The introduction of depot buprenorphine products into Australia

International Medicine in Addictions Conference 2019

Conjoint Professor Nicholas Lintzeris MBBS PhD FAChAM

Director D&A Services, South East Sydney Local Health District Division Addiction Medicine, University Sydney

President-Elect, Chapter Addiction Medicine, RACP

Overview presentation

• Overview of new products

• Formulations, clinical pharmacology, safety & efficacy, clinical issues

• Implementation issues

• Experience in Australia to date

• Likely roll-out in Australia

• Clinical Guidance and training programs

• Implications for future practice

Overview of depot products

Depot buprenorphine injections

• Two products for either weekly or monthly subcutaneous injection

• Rationale:

• Less need for frequent attendance at clinic / pharmacy

• Less inconvenience and costs for clients and staff

• Better adherence to medication (no missed doses) and ?better outcomes

• Less diversion of medication & less risk of injecting BPN designed for SL use (safety and community perceptions)

Buvidal Weekly and Buvidal Monthly® (Camurus) 1-week and 4-week BPN depots

– Registered in Australia and Europe, awaiting PBS listing

– Dose options: 4 x Weekly and 3 x Monthly doses

• Weekly doses: 8mg, 16mg, 24mg and 32mg

• Monthly doses: 64mg, 96mg, 128mg

– Ready-for-use in prefilled syringe (0.16–0.67mL)

– Subcutaneous injection by Health Care Provider

– Stored at room temperature

– Not to be dispensed to patient

Buvidal: The evidence Active-control RCT (Lofwall JAMA Int Med June 2018)

• Buvidal vs SL BPN • Illicit opioid users entering

treatment

• Double blind, double dummy RCT with flexible doses

• Buvidal at least as good as SL BPN treatment (non-inferiority analysis)

Buvidal: The evidence ‘Study 499’: Long-term patient safety study (Frost et al submitted)

• 227 patients in >30 centres across Europe, USA & Australia • 4 Australian sites with 29 patients

• Open label, ‘natural’ conditions, 12 months treatment

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 0 4 4 4 8

0

2 0

4 0

6 0

8 0

1 0 0

T re a tm e n t w e e k

% R

ete

nti

on

of

pa

tie

nts W e e k 2 4

8 2 .8 %

W e e k 4 8

7 3 .6 %

Clinical issues in using Buvidal • Initiate with 7-days SL BPN treatment, then

transfer to Buvidal according to SL dose • May initiate directly to Buvidal if necessary

• Titrate frequency and doses according to stages of treatment and response

• Peak effects: within 6-24 hrs of dose

• Duration effects: • Weekly dose every 5-9 days (t1/2=3-5 days) • Monthly dose every 3-5 weeks (t1/2=19-25 days)

• Accumulation of BPN plasma levels with time (steady state after 3-4 injections)

• Supplemental BPN doses: • Top-up Buvidal 8mg doses (up to 24hrs apart); • SL BPN if necessary

• Adverse Events: Local site reactions (redness, pain) generally mild & transient in about 10% patients

Daily SL BPN dose

Buvidal weekly dose

Buvidal monthly dose

6mg 8 mg No monthly equivalent

8-10 mg 16 mg 64 mg

12-16 mg 24 mg 96 mg

18-32 mg 32 mg 128 mg

Sublocade®: The medication

• Licensed 2018 with FDA; TGA pending

• Prefilled syringe with either 300mg (1.5ml) or 100mg (0.5ml) doses

• 4-week SC injections administered by HCP into abdominal area

• Cold-storage requirements (4◦ Celsius), can be stored at room temperature for 7 days

• Not to be dispensed to patient

Sublocade: The evidence Haight et al Lancet 2019

• Double-blind 6-month RCT comparing: • 300mg/100mg Sublocade

• 300mg/300mg Sublocade

• Placebo

• Sublocade > placebo on all outcomes

• No difference between Sublocade doses

Clinical issues in using Sublocade

• Must be on SL BPN (≥ 7 days) prior to starting Sublocade

• Commence 300mg monthly for first 2 doses (2x4weeks) • ?consider starting 100mg if transfer from low dose (≤4mg) BPN

• Thereafter choose between 100mg or 300mg injections • Peak effects in 24hrs post dose

