Buprenorphine Implants For the Treatment of Opioid Dependence

Buprenorphine Implants for the
Treatment of Opioid Dependence
Eric Kosky
Pharm D. Candidate 2017
June 30th 2016

Overview
 Opioid Dependence
– Prevalence, Pathophysiology, Diagnostic Criteria
 Current Treatment Options
 Buprenorphine Implants
– MoA, AEs, Kinetics, Insertion Technique
 Clinical Trial Safety & Efficacy Data
 Pharmacoeconomic Analysis
 Clinical Context
 Recommendation
2

Abbreviations
Term Abbreviation
Objective Opiate Withdrawal Scale OOWS
Clinical Opiate Withdrawal Scale COWS
Subjective Opiate Withdrawal Scale SOWS
Visual Analog Scale VAS
Ethylene Vinyl Acetate EVA
Buprenorphine Implant BI
Buprenorphine/Naloxone Sublingual BNX
Placebo Implant PI
Standard Deviation SD
Pharmacokinetic PK
Clinical Global Impressions-Severity CGI-S
Clinical Global Impressions-Improvement CGI-I
3

Epidemiology
4
 Pain Reliever Use
Disorder
– 1.9 million people (12+ y/o)
Center for Behavioral Health Statistics and Quality. (2015). Behavioral health trends in the United
States: Results from the 2014 National Survey on Drug Use and Health (HHS Publication No.
SMA 15-4927, NSDUH Series H-50). Retrieved from http://www.samhsa.gov/data/
 Heroin Use Disorder
– 586,000 people (12+ y/o)

5
Epidemiology (cont.)
 259 million prescriptions for opioids in 2012
 >420,000 emergency room visits due to opioid
abuse
 America alone consumes 80% of the world’s
opiates
 In 2007, every 19 minutes, a drug overdose
occurred
 165,000 overdose related deaths
– 1999 to 2014
 #1 cause of accidental death in America
Dowell, D, Haegerich TM, Chou, R. Background. MMWR Recomm Rep 2016;65[1-2]
http://lab.express-scripts.com/lab/insights/drug-safety-and-abuse/americas-pain-points
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm

6
Pathophysiology
NAABT. How Buprenorphine Works. Available from:
http://www.naabt.org/collateral/How_Bupe_Works.pdf
Probuphine (buprenorphine) prescribing information. Princeton (NJ): Braeburn Pharmaceuticals, Inc;
2002. Revised 2016 May.

7
Pathophysiology (cont.)

8
DSM5 Diagnostic Criteria
1. Opioids are often taken in larger amounts or over a longer period than was intended
2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use
3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid,
or recover from its effects
4. Craving, or a strong desire or urge to use opioids
5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work,
school, or home
6. Continued opioid use despite knowledge of having a persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of opioids
7. Important social, occupational, or recreational activities are given up or reduced
because of opioid use
8. Recurrent opioid use in situations in which it is physically hazardous
9. Continued opioid use despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or exacerbated by the substance
10. Tolerance
11. Withdrawal
American Psychiatric Association: Diagnostic and Statistical manual of mental Disorders, Fifth
Edition. Arlington, VA, American Psychiatric Association, 2013.

9
Mild Opioid Use Disorder
school, or home
10. Tolerance
11. Withdrawal
✔
✔
✔
✔
✔
2-3 Symptoms

10
Moderate Opioid Use Disorder
school, or home
10. Tolerance
11. Withdrawal
✔
✔
✔
✔
✔
✔
4-5 Symptoms

11
Severe Opioid Use Disorder
school, or home
10. Tolerance
11. Withdrawal
✔
✔
✔
✔
✔
✔
✔
✔
6+ Symptoms

12
Mini-International
Neuropsychiatric Interview (MINI)
 Widely used psychiatric structured
diagnostic interview instrument
 Requires only “yes” or “no” answers
 Divided into modules identified by letters
corresponding to diagnostic categories
 Approx. 15 minutes
Sheehan DV, Lecrubier Y, Sheehan KH, et al. (1998). "The Mini-International Neuropsychiatric
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric
interview for DSM-IV and ICD-10". J Clin Psychiatry. 59 Suppl 20: 22–33

