abilify (aripiprazole tablets), which is the Canadian Reference Product (CRP).

This submission was filed for 1 milligram per millilitre (mg/mL) Aripiprazole Oral Solution, for the treatment of schizophrenia, manic or mixed episodes in bipolar I disorder, and as an adjunct to antidepressants for the treatment of major depressive disorder.

The efficacy and safety of Aripiprazole Oral Solution for the treatment of schizophrenia, bipolar I disorder and as an adjunct to antidepressant have been previously demonstrated through the approval of the innovator drug, Abilify. Therefore, the aim of this New Drug Submission was not to demonstrate a positive benefit-harm-uncertainty profile but rather to demonstrate comparable bioavailability of the proposed Aripiprazole Oral Solution to the Abilify tablet. The Aripiprazole Oral Solution showed a comparative bioavailability to Abilify and this conclusion was confirmed by the Division of Biopharmaceutics Evaluation.

In Europe and in the United States, Abilify oral solution was approved but this formulation of Abilify was never submitted in Canada and there is no other oral solution formulation of aripiprazole available in Canada. In both the United States and Europe, Abilify (oral solution) was approved based on a comparative bioavailability study that compared multiple doses. At the higher dose of 30 mg, as described in the United States Product Information (USPI), the exposure was shown to be higher with the oral solution compared to the tablet. This finding led to a dosing recommendation in the USPI to use a maximum of 25 mg of the oral solution when switching from a 30 mg tablet. However, this dosing recommendation was not included in the European Summary of Product Characteristics (SmPC), despite the assessment of the same dataset. Although a higher exposure for the Abilify oral solution compared to the tablet at the 30 mg dose, the solution to tablet ratios of geometric mean the concentration of the drug in the body (C_max) and Area Under the Curve (AUC) values, of 122% and 114%, respectively remain within the acceptable range of 80-125% (data from the Abilify oral solution USPI).

Therefore, considering all the data, it was concluded that a mg-per-mg interchangeability, without a 25 mg cap was appropriate. To overcome the lack of data for the 30 mg and ensure a safe use of the highest dose, a recommendation for enhanced monitoring of patients upon switching formulations at the higher dose was added to the Product Monograph (PM) under section 4.1 Dosing Considerations.

The PM was largely based on the Abilify PM with some formulation-related revisions made in sections 4.1 Dosing Considerations and 10.3 Pharmacokinetics.

The final labelling and PM were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Aripiprazole Oral Solution for the approved indications when used under the conditions of use recommended in the approved PM. Therefore, a Notice of Compliance was recommended.

For further details about Aripiprazole Oral Solution please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.