Regulatory Decision Summary for Okedi

This New Drug Submission was submitted by Laboratorios Farmaceuticos Rovi S.A. to obtain marketing authorization for Okedi, a new extended-release injectable suspension of the atypical antipsychotic risperidone, which has been formulated for intramuscular injection (gluteal and deltoid) at a dosing frequency of once a month for the treatment of schizophrenia in adults.

In this New Drug Submission (NDS) the sponsor sought to obtain approval for Okedi, a prolonged-release suspension of risperidone for intramuscular injection offered in two strengths: 75 and 100 milligrams (mg). After reconstitution, the Okedi formulation is administered by intramuscular administration, in either deltoid or gluteal muscles. It was developed to provide sustained therapeutic levels of risperidone for 28 days, eliminating the need for daily treatment. The results from study ROV-RISP-2020-02 showed that therapeutic levels were reached from the first hours after administration, thereby removing the need for an oral loading dose at the initiation of treatment. A bioavailability study was conducted to demonstrate similar steady-state plasma concentrations of risperidone active moiety (risperidone + metabolite 9-OH-risperidone) achieved with Okedi 100 mg compared to 4 mg oral risperidone. Dose similarity between Okedi 75 mg and 3 mg oral risperidone was supported by population pharmacokinetic (popPK) models and extrapolation. The pharmacokinetic (PK) characteristics of Okedi indicated a rapid initial rise in concentration reaching a first peak 48 hours after the administration, followed by a second peak observed between 18 to 25 days post-administration, resulting in therapeutic plasma exposure for 28 days after administration. Drug elimination was completed between 40 to 45 days after administration. The second peak was followed by a rapid elimination rate where the minimal concentration for therapeutic level was not maintained past the 28^th day post-administration. This information was emphasized in the dosing recommendations section of the Product Monograph (PM) with respect to planning of the subsequent dose.

The efficacy of Okedi was demonstrated with a single placebo-controlled, randomized, double-blind (DB), 12-week study (ROV-RISP-2016-01, PRISMA-3) followed by a safety 12-month open-label extension (OLE). The DB segment of PRISMA-3 was conducted in adult patients (18-64 years of age) with schizophrenia, experiencing acute exacerbation of their symptoms. The patients were treated with four Okedi injections of either 75 mg (n = 129) or 100 mg (n = 129); or treated with placebo (n = 132). The primary endpoint was the total Positive and Negative Syndrome Scale (PANSS) score change from baseline, a validated and widely used measure for antipsychotic efficacy. Both doses of Okedi achieved statistically significant and clinically meaningful improvement compared to placebo (least square means difference). Direct comparison with oral risperidone was not possible, although the efficacy observed with Okedi was typical of the efficacy expected from a risperidone treatment. Both injection sites were assessed at the preference of the participants. No significant difference was observed between the PK parameters and safety profile of the two injection sites.

The safety profile observed with Okedi was in line with risperidone and other atypical antipsychotics, including weight gain, hyperprolactinemia, headache, and somnolence.

In the short-term (12 weeks), double-blind segment of the pivotal study (ROV-RISP-2016-01, PRISMA-3) the most common (greater than 5% of patients) treatment emergent adverse events were hyperprolactinemia, akathisia, headache, somnolence, weight increased and injection site pain. These findings were consistent with other risperidone products. Other laboratory parameters of interest in atypical antipsychotics in general, and risperidone in particular (glucose, lipids and prolactin) were also consistent with the known risperidone safety profile. Care was taken to ensure consistency in the labelling. No unexpected safety signal was detected.

Pain was the most frequent adverse event observed at the injection site and was reported by 3.9% and 0.9% of the participants in the double-blind segment and open-label extension, respectively of pivotal trial PRISMA-3. Injection site pain frequency was similar across placebo and treatment groups during the double-blind portion of the study. In the open-label extension segment, the safety profile remained consistent with that of risperidone. Sparse efficacy measurements did not indicate unexpected variability during long-term use and most common serious adverse events were related to worsening symptoms of schizophrenia.

The chemistry and manufacturing information submitted for Okedi (risperidone) has demonstrated that the drug substance and drug products can be consistently manufactured to meet the approved specifications.

Overall, the benefit-harm-uncertainty profile is favourable for Okedi for the currently authorized indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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