13
Opiate Abuse Rating Scales
 COWS
– Clinician administered
– 11 clinical withdrawal symptom rating scale
 OOWS
– Clinician administered
– Yes/no responses to 13 withdrawal symptoms
 SOWS
– Self-reported
– 16 Questions rated 0-4 related to withdrawal symptoms
 VAS
– Self-reported
– Quantify craving for opioids from 0 to 100

14
Treatment Options
Practice Guideline for the Treatment of Patients With Substance Use Disorders [Internet].
Arlington (VA): American Psychiatric Association; [updated 2006 May; cited 2016 June 27].
Methadone
• Full Agonist
• Oral tablet
• Oral solution
Buprenorphine
• Partial Agonist
• Buccal film
• SQ implant
• Transdermal
patch
• Sublingual
tablet
• IM injection
Bup/Naloxone
• Partial
Agonist/Antag
onist
• Sublingual
film
• Buccal film
• Sublingual
tablet
Naltrexone
• Antagonist
• Oral tablet
• IM injection
CII CIII
CIII

Probuphine (buprenorphine)
15
 Four implants inserted
subdermally for 6 months
 Eligible patients must be
clinically stable on low-to-
moderate doses of
buprenorphine (≤8mg)
 Each implant is an (EVA)
implant containing 74.2
mg of buprenorphine
– Utilizes Titan Pharmaceutical’s
ProNeura Drug Releasing System
Probuphine (buprenorphine) prescribing information. Princeton (NJ): Braeburn
Pharmaceuticals, Inc; 2002. Revised 2016 May.
26 mm Length
2.5 mm Diameter

16
Buprenorphine MoA

17
Buprenorphine MoA

18
Probuphine BBW

19
Probuphine Kinetic Overview
A
• Initial peak and median Tmax occurred at 12 hours after insertion
• Steady-state concentration reached by week 4
• Buprenorphine SS comparable to trough levels of 8mg sublingual buprenorphine
D
• Approximately 96% protein bound
• Bound primarily to alpha and beta
• globulin
M
• N-dealkylation to norbuprenorphine
• primarily via CYP3A4
• Further undergoes glucuronidation
E
• Eliminated as unchanged drug, norbuprenorphine, and two unidentified metabolites
in urine (30%) and feces (69%)
• Mean elimination half-life ranging from 24 to 48 hours
Probuphine (buprenorphine) prescribing information. Princeton (NJ): Braeburn Pharmaceuticals, Inc; 2002. Revised 2016 May.
[image]https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/Buprenorphine2DCSD.svg/1006px-
Buprenorphine2DCSD.svg.png
[image] https://upload.wikimedia.org/wikipedia/commons/0/09/Buprenorphine3DanBS.gif

20
Sustained Buprenorphine
Plasma Levels via Probuphine
White J, et al. Drug Alcohol Depend. 2009;103(1-2):37-43.

21
Adverse Events
 Implant-site related events(>10%)
– Implant-site pain, pruritus, and erythema
 Non-implant-site related events (≥5%)
– Headache, depression, constipation, nausea,
vomiting, back pain, toothache, and oropharyngeal
pain
 Serious/rare adverse events
– Respiratory depression, pulmonary embolism

22
Drug Interactions
 CYP3A4 Inhibitors & Inducers
– Monitor patients starting or ending CYP3A4
inhibitors or inducers
– Potential for over- or under-dosing
 Serotonergic Drugs
– Concomitant use may result in serotonin syndrome
– Discontinue PROBUPHINE if serotonin syndrome is
suspected

23
Ideal Probuphine Placement
[image] https://static01.nyt.com/images/2016/01/13/science/13-ADDICT/13-ADDICT-master768.jpg

