Regulatory Decision Summary for NALOXONE HYDROCHLORIDE NASAL SPRAY

Naloxone is a pure opioid antagonist that has been used to reverse opioid overdose for several decades in medical facilities. Because North America is facing a catastrophic increase of opioid misuse and death by overdose, the availability of naloxone has become a high priority. Health Canada has increased access to naloxone by exempting it from the prescription drug list so that it could be access without a prescription and used outside of the hospital setting. The first naloxone product approved following the exemption was an injectable formulation.

This New Drug Submission is for Naloxone Hydrochloride Nasal Spray, a needleless device providing a fixed intranasal (IN) dose of either 2 mg or 4 mg of naloxone. The intranasal route of administration is more convenient for bystanders as it decreases the fear of users and risks associated with injectable naloxone formulations.

Rapid systemic absorption of naloxone is paramount to reversing a life-threatening opioid overdose. The systemic rate of absorption of Naloxone Hydrochloride Nasal Spray is comparable to that of naloxone via intramuscular (IM) administration. The maximum plasma concentration of a 2mg spray (and a fortiori that of a 4 mg spray) of Naloxone Hydrochloride Nasal Spray is higher than the 0.4 mg intramuscular administration (a standard overdose (OD) treatment dose) and is reached at approximately the same time. As well, the exposure to naloxone was much greater.

This NDS was supported by literature information and two pharmacokinetic (PK) studies in healthy adult subjects. The PK data left some uncertainties with regard to the levels of naloxone achieved by IN administration relative to the IM administration. However, as linearity can be reasonably assumed between IM doses, it was estimated that the relative bioavailability of the IN formulation is 50% of the IM formulation. Based on this, the 4 mg IN dose would provide a systemic naloxone level equivalent to a 2 mg IM dose, which corresponds to the maximum recommended initial dose in clinical guidelines in adults. It is important to note that the maximum total dose than can be given to a patient, if initial doses did not suffice to treat the overdose, is 10 mg. Thus, the uncertainty with regard to the levels achieved with the 4 mg IN dose, is not considered a concern. However, higher levels of naloxone could potentially pose a greater risk of triggering an Acute Opioid Withdrawal Syndrome (AOWS) in opioid dependent patients, which may manifest as sudden aggressive reactions. AOWS are usually not life-threatening in adults but aggressive reactions could pose a risk for bystanders.

The safety and efficacy of the proposed formulations were not evaluated in children, including neonates. The size of the nasal tip that cannot be properly inserted in the nostril of a young child, or the fact that young children are obligate nasal breathers could be problematic. It is well known that Naloxone could trigger an AOWS that can be life-threatening in dependent neonates if not recognized and properly treated. As naloxone crosses the placenta, opioid dependent fetuses are at risk of AOWS that could precipitate fatal preterm labor, fetal distress and be also life-threatening to the mother.

The usual IM dose of naloxone recommended in clinical guidelines to reverse an opioid overdose in pediatrics is an IM injection of 0.1 mg/kg (milligrams per kiloram) (that would be equivalent to approximately 0.2 mg/kg via the IN route). Based on the recommended dose/weigh, the 2 mg dose of Naloxone Hydrochloride Nasal Spray should not be used in children under 10 kg and the 4 mg dose should not be used in children under 20 kg. It was estimated that 97% of children will be heavier than 10 kg after 2 years of age, and that 97% of children will reach 20 kg only after about 3.5 years of age (male and female included in all cases). Of course, if only Naloxone Hydrochloride Nasal Spray (2 mg or 4 mg) is available, the benefit of saving the life of a child having an OD, far outweighs the risk associated with high dose/ overtreatment with naloxone.

Rebound opioid toxicity is the re-emergence of respiratory depression and other symptoms of opioid overdose following the temporary reversal of opioid overdose symptoms with an opioid antagonist such as naloxone. Naloxones half-life is relatively short compared to most opioids; therefore, its effect can wear off while the opioid is still present. Additionally, its effectiveness is dependent upon the dose and potency of the opioid responsible for the overdose and therefore the rebound opioid toxicity is difficult to predict.

Although there are potential safety issues associated with naloxone, these are well known and naloxone is a life-saving drug. Both doses were considered acceptable with adequate labelling to mitigate potential risks. While the risk of AOWS may increase with the dose of naloxone, any dose of naloxone should be used in case of an OD as benefits outweigh any risks. The Product Monograph states that bystanders must call 9-1-1, or ask someone to call for them, as soon as an opioid overdose is suspected. The Product Monograph also emphasizes that if Naloxone Hydrochloride Nasal Spray is used successfully to reverse an opioid overdose, the patients must be monitored while waiting for emergency medical assistance and that subsequent doses of Naloxone Hydrochloride Nasal Spray may be needed if the patient relapses into respiratory depression (rebound opioid toxicity).