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PRE-PUBLICATION DRAFT This is the pre-publication draft of a paper published in the Medical Journal of Australia. The full reference is Lenton, S., Dietze, P. and Jauncey, M. (2016). Perspective: Australia reschedules naloxone for overdose. Medical Journal of Australia, 4(7), 146-147. The published version is available at: https://www.mja.com.au/journal/2016/204/4/australiareschedules-naloxone-opioid-overdose. Perspective: Australia reschedules naloxone for overdose Simon Lentona Paul Dietzeb Marianne Jaunceyc a

National Drug Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia, Australia. b Centre for Population Health, Burnet Institute, Melbourne, Vic, Australia. c Sydney Medically Supervised Injecting Centre, Sydney, Australia.

Australia’s Therapeutic Goods Administration (TGA) has changed naloxone scheduling to make it available over-the-counter (OTC) for treating opioid overdose. On November 24 2015, the TGA announced its final decision to place ‘naloxone when used for the treatment of opioid overdose’ on Schedule 3 thereby allowing OTC purchase (1). This measure comes into effect on February 1, 2016, making Australia the second country, after Italy (in 1995), to have naloxone formally available OTC. Background With much of recent media focus on problems due to crystalline methamphetamine use in Australia, few may be aware that opioid overdose deaths have been increasing over recent years (2). Following the ‘heroin drought’ of late 2000, accidental deaths from heroin and other opioids among Australians aged between 15 and 54 years dropped from 1116 deaths in 1999 (10.19 deaths per 100 000 persons) to 386 deaths (3.46 deaths per 100 000) in 2001. However, opioid related deaths have been rising steadily since 2007 with the most recent confirmed data available indicating that 617 Australians aged between 15 and 54 years died in 2011 (4.95 deaths per 100,000). Estimates for the 2012/2013 years suggest this trend continues (2). Take-home naloxone (THN) programs are designed to assist in the management of opioid overdose events in the pre-hospital setting (3). These programs involve training potential overdose witnesses (typically opioid users, their friends and families) in overdose response (including naloxone administration) and then prescribing and distributing naloxone to

potential overdose victims for later use in an overdose situation. Training typically includes risk factors for opioid overdose, signs of opioid overdose, Basic Life Support and overdose response including resuscitation techniques, calling for an ambulance, administration of naloxone and post-naloxone management. Training addresses the possibility of rebound opioid toxicity due to the relatively short half-life of naloxone (mean: 60 mins, range 30-80 mins) (4) compared to many opioids and the need to monitor the person and possibly administer another dose of naloxone if required. However, the evidence indicates rebound toxicity is rare (5). To date, naloxone kits provided to trainees in Australian THN programs have typically comprised between 2 and 5 mini-jets® of naloxone 400 μg/mL along with IM needles, swabs, gloves and instructional materials. Reports on THN programs, including successful reversals with few adverse effects, emerged in the late 1990s and programs have expanded since that time. A survey of programs in the USA in 2010 found that since 1996, 53,000 kits containing naloxone were distributed through 188 programs across 16 US states, and naloxone was administered in over 10,000 successful overdose reversals(6). In November 2010 Scotland became the first jurisdiction to implement THN nationally (7); however, like most current programs this national program involves prescription. Many THN advocates have called for better access to naloxone by making it available OTC (8). To our knowledge, only Italy and some US states have naloxone available OTC (the US has inconsistent policy across state pharmacy boards; at least one pharmacy chain recently began offering naloxone OTC) (9) and there are plans to expand OTC naloxone availability (10). There are no published accounts of the extent and consequences of naloxone use in Italy. Timely naloxone administration is crucial in preventing morbidity and mortality associated with opioid overdose. Wider access, through making the drug available OTC, is a positive step towards reducing the morbidity and mortality of opioid overdose (11). The TGA’s decision The TGA’s decision creates a new listing for OTC naloxone (under Schedule 3) whilst keeping the original listing under Schedule 4 (requiring prescription). This dual system means that the drug will be government-subsidised, but only when on prescription. The decision was made in response to a Melbourne community pharmacist’s rescheduling application, which resulted in 96 individual submissions to the TGA in the subsequent consultation process. According to the TGA all submissions supported the proposal to downschedule naloxone with the main points being that: making it OTC will remove barriers to access; naloxone is safe and has no effect on anyone without opioids in their system; and it has little to no abuse potential. The TGA’s reasons for the recommendation included that: • •