24
Insertion of Probuphine

25
Mark Insertion Site

26
Inserting the Applicator
Applicator

27
Advancing the Applicator

28
Insert Implant into Cannula
Cannula Probuphine Implant

29
Insert the Obturator
Obturator

30
Retract the Cannula
Obturator

31
Lock Cannula to Obturator

32
Retract Applicator
Implant Successfully Inserted

33
Verify Implant Presence

34
Probuphine Physician Locator
httphttp://www.Probuphine.com

35
httphttp://www.Probuphine.com/physician-locator/
✔

36
✔

37
“We have capacity to train up to
3,000 providers within this six-
week period.1 We will have
capacity to train a total of 4,000
providers by the end of 2016.”2
-Braeburn CEO Behshad Sheldon
1. “…six-week period” refers to the six-weeks following FDA approval on May 26, 2016
2. Arlotta CJ. The First-Ever FDA-Approved Buprenorphine Implant For Opioid Dependence [Internet]. Jersey City (NJ):
Forbes; May 27, 2016 [cited: June 24, 2016]. Available from: http://www.forbes.com/sites/cjarlotta/2016/05/27/the-
first-ever-fda-approved-buprenorphine-implant-for-opioid-dependence/print/
✔
4,000
providers by the end of 2016.”2

38
Road to FDA Approval
1. White J, et al. Drug Alcohol Depend. 2009;103(1-2):37-43.
2. Ling W, et al. JAMA. 2010;304(14):1576-83.
3. Rosenthal RN, et al. Addiction. 2013;108(12):2141-9.
Phase 1/2 - March 2009
Phase 3 – October 2010
Phase 3 - July 2013
FDA Approval - May 2016
Final Phase 3 Study not available to public

39
Study Objective & Design
Objective Design
White J, et al. 2009 Assess the efficacy of
two doses of BI in
suppression of
withdrawal symptoms,
heroin cravings, and use
of illicit opioids, and to
evaluate safety and PK
• Open-label, 6-month
phase I/II study in
Australia
• Two Cohorts (2 vs 4
implants)
Ling W, et al. 2010 Determine the efficacy
of BI for the treatment
of opioid dependence
• Randomized, placebo-
controlled, 6-month
trial in the US
Rosenthal RN, et al. 2013 Evaluate the safety and
efficacy of BI vs. PI for
the treatment of opioid
dependence
• Randomized, double-
blind, placebo-
controlled trial at 20
sites around the US
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

40
Patient Sample
Patient Size Characteristics
White J, et
al. 2009
• 12 heroin-dependent volunteers
• 2 equal cohorts
• 2 BI (n=6)
• 4 BI (n=6)
• No Difference between
treatment groups
• Primarily white
males
Ling W, et
al. 2010
Induction Phase (n=163)
• Received 12-16mg per day BNX
for 3 days
Randomized in 2:1 fashion
• BI (n=108)
• PI (n=55)
• No difference between
groups
• Clinicians allowed to
prescribe supplemental
BNX
Rosenthal
RN, et al.
2013
Stratified in a 2:1:2 ratio (n=287)
• BI (n=114)
• PI (n=54)
• BNX (n=119)
• 12-16mg/day
• No difference between
groups
• Clinicians allowed to
prescribe supplemental
BNX
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

41
Inclusion/Exclusion Criteria
Inclusion Exclusion
White J, et
al. 2009
• Male or non-pregnant female
• Age 18-55, inclusive
• DSM-IV diagnosis of Opioid
Dependence
• Stable on PO Buprenorphine
• Dependent on any other
substance besides nicotine
• Severe psychiatric illness
• Currently prescribed
anticonvulsants
Ling W, et
al. 2010
• Male or non-pregnant female
• Age 18-55, inclusive
Dependence
• AIDS
substance besides nicotine
• NonRx Benzo
• Chronic Opioid Use
Rosenthal
RN, et al.
2013
• Male or non-pregnant females
• Age 18-55 inclusive
Dependence
• AIDS
• Low platelet count
substance
• NonRx Benzo
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

