Regulatory Decision Summary for Diacetylmorphine Hydrochloride

This NDS, reviewed in accordance with the Health Canada Guidance Drug Submissions Relying on Third-Party Data (Literature and Market Experience), evaluated the safety and efficacy of diamorphine (DAM) for supervised injectable opioid agonist therapy (siOAT), based on two phase 3, randomized, active control clinical trials, the NAOMI and SALOME studies, and evidence from two systematic reviews and meta-analyses of international clinical studies using siOAT. Participants were predominantly male, had average age of 40-44.3 years, had been using intravenous drugs for a mean of 15.4-16.5 years, and were using street heroin a mean of 25-27 days per month.

The NAOMI trial showed evidence that siOAT with DAM was superior to treatment with oral methadone maintenance therapy (MMT) in illicit opioid injecting participants with severe opioid dependence (DSM-IV) who had failed prior oral opioid agonist therapy, in a 12 month, randomized, active control, open label trial. Participants had a mean of 11 previous attempts at drug treatment including 3.2 courses of MMT. Although NAOMI was an open label design to compare siOAT with DAM to oral MMT, it also included a sub-study of participants that received injectable hydromorphone (HDM); these participants and those receiving DAM were treated in a double blind fashion.  Overall, 111 participants received methadone, 115 received injectable DAM and 25 received injectable HDM, and participants receiving injectable treatment could also receive supplementary methadone if needed. For outcomes of reduction in illicit drug use or other illegal activities, and retention in addiction treatment, the DAM group showed significant superiority compared to oral methadone. The sub-study revealed that subjects were not able to distinguish HDM from DAM. Outcomes were also comparable between HDM and DAM groups, although the study was not sufficiently powered for non-inferiority. Overdose and seizures were the most frequent serious adverse events related to DAM treatment. A total of 29 seizures and 13 overdoses were reported in the DAM group, compared to no seizures and two cases of overdose (both fatal) in the oral MMT arm.

SALOME was a double-blind, non-inferiority trial to compare siOAT with HDM versus (vs.) DAM in chronic illicit injection opioid users with severe treatment-resistant opioid dependence. A total of 202 participants were randomized to receive either HDM (n = 100) or DAM (n = 102). Review of the SALOME trial data within the context of this submission focused on safety only, given that the efficacy objectives were not central to support the approval of DAM. Participants had a mean of 2.8 attempts of MMT in the 5 years prior to study enrollment. There were 29 serious adverse events (SAEs) considered to be study drug-related, including 5 SAEs in the HDM group. Seizures and overdoses accounted for 25 of these 29 SAEs. A total of 11 seizures and 11 overdoses were reported in the DAM group, compared to 3 overdoses in the HDM subjects. All SAEs were reported as recovered with no sequelae. The two cases of deaths that occurred during the SALOME trial (both in the DAM arm) were unrelated to the study drug.

The safety profile of injectable DAM was judged acceptable under the proposed conditions of use in the context of a potentially fatal condition for which alternate therapies have been unsuccessful. The risks of injectable DAM, including overdose and seizures, were considered adequately mitigated in the setting of close monitoring by appropriately trained health care professionals, and outweighed by the substantial risks of continued unsupervised injection of illicit drugs. The approved product monograph (PM) adequately labeled the benefits and risks associated with supervised use of injectable Diacetylmorphine Hydrochloride at the time of authorization, and Diacetylmorphine Hydrochloride is only available through a controlled distribution process.

The benefit-harm-uncertainty assessment of Diacetylmorphine Hydrochloride (diamorphine hydrochloride) was considered favourable for an indication for supervised injectable opioid agonist therapy in adult patients with severe opioid use disorder who are using illicit injectable opioids and have failed previous attempts at opioid agonist therapy, including methadone maintenance therapy.