naloxone is a well-tolerated life-saving medicine with minimal side effects and the benefits outweigh the risks; international experience and the outcomes of a program conducted in the Australian Capital Territory (12) show that easier availability of naloxone will likely decrease the proportion of opioid overdoses that result in fatality.

The TGA further suggested that OTC naloxone would need to be supplied with full and clear instructions for use, understandable by consumers (rather than simply for the trained health care professional, as is currently the case), and emphasised that naloxone does not replace other resuscitation treatments (1). Further issues Several matters must be addressed before OTC naloxone is effectively implemented. Currently available products do not include needles for administration (the kits mentioned above are assembled by individual programs) and product instructions need to be modified for laypeople using the mini-jet® to give the intramuscular injection . These issues are typically addressed in THN programs that involve extensive training, but recent research (13) found no significant differences between trained and untrained lay rescuers utilising naloxone to manage an overdose. As a schedule 3 medication, the most important requirements for THN are therefore: an easily used product with appropriately designed information materials and needles to administer the drug within the package; pointers to online and other training; and brief advice from pharmacy staff. A major issue for OTC availability concerns cost to consumers. The cost of naloxone is currently listed (exclusive of dispensing fee) as A$16.90 per mini-jet®, distributed by UCB Australia. However, under the Pharmaceutical Benefits Scheme, five mini-jets® cost A$37.70, or A$6.10 on concession. Although the dual listing means naloxone will be available at the discounted price on prescription, it is important that the retail price per OTC unit is kept as low as possible as price will be a significant barrier to initial access, and any subsequent replacement of expired naloxone, especially for opioid users who are financially disadvantaged. One final issue for OTC availability concerns the implications for the THN programs such as those operating in ACT, NSW, WA and Vic. These programs may be run by specialist drug treatment or other services but often involve community services/groups such as drug user organisations or community health services. These programs have access to particularly marginalised and financially disadvantaged drug users. They currently provide naloxone via prescription, typically engaging a medical practitioner to attend small-group training sessions. The doctor must then review participants and both prescribe and dispense the medication. While OTC access removes the need for a doctor’s prescription, the requirement for dispensing by a doctor or pharmacist remains. Access to naloxone will be maximised when those providing instruction (including, for example, allied health or peer workers) also provide the medication. Thus S3 rescheduling does little to simplify dispensing arrangements for current THN programs. We note that in other countries where THN programs operate, health authorities have put in place arrangements such that approved programs, that meet defined training and other criteria, can dispense naloxone to their program participants. We hope that the rescheduling of naloxone to make it available OTC will facilitate state and territory health officials exploring ways to similarly allow Australian THN programs to dispense this medication directly to their clients in a cost effective manner.

Implications The TGA decision sets a new precedent for other countries exploring ways to make naloxone available OTC. We recommend that the rescheduling of naloxone is accompanied by regulatory changes to allow current THN programs to dispense naloxone directly to their clients for later use in an overdose situation.

Contributors All authors made substantial contributions to the concept and design of the article, revised it critically for important intellectual content and take accountability for all aspects of the final version. Role of funding source The National Drug Research Institute at Curtin University receives funding from the Australian Government Department of Health. The Burnet Institute gratefully acknowledges the funding received through the Victorian Operational Infrastructure fund. PD is a National Health and Medical Research Council Senior Research Fellow. MJ is employed as a staff specialist by Uniting Care as medical director of the Sydney Medically Supervised Injecting Centre (MSIC) which funded by confiscated proceeds of illicit activity funds managed by NSW Treasury. The funding bodies had no role in the drafting or submission of this article.

