Regulatory Decision Summary for Kloxxado

The purpose of this New Drug Submission was to obtain market authorization for Kloxxado (naloxone hydrochloride), an 8 milligram (mg), metered dose intranasal spray, for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, for adult and pediatric patients. This indication would meet the requirements for an ethical designation, which would allow wide distribution to the general population without the intermediary of a health care practitioner.

Upon review of the submitted data package, and with consideration for the risks associated with the use of naloxone at an 8 mg dose in some vulnerable populations, Health Canada restricted the authorization of Kloxxado (naloxone hydrochloride), 8 mg, metered dose intranasal spray, to the treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. The change in indication restricts the authorization to a prescription drug status, to ensure proper education and training regarding the use of Kloxxado in vulnerable populations.

To support the safety and efficacy of Kloxxado (8 milligram [mg] naloxone intranasal [I.N.]) for the treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, for adult and pediatric patients, the sponsor filed a New Drug Submission (NDS) which included published literature as well as two pivotal comparative biopharmaceutic studies.

The two pivotal biopharmaceutic studies compared Kloxxado (8 mg I.N.) to naloxone hydrochloride 0.4 mg intramuscular (I.M) injection and 2 mg intravenous (I.V.). Of note, the 2 mg I.V. route of administration is only for health care professional use. The comparative bioavailability data from the studies demonstrated that Kloxxado provided 10 to 15 fold higher blood plasma concentration levels (AUC) between 2 to 30 minutes post-dose, compared to the reference product, Naloxone Hydrochloride 0.4 mg I.M. injection.

Some first responders have reported an increase in the number of naloxone doses used to reverse overdoses due to the presence of stronger illicit opioids. This has led to the suggestion that higher doses of naloxone may be beneficial under these circumstances. However, the data and published literature provided in the submission did not support superiority of the Kloxxado 8 mg product over other currently approved naloxone products in Canada. While this information is not necessary for the approval of Kloxxado, it was used to inform on the prescription status.

Safety

The sponsor provided eight repeat-dose, and two juvenile toxicology studies to support the non-clinical safety for this naloxone formulation containing 20% ethanol-5% propylene glycol (PG). Overall, the toxicology review found the formulation to be well tolerated with mild to moderate effects that were transient in nature. The results of the three impurity studies provided with the submission were also considered acceptable.

From a clinical standpoint, no safety signals were identified in the three biopharmaceutic studies (one pilot and two pivotal) provided with this NDS. However, the studies were conducted in healthy adult subjects that were not exposed to opioids. Specifically, no opioid exposed pediatrics, pregnant women, or adults were included in any of the three studies. The clinical safety assessment of Kloxxado in opioid exposed patients was solely based on studies selected from the two hundred clinical literature references provided in the submission, and additional literature searches. Most of the studies could only be considered as supportive and not pivotal due to differences in dosing and a lack of detailed information included in the publications. Most safety risks identified were previously known and labeled in the Product Monograph (PM). However, treatment guidelines recommend titration of naloxone in certain populations to mitigate additional risks of Acute Opioid Withdrawal Syndrome (AOWS). That is, AOWS can be triggered by high doses of naloxone in opioid dependent pregnant women, which can result in a miscarriage. In addition, AOWS can be fatal in opioid dependent neonates, and can cause severe opioid withdrawal and aggressive behavior in opioid dependent people of any age. While the benefits of treating an opioid overdose always outweigh the risks, even with the potential of AOWS, urgent follow up care by a Health Care Professional (HCP) can mitigate the safety concerns and uncertainties for these populations with immediate treatment. As the risks of AOWS could be higher with Kloxxado due to the higher dose and inability to be titrated, HCP oversight is necessary for these populations. For this reason, Kloxxado is recommended for approval as a prescription product, to enable education and training to individuals receiving the prescription. Warnings regarding treatment, follow up and education for these populations were included in the PM.

Benefit-Harm-Uncertainty (BHU) Profile

The submission did not include evidence of an increase in efficacy for Kloxxado (8 mg I.N.) compared to other available naloxone products in the reversal of opioid overdose. An ethical designation would allow the product to be used in emergency situations without practitioner oversight and potentially be distributed in naloxone take-home kits. Due to the risk of AOWS in vulnerable populations which would require immediate follow-up medical care, and the availability of other naloxone products in Canada to be used in these circumstances with an ethical designation, the BHU for Kloxxado is positive only as a prescription drug product. The prescription designation will allow HCP and patient education on the importance of these severe risks prior to distribution.

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