Regulatory Decision Summary for Perseris
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.
Type of Submission:
Supplement to a New Drug Submission
Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations
What was the purpose of this submission?
The purpose of this Supplement to a New Drug Submission – Clinical Only (SNDS-Clin Only) was to include a new 180 milligram (mg) dose given as 2 doses of 90 mg, as well as to add an alternate injection site on the back of the upper arm. After review, only the alternate injection site was considered approvable. The evidence provided in the submission in support of the new 180 mg dose was not deemed sufficiently robust, at this time. No changes to the indication were made or requested.
A Notice of Non-Compliance was issued for this submission related to the nonconformity with the Canadian labelling regulations. The response to NON (r/NON) was accepted into review on January 9, 2023.
Why was the decision issued?
Perseris was approved as a long-acting risperidone subcutaneous injection formulation.
This submission was based on a pharmacokinetic (PK) study initiated to investigate the use of a 180 milligram (mg) dose for Perseris, in addition to the approved 90 mg and 120 mg doses, as well as the use of the upper arm injection site in addition to the approved abdominal site.
Risperidone in its original oral formulation has been approved for use at doses up to 16 mg daily, though the usual recommended dose is 6 to 8 mg, and increased benefit of doses above 10 mg has not been established.
The original approval of Perseris was based on the demonstration of safety and efficacy of acute Perseris treatment at doses of 90 mg and 120 mg in an appropriately designed phase 3 study.
In the current study, participants were properly treated for schizophrenia at screening, then stabilized on a 6 mg daily oral risperidone dose. After 5 days of stable oral risperidone treatment, participants were switched to Perseris injections at a dose of 180 mg (2 injections of 90 mg at the same time). As this was a PK study, only 23 participants received Perseris injections, with only 16 participants receiving all 4 series of injections, with no placebo or active comparator arm.
The PK analysis indicated that exposure (average concentration at steady state) to the active moiety (non-metabolized risperidone and 9-OH-risperidone) was similar between 6 mg daily oral dosing and Perseris 180 mg injections. The mean concentrations of the oral doses and of the third Perseris dose were very similar (Cavg (ss) 46.229 nanogram [ng]/mL versus [vs] 45.185 ng/mL), as were the median values (41.450 ng/mL vs 44.605 ng/mL). Nonetheless, given the oral and monthly subcutaneous PK profiles were quite different, this was not considered an appropriate bioequivalence evaluation. Therefore, it could not be concluded that similar exposure equated to similar efficacy and safety profiles.
Since the study design and participant numbers were insufficient to draw efficacy and safety conclusions, this study, on its own, was not considered sufficient to support an increased dose of Perseris, which could result in an expansion of the target population, and would expose patients to Perseris doses exceeding what was previously evaluated. Additionally, doubling injection sites could result in changes in safety (namely, injection site reactions), which could not be properly evaluated in the current study.
For these reasons, the addition of a 180 mg dose of Perseris was not recommended for approval.
The study also investigated upper arm subcutaneous injections compared to abdominal subcutaneous injections. The comparison was done using the 180 mg dose. The PK results demonstrated that upper arm injections have very similar profiles to injections in the abdomen (Cavg 45.185 ng/mL for dose 3 in the abdomen versus 44.798 ng/mL for dose 4 in the upper arm; AUC0-28 days 30368.35 hour [hr]*ng/mL versus 29844.03 hr*ng/mL). Although the injections were done at the 180 mg dose rather than the approved 90 mg or 120 mg doses, the similarity in PK profiles was acceptable to establish some equivalence between the two injection sites. The inclusion of the alternate injection site was therefore recommended for approval.
Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.
For further details about Perseris, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.
Date of Decision:
Manufacturer / Sponsor:
Drug Identification Number(s) Issued:
Available by prescription only