Regulatory Decision Summary for Probuphine
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:
What was the purpose of this submission?
With this New Drug Submission, the sponsor is seeking marketing authorization of Probuphine (buprenorphine) for the treatment of adult patients with opioid drug dependence.
Why was the decision issued?
Probuphine is an implant formulation of buprenorphine. Buprenorphine is a partial agonist at µ and ORL-1 receptors and an antagonist at κ and δ opioid receptors. Its mechanisms of action in the treatment of addiction are not fully understood; however, it binds to the same µ-receptors as full opioid agonists but with a higher affinity. This is thought to prolong the partial opioid activity at the opioid receptors and hence alleviate opioid withdrawal symptoms.
Three key studies were provided to support the application of Probuphine (study 805, 806 and 814). The efficacy of the implant was measured by evaluating the incidence of patients that were resorting to illicit opioid consumption while under treatment with the implant. The main the difference between studies was that patients in study 814 (24 week duration with 173 subjects) had to be on a maintenance treatment of sublingual buprenorphine and tapered down to 8 mg of sublingual buprenorphine for three months prior to receiving the implant while in the other studies, patients were on 16 mg of sublingual buprenorphine for a maximum of 10 days before implantation.
Results of Study 814 showed that 79% of patients had urine samples free of illicit opioids compared to 64% in controls (sublingual buprenorphine). However, for studies 805 and 806, no patients from either the placebo or treated groups had negative urine samples (free of illicit opioids). This difference in efficacy is likely due to the fact that patients were not stabilized before implantation in study 805 and 806. In response to these findings, the product is recommended to be used after the patient is clinically stabilized on sublingual buprenorphine.
As an implant, Probuphine dosing happens only once for 6 months of opioid dependence management. Therefore, dosing errors are eliminated and patients quality of life as well as treatment compliance should be improved. Another advantage of Probuphine is that it is available only through a controlled distribution process (directly from pharmacy to healthcare professionals), thus the probability of diversion or tampering with the implants is decreased.
The safety profile of Probuphine was similar to other buprenorphine formulations used for a similar purpose. As Probuphine is an implant, there were local adverse events (AEs) specific to this formulation (bleeding, bruising, edema, erythema, infection, itching and pain etc.) and most were not severe or serious in nature. There were a total of 258 subjects exposed to Probuphine for at least 24 weeks and 82 subjects exposed for 48 weeks. The electrocardiogram (ECG) data for Probuphine were inconclusive because of limitations of clinical trial design and methodology. A QTc study is planned (report expected in 2019) to assess the risk of QT prolongation with Probuphine. Since concentration-dependent QTc prolongation has been reported with other buprenorphine-containing products, contraindications, warnings and precautions as well as potential drug interactions were added to the Probuphine Product Monograph (PM) to mitigate potential cardiovascular risks.
Overall, the benefit-harm-uncertainty profile of Probuphine is considered acceptable at this time when Probuphine is used as described in the approved PM.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.