1. New non-injectable naloxone products: Global overview
Rebecca McDonald
National Addiction Centre
King’s College London

2. Declarations
RM has undertaken an unpaid student industry placement with Mundipharma Research Ltd., with focus on the analysis of naloxone nasal spray formulations.
King’s College London has separately applied to register intellectual property on a novel buccal naloxone formulation with which JS and RM are involved.
RM is a consultant for the United Nations (UNODC), supporting a naloxone study in Central Asia. 
Do I need to include a slide?

3. Overview Background: Why is non-injectable naloxone needed?
Method: Criteria for non-injectable routes
Non-injectable naloxone: old and new products

4. Insert UNODC map of opioid use
WHO (2014). Community Management of Opioid Overdose. Geneva: WHO.

5. WHO (2014). Community Management of Opioid Overdose. Geneva: WHO.

7. 1 | Why is non-injectable naloxone needed?
Training required
Risk of needle-stick-injury
Prescription-only medication status (Article 71, EU Medicinal Products Directive, 2001/83)
Why is injection-free naloxone needed?
Administering injections can be intimidating, requires training; creates professional inertia
Injections bear the risk of needle-stick-injury and blood-borne virus transmission (HIV, HBV, HCV)
Injections have prescription-only (POM) status in Europe: ‘Medicinal products shall be subject to medical prescription where they […] are normally prescribed by a doctor to be administered parenterally.’ 
Source: goo.gl/QxHcRJ

8. Overview Background: Why is non-injectable naloxone needed
Method: Criteria for non-injectable routes
Non-injectable naloxone: old and new products

9. 2.1 | Identification of non-injectable routes
Strang, J., McDonald, R., Alqurshi, A., Royall, P., Taylor, D., & Forbes, B. (2016). Naloxone without the needle− systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug and Alcohol Dependence, 163,

10. 2.1 | Identification of non-injectable routes
Review of 112 FDA-recognized routes of drug administration (FDA, 1992)
Inclusion if the route…
Suitable for OD emergency situation
Exclusion if the route…
Involves injection or invasive procedure
Requires medical training
Is not acceptable in public (e.g., rectal)
Does not produce adequate drug absorption
Does not produce sufficiently rapid drug absorption relative to parenteral administration (Hertz, 2012)
Strang, J., McDonald, R., Alqurshi, A., Royall, P., Taylor, D., & Forbes, B. (2016). Naloxone without the needle− systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug and Alcohol Dependence, 163,

11. 2.1 | Identification of non-injectable routes
Nasal route most advanced (PubMed entries, clinical trials activity)
Strang, J., McDonald, R., Alqurshi, A., Royall, P., Taylor, D., & Forbes, B. (2016). Naloxone without the needle− systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug and Alcohol Dependence, 163,

12. Overview Background: Why is non-injectable naloxone needed
Method: Criteria for non-injectable routes
Non-injectable naloxone: old & new products

13. 3.1 | Since 2005: Off-label Nasal Kits
Used for THN distribution in the US, Norway, Denmark, parts of Scotland
Dilute injectable solution (2mg/2ml) + mucosal atomizer device
But:
Human nostril can only absorb volume < 0.2mL
Low bioavailability of F=10% 0.2mg absorbed, below WHO-recommended minimum dose of 0.4mg!
2012 FDA meeting with NIDA and CDC

14. 3.1 | Since 2015: New Nasal Kits NARCAN 4mg/0.1ml NALSCUE 0.9mg/0.1ml
USA (Nov 2015)
Canada (Oct 2016; OTC)
France:
July 2016 (temp.), July 2017 (Marketing Authorization); OTC
EMA Sept 2017 (initial authorization)
NARCAN 4mg/0.1ml
NALSCUE 0.9mg/0.1ml
NYXOID 2mg/0.1ml
The FDA and Health Canada approved a first nasal naloxone product in November 2015 and October 2016, respectively.
Adapt Phama's application to the EMA was submitted in February 2017 (should be through in the spring of 2018).
Mundipharma's "Nyxoid" was recommended for acceptance by the EMA on September 14th. and it seems it will be "normally" be accepted by the Commission in 67 days later, which would be around November 20th.
Adapt Pharma
Indivior
Mundipharma

15. 3.1 | Since 2015: New Nasal Kits NARCAN 4mg/0.1ml NALSCUE 0.9mg/0.1ml
USA (Nov 2015)
Canada (Oct 2016; OTC)
France:
July 2016 (temp.), July 2017 (Marketing Authorization); OTC
EMA Sept 2017 (initial authorization)
NARCAN 4mg/0.1ml
NALSCUE 0.9mg/0.1ml
NYXOID 2mg/0.1ml
FIM= 46%
FIM= 37%
FIM = 47%

16. New Nasal Kits: 2mg or 4mg Dose?
McDonald R, Lorch U, Woodward J, Bosse B, Johnson H, Mundin G, Smith K, & Strang J. (in press). Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase-I healthy volunteer study. Addiction.

17. 3.2 | New Nasal Kits: 2mg or 4mg Dose?
Higher risk of withdrawal symptoms with higher doses
2mg dose: FDA approved Adapt product in January 2017; EMA approved Mundipharma product in Sept 2017 (not yet launched)
Adapt Pharma survey of 4mg dose (2016):
242/245 OD victims successfully revived
Withdrawal syndrome in 14% of cases
Limitations:
Unconfirmed data
Only 8 out 152 communities provided data – response bias?
Controlled study in medical setting needed!

18. Naloxone nasal spray: A global solution?
> 20 EUR?

19. Naloxone nasal spray: A global solution?
> 20 EUR?
~ 0.50 EUR

20. Next generation: Buccal naloxone?
Preclinical PK study: good bioavailability (F=71%) (Hussain et al., 1987, 1988)
King’s College London: instant-dissolving buccal naloxone tablet (Alqurshi et al., 2016)
Greater stability than nasal spray and easy of transport?
Aug 2017: Purdue Pharma & Klaria agreement

21. Conclusion Now three concentrated nasal spray products
Adapt: US, Canada, (Denmark); Europe?
Indivior: France
Mundipharma: Europe (as of early 2018)
Over-the-counter status?
Remaining issues:
Impact of nasal membrane damage?
Impact of vomitus and secretions?
Dose titration?