42
Study Endpoints
Primary Endpoints Secondary Endpoints
White J, et al.
2009
• Opioid Withdrawal
Symptoms
• SOWS, OOWS
• Cravings
• VAS, Urine Tox
• Safety & Pharmacokinetic
Variables
Ling W, et al.
2010
• Percentage of urines
negative for opioids
weeks 1 to 16
• Percentage of urines negative for
opioids weeks 17 to 24
• Proportion of treatment failures,
study completers, SOWS, COWS,
VAS
Rosenthal
RN, et al.
2013
• Percentage of urines
negative for opioids
weeks 1 to 24
• Patient self-reported
opioid use
• Percentage of urines negative for
opioids for weeks 1-16 and 17-24
• Proportion of study completers,
SOWS, COWS, VAS, CGI-S, CGI-I
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

43
Statistical Analysis
Primary Endpoints
White J, et al.
2009
• Percent changes from baseline
• Statistical significance determined using two tailed t-
tests (alpha=0.05)
• Mean±SD calculated and graphed for kinetic data
Ling W, et al. 2010 • Cumulative distribution function (% of negative urines)
• Approximately 150 subjects were required to provide
an 80% power
• Missed samples considered positive for opioids
Rosenthal RN, et
al. 2013
• Cumulative distribution function (% of negative urines)
• Approximately 150 subjects were required to provide
an 80% power
• Noninferiority demonstrated if the lower bound of the
CI was greater than -15%
• Missed samples considered positive for opioids
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

44
Primary Endpoint Results
White J, et al.
2009
• % change from baseline after 24 weeks (SOWS)
• 2 implant: +2.0, 4 implant: -25.5 (p=0.013)
• No significant changes in OOWS
• No significant changes in VAS, or self-reported opioid
abuse
Ling W, et al. 2010 Mean difference in urines negative for opioids, weeks 1-16
• BI mean 40.4%. PI mean 28.3% (p=0.04)
Rosenthal RN, et
al. 2013
Mean difference in urines negative for opioids, weeks 1-24
• BI vs PI (p<0.0001)
• BI vs BNX (p=0.81)
• 95% CI (-10.7,6.2)
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

45
Secondary Endpoint Results
White J, et
al. 2009
• 2 Implants (Steady State reached at 21 days)
• Tmax=17.3±5hrs
• Cmax=2.00±0.41ng/ml
• t1/2=13.7±2.5hrs
• 4 Implants (Steady State reached at 21 days)
• Tmax=15.9±4.9hrs
• Cmax=3.23±0.48ng/ml
• t1/2=23.8±8.6hrs
• Reported AEs were mild/moderate. No serious AE or deaths. No AE related
discontinuations
Ling W, et
al. 2010
• BI vs PI(p<0.001)
• BI mean 36.6%. PI mean 22.4% (p=0.01)
Rosenthal
RN, et al.
2013
• % of urines negative for opioids
• Weeks 1-16: BI vs PI (p< 0.0001)
• Weeks 17-24: BI vs PI (p=0.0002)
• 64.0% vs 25.9% patient completion after 24 weeks (p=0.0002)
• SOWS, COWS, VAS
• All statistically significant differences (p<0.0001)
• CGI-S (p=0.031), CGI-I (p=0.022)
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

46
Study Critique
Strengths Limitations
White J, et al. 2009 • First report on PK,
safety, & efficacy of BI
• Small patient sample
• Only heroin addicts
• Open-label
• No active comparator
Ling W, et al. 2010 • Diversion appeared
unlikely
• No BI patients met the
definition for treatment
failure
• High BNX start dose
• Psychosocial
counseling
• Supplemental BNX
• High attrition rate
• No active comparator
Rosenthal RN, et al.
2013
• Use of a cumulative
distribution function
curve (% of neg. urine)
• Diversion appeared
unlikely
• High BNX start dose
• Noninferiority margin
• Noninferiority
comparison was un-
blinded
• Supplemental BNX
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