• Half life= 43-60 days; steady state equilibrium after 3-5 doses

• Duration effects: 4-8 weeks, depends on dose & duration

• Recommend dose no closer than 26 days apart, and up to 14-days ‘late’ without concerns (ie. 4-6 week doses)

• Supplemental BPN: If required can add low dose SL BPN (No ‘top up’ depot doses)

• Adverse Events • Local site reactions (redness, pain) - generally mild and transient in

about 10% patients. Small ‘lump’ routine

Comparing doses between BPN products

4.74

5.35

6.72

8.45

4.88

10.12

4.30

5.50

6.87

3.81

5.47

6.59

7.54

0.68 0.81 1.05

1.61

2.48

5.01

0.84

1.40

2.63

0.45 0.54

0.93 1.26 1.24

1.71 1.90

2.91 3.21

6.54

2.09

2.85

4.17

1.95

2.85

3.85

0

2

4

6

8

10

12

8mg Subutex 12mg Subutex 16mg Subutex 24mg Subutex 100mgSublocade

300mgSublocade

8mg BuvidalWeekly

16mg BuvidalWeekly

24mg BuvidalWeekly

32mg BuvidalWeekly

64mg BuvidalMonthly

96mg BuvidalMonthly

128mg BuvidalMonthly

192mg BuvidalMonthly

Stea

dy

Stat

e n

g/m

l

Pharmacokinetic parameters (Steady State - Subutex, Sublocade and Buvidal Cmin, Cavg and Cmax)

Subutex

Sublocade

Buvidal Weekly Buvidal Monthly

Implementation in Australia

Depot BPN use in Australia till now …

• Buvidal • Study 499: 29 Australian patients in 4 sites (Langton, Newcastle, Adelaide, RPAH).

Open label, 12 month patient safety study (Frost submitted)

• DEBUT Study: RCT comparing Buvidal to SL BNX currently underway in 6 sites. N=120,

6 month treatment, comparing patient satisfaction, substance use & health

outcomes, treatment costs (Lintzeris PI)

• UnLOCT Study: Feasibility study in 60 depot patients in 7 prisons in NSW (Dunlop PI)

• Sublocade • CoLAB Study: Open label single group N=100 across 7 sites (Victoria, NSW, SA),

examining patient satisfaction, patient outcomes, treatment costs, patient and

clinician experience. Expected to commence recruitment May 2019. (Farrell PI)

• SAS-B: patients treated in Queensland and WA

Timelines from here …

• Introduction Buvidal to clinical practice

• Product Familiarisation Program by Camurus to be implemented in May 2019 making Buvidal available to restricted practices

• Awaiting PBS listing for generalised availability

• Introduction Sublocade to clinical practice

• SAS-B currently underway

• Awaiting TGA and PBS listing for generalised availability

• Expect both products to become generally available in Q3-Q4 2019

Timelines from here …

• Clinical guidelines • NSW Health leading development of clinical guidelines, (Lintzeris, Dunlop, Masters)

• Other jurisdictions will tailor these to local conditions

• Combined guidance on Buvidal & Sublocade; ‘best evidence’ & consensus approach

• Expect draft NSW Guidance in March, completed by end April 2019

• Credentialing and Training Programs • Training can be achieved within 60 minute courses

• ‘Permit’ (Authority) systems • Different jurisdictions considering different approaches

• Preferred clinical model is ‘one permit for all BPN products’

• Consumer information

Implications for clients and services • May have big impact upon MATOD in Australia

• No need for supervised dosing or take-aways

• ?Role of UDS & 2 weekly ‘reviews’ (if no Take-away decisions to be made)

• Reduced costs and inconvenience for patients

• Reduced diversion concerns

• Reduces much of the source of conflict between providers and clients (e.g. money, intoxicated presentations, urine testing, take-away restrictions)

• May change the balance between methadone and BPN • 70:30 split for >15 years may be flipped around

• May have impact upon how services operate • specialist OTP services operating ‘depot clinics’ rather than ‘methadone queues’

• relationship between specialist and primary care services

• role of community pharmacies / co-located services

The importance of clinical research in our settings

• Introduction of opioid treatments in Australia facilitated by clinical research activities • 1990’s: Subutex, LAAM, naltrexone

• 2005: Suboxone tablets

• 2012: Suboxone Film

• 2016-19: depot formulations

• Allows development of clinical models, guidelines, training programs, examine safety and outcomes tailored to local conditions

• It is time to establish a National AoD Clinical Research Network