Competing interests statement Simon Lenton receives funding from the Australian Government Department of Health through its core funding of the National Drug Research Institute at Curtin University and has conducted research based advocacy for the wider availability of naloxone for more than 10 years. Paul Dietze has been the recipient of an untied educational grant from Reckitt Benckiser and investigator-driven research funding from Gilead Sciences Inc. for unrelated work. Dr Jauncey is the Director of the Medically Supervised Injecting Centre and prescriber for all THN training conducted onsite. References 1. Therapeutic Goods Administration DoHA. Final decisions and reasons for decisions by a delegate of the Secretary to the Department of Health. Canberra. Available at: https://www.tga.gov.au/sites/default/files/final-decisions-and-reasons-decisions-delegatemedicines-secretary-department-health-november-2015.pdf (Accessed 24.11.2015): 2015. 2. Roxburgh A, Burns L. Accidental drug-induced deaths due to opioids in Australia, 2011. Sydney: National Drug and Alcohol Research Centre, 2015. 3. Giglio RE, Li1 G, DiMaggio CJ. Effectiveness of bystander naloxone administration and overdose education programs: a meta-analysis. Injury Epidemiology. 2015;2(10):DOI 10.1186/s40621-0150041-8. 4. Ltd HAP. DBL™ Naloxone Hydrochloride Injection - Product Information - Australia. Melbourne. Available at :

https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI00410-3 (Accessed 8.12.2015): Hospira Australia, 2012. 5. Rudolph SS, Jehu G, Nielsen SL, Nielsen K, Siersma V, Rasmussen LS. Prehospital treatment of opioid overdose in Copenhagen-Is it safe to discharge on-scene? Resuscitation. 2011;82(11):141013. 6. Wheeler E, Davidson PJ, Stephen Jones T, Irwin KS. Community-Based Opioid Overdose Prevention Programs Providing Naloxone — United States, 2010. Morbidity and Mortality Weekly Report. 2012;61(6):101-5. Available at: http://www.cdc.gov/mmwr/pdf/wk/mm6106.pdf (Accessed 22/03/12). 7. McAuley A, Best D, Taylor A, Hunter C, Robertson R. From evidence to policy: The Scottish national naloxone programme. Drugs: Education, Prevention, and Policy. 2012;19(4):309-19. 8. Top 5 Reasons Why We Need Over-the-Counter Naloxone to Combat Drug Overdose [Internet]. 2014 [cited 7/10/2015]. Available from: http://www.huffingtonpost.com/tessie-castillo/top-5reasons-why-we-need_b_5475235.html[23/06/2014 1:45:18 PM]. 9. CVS To Sell Overdose Reversal Drug Without A Prescription In 12 More StatesThe pharmacy giant says it wants to help save lives. [Internet]. 2015 [cited 24/09/2015]. Available from: http://www.huffingtonpost.com.au/entry/cvs-naloxone-overdosereversal_5602dba2e4b0fde8b0d0d189?section=australia&adsSiteOverride=au[24/09/2015 10. FACT SHEET: Obama Administration Announces Public and Private Sector Efforts to Address Prescription Drug Abuse and Heroin [press release]. Washington: The White House Available at: https://www.whitehouse.gov/the-press-office/2015/10/21/fact-sheet-obama-administrationannounces-public-and-private-sector. (Accessed 22/10/2015), October 21 2015 2015. 11. World Health Organization. Community management of opioid overdose. Geneva: WHO, 2014. 12. Olsen A, McDonald D, Lenton S, Dietze P. Independent evaluation of the ‘Implementing Expanded Naloxone Availability in the ACT (I-ENAACT)’ Program, 2011-2014, final report. Canberra. : ACT Health. Available at: http://www.atoda.org.au/wp-content/uploads/NaloxoneEvaluation-Report-FINAL_August-2015_BI.pdf (Accessed 7/10/15), 2015. 13. Doe-Simkins M, Quinn E, Xuan Z, Sorensen-Alawad A, Hackman H, Ozonoff A, et al. Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: A retrospective cohort study. BMC Public Health. 2014;14(1).