47
Conclusion
Author’s Conclusion My Conclusion
White J, et
al. 2009
These initial PK, safety,
and efficacy data provide a
basis for further evaluation
of this product.
Although open-label, this dose-
finding study provides encouraging
data about the potential clinical use
of BI.
Ling W, et
al. 2010
The use of BI compared to
PI resulted in significantly
less opioid use over 16
weeks.
Diversion is not completely
eliminated with the use of supp
BNX. Further research is needed to
assess how BI compares with current
opioid maintenance treatments.
Rosenthal
RN, et al.
2013
Compared with placebo, BI
resulted in significantly
less frequent opioid use,
and are non-inferior to
BNX tablets.
BI is an important innovation to
reduce abuse potential. However, a
blinded, randomized trial should be
conducted with a smaller
noninferiority margin to further
validate the findings.
2. Ling W, et al. JAMA. 2010;304(14):1576-83.

48
Trial Comparison
2. Ling W, et al. JAMA. 2010;304(14):1576-83.
All Trials
• Inclusion Criteria
• Supp. Buprenorphine
• MINI, SOWS, VAS
• No signs of diversion
or abuse
Rosenthal & Ling
• Conducted in USA
• Compared BI to PI
• 12-16mg/day
Buprenorphine
induction phase
Rosenthal RN, et al.
2013
• Efficacy & Safety
from 1-16 weeks &
17-24 weeks
• Compared BI to
BNX
White J, et al. 2009
• Inpatient insertion
and removal by
surgeon
• Australia
Ling W, et al. 2010
• Efficacy over 24
weeks

49
Pharmacoeconomic Analysis
Dose Package
Size
AWP AWP
Unit
Price
6 Months of
Treatment*
Probuphine 74.2mg/
Implant
4 Implants $5,940 $1,485 $5,940
Methadone 10mg 100 Tabs $14.95 $0.15 $100.80**
Buprenorphine 8mg 30 Tabs $232.30 $7.74 $1,300.32
Bup /Naloxone 8mg/2mg 30 Tabs $253.75 $8.46 $1,421.28
Suboxone 8mg/2mg 30 Strips $266.04 $8.87 $1,490.16
Bunavail 4.2mg/.7 30 Strips $266.04 $8.87 $1,490.16
Naltrexone 50mg 30 Tabs $75.60 $2.52 $4,23.36
Vivitrol 380mg 1 IM Inj $1,570 $1,570 $9,420
Red Book Online [database online]. Greenwood Village, CO: Truven Health Analytics.
http://www.micromedexsolutions.com/. Accessed June 27, 2016
* = 6 months translates to 24 weeks
** = Calculated using 50 mg/day of methadone

50
Clinical Considerations
Pregnancy Category Category C
Monitoring Diversion or progression of opioid dependence and
addictive behaviors
Storage 20-25°C (68-77°F)
Breakthrough Cravings Manage with clinician supervised prescribing of
supplemental oral buprenorphine
Continuation of therapy After one insertion in each arm, most patients should
be transitioned back to transmucosal buprenorphine
REMS Requirement All HCP’s must successfully complete a live training
program on the insertion and removal procedures
and become certified in the PROBUPHINE REMS
program
Risk of Respiratory and CNS
Depression
Buprenorphine in combination with benzodiazepines
or other CNS depressants (including alcohol), has
been associated with significant respiratory
depression and death.

51
Conclusions & Recommendation
Efficacy
• Non-Inferior to sublingual formulations of buprenorphine
• Still requires PO buprenorphine for breakthrough cravings
• Psychosocial counseling may be required to see full benefits
Safety
• Requires minor surgery for placement of rods that are indwelling for 6 months
• Lack of long-term safety data
• Buprenorphine AE profile already known by clinicians
Cost
• Although expensive, Braeburn is prepared to provide a rebate if the overall cost of care for
a group of patients taking Probuphine exceeds the cost of treatment for the same patients in a
prior six month period, or a comparable group of patients taking other forms of buprenorphine
for a six month period.
Place in Therapy
• Reserved for patients who have a high risk of abuse OR are noncompliant to PO buprenorphine.
• Patients should only be transitioned to buprenorphine if they are clinically stable on ≤ 8mg
buprenorphine
Commercialization Plans for Probuphine® (buprenorphine) Implant, Six-Month Treatment for Opioid
Dependence[Internet]. Princeton (NJ): May 31, 2016 [cited: June 24, 2016]. Available from:
https://braeburnpharmaceuticals.com/braeburn-pharmaceuticals-announces-commercialization-plans-
for-probuphine-buprenorphine-implant-six-month-treatment-for-opioid-dependence/

53
References
1. Murthy VH. Surgeon General's Perspectives: A Promise Fulfilled—
Addressing the Nation’s Opioid Crisis Collectively. Public Health Rep. 2016
May/June;131(3):387-389.
2. [image]https://media.npr.org/assets/img/2016/01/15/probuphine-
1_wide-61003f6c468a4d1327ce4321961ffa432e5afef4.jpg?s=1400
3. Center for Behavioral Health Statistics and Quality. (2015). Behavioral
health trends in the United States: Results from the 2014 National Survey
on Drug Use and Health (HHS Publication No. SMA 15-4927, NSDUH
Series H-50). Retrieved from http://www.samhsa.gov/data/
4. Dowell, D, Haegerich TM, Chou, R. Background. MMWR Recomm Rep
2016;65[1-2]
5. NAABT. How Buprenorphine Works. Available from:

54
References
6. American Psychiatric Association: Diagnostic and Statistical manual of
mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric
Association, 2013.
7. Sheehan DV, Lecrubier Y, Sheehan KH, et al. (1998). "The Mini-
International Neuropsychiatric Interview (M.I.N.I.): the development and
validation of a structured diagnostic psychiatric interview for DSM-IV and
ICD-10". J Clin Psychiatry. 59 Suppl 20: 22–33
8. Practice Guideline for the Treatment of Patients With Substance Use
Disorders [Internet]. Arlington (VA): American Psychiatric Association;
[updated 2006 May; cited 2016 June 27].
9. Commercialization Plans for Probuphine® (buprenorphine) Implant, Six-
Month Treatment for Opioid Dependence[Internet]. Princeton (NJ): May 31,
2016 [cited: June 24, 2016]. Available from:
https://braeburnpharmaceuticals.com/braeburn-pharmaceuticals-
announces-commercialization-plans-for-probuphine-buprenorphine-
implant-six-month-treatment-for-opioid-dependence/

55
References
10. [image] https://static01.nyt.com/images/2016/01/13/science/13-
ADDICT/13-ADDICT-master768.jpg
11. Arlotta CJ. The First-Ever FDA-Approved Buprenorphine Implant For
Opioid Dependence [Internet]. Jersey City (NJ): Forbes; May 27, 2016
[cited: June 24, 2016]. Available from:
http://www.forbes.com/sites/cjarlotta/2016/05/27/the-first-ever-fda-
approved-buprenorphine-implant-for-opioid-dependence/print/
12. [image]https://upload.wikimedia.org/wikipedia/commons/thumb/f/fe/B
uprenorphine2DCSD.svg/1006px-Buprenorphine2DCSD.svg.png
14. Ling W, et al. JAMA. 2010;304(14):1576-83.
16. Red Book Online [database online]. Greenwood Village, CO: Truven Health
Analytics. http://www.micromedexsolutions.com/. Accessed June 27, 2016

ekosky@mail.usciences.edu
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Buprenorphine Implants For the Treatment of Opioid Dependence

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