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® SUBLOCADETM P&T PREP Sheet

Draft No. 1 – original posting dateUpdate No. – date of revision

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SUBLOCADE Overview

SUBLOCADETM OverviewGeneric name & manufacturer

buprenorphine extended release injectionIndivior PLC

FDA Approval Date Nov 30, 2017Proposed indication Treatment of moderate to severe opioid use disorder (OUD) in

patients who have initiated treatment with a transmucosal buprenorphine containing product, followed by dose ‐adjustment for a minimum of 7 days.1

Pharmacology/MOA Buprenorphine is a partial agonist of mu-opioid receptors, which is the mechanism for the drug’s analgesic effect. Buprenorphine reduces cravings with less euphoria or other undesired side effects of full-agonist opioids. It is also a kappa-opioid–receptor antagonist, a delta-opioid–receptor agonist, and an ORL-1 receptor partial agonist.

SUBLOCADETM is formulated with the ATRIGEL® Delivery System to create a solid depot of buprenorphine upon subcutaneous injection. Buprenorphine releases from the depot at a sustained rate.

Disease overview Opioid use disorder (OUD) is defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria (DSM-5) as “a problematic pattern of opioid use leading to significantly impairment or distress”.2 DSM-5 combined “opioid abuse” and “opioid dependence” into OUD. Opioid use can be either illicit (heroin) or prescription opioids (e.g. oxycodone, hydrocodone, hydromorphone, methadone, etc.). OUD is a chronic disease of neurological origin that impairs social, psychological, and physical behaviors. The severity of OUD is based on the number of symptoms present, with mild

defined as two to three, moderate as four to five, and severe presence as six or more symptoms.

Symptoms generally overall include excessive use of opioid (than prescribed/intended), failure to reduce or control opioid use, cravings for medication, and impairment from recurrent opioid use.2 Tolerance and withdrawal are not considered diagnostic criteria if patients are taking opioids as prescribed under medical supervision.

Disease epidemiology (prevalence/incidence)

In 2016, approximately 66 million people in United States were prescribed and filled at least one prescription opioid, a rate of 20.7 per 100 persons.3 In the same year, nearly 2.1 million people (0.8% people 12 years or older) have OUD, the majority (1.8 million) with prescription OUD.4 An estimated 1.6 million adults (0.8% people 26 years or older) have OUD. In 2016, there were 42,249 opioid overdose deaths, five times higher than in 1999.5

Target population SUBLOCADETM is indicated for treatment of moderate to severe opioid use disorder (OUD) in patients who have initiated treatment with a transmucosal buprenorphine‐containing product.1 It is an option for the 1.8 million Americans with prescription OUD.4

Moderate to severe OUD: Approximately 9.7% of patients on long-term opioid therapy in their lifetime have moderate OUD and 3.5% have severe opioid use disorder.6 Therefore, approximately 237,600 individuals have moderate to severe OUD in the United States.

Seeking treatment with a Drug Addiction Treatment Act (DATA)-registered healthcare provider and initiated treatment with a transmucosal buprenorphine containing ‐product. In 2012, there were 22,715 DATA-waived physicians, with a capacity to provide 1,093,150 patients with buprenorphine Medication-Assisted Treatment (MAT).7

Difficulty adhering to daily dosing of MAT or high likelihood of drug diversion. Buprenorphine is within the top four diverted opioid medications.8 One-year adherence to buprenorphine daily therapy was 32% in one study.9 However, patients may also be over-adherent to buprenorphine therapy.

Dose and administration Patients must have been inducted and stabilized on a

transmucosal buprenorphine containing product for a ‐minimum of 7 days.1 Transmucosal inductions should not exceed 8 mg of buprenorphine.

Patients should receive concurrent counseling and psychosocial support.

The recommended dose of SUBLOCADETM is two monthly initial doses of 300 mg followed by 100 mg monthly maintenance doses.1 Increasing up to a 300 mg monthly maintenance dose may be considered for patients in high-risk groups (IV-drug users).10

Available as 100 mg/0.5 mL and 300 mg/1.5 mL dosages administered monthly only by subcutaneous (SQ) injection in the abdomen.1

Common adverse events (for 300/100 mg regimen)

(In ≥5% of subjects) constipation (8.0%), headache (8.5%), nausea (8.0%), injection site pruritus (6.4%), vomiting (5.5%), increased hepatic enzymes (9.5%), fatigue (6.0%), and injection site pain (4.9%)1

Severe adverse events Injection site ulcer leading to discontinuation (1 case), severe injection site pruritus (1 case)1

Post-marking (no frequencies provided): serotonin syndrome, adrenal insufficiency, anaphylaxis, and androgen deficiency

Current Treatment Landscape

Current Standard of CareDescription Guideline/Reference Utilized11

The standard of care for OUD combines counseling/psychosocial therapy and withdrawal treatment with one of three medications: methadone, buprenorphine (alone or in combination with naloxone), or naltrexone. Medications may be oral or extended-release injectable formulations. A care plan for OUD can be considered with or without medication-assisted therapy.

ASAM guidelines state that selection of OUD treatment should be based on provider and patient’s shared decision-making, incorporating the patient’s preference, treatment history, and risk of noncompliance/diversion. The setting of treatment is also important and can include office-based opioid treatment (OBOT), which is limited to buprenorphine

Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. J Addict Med. 2015;9(5):358-367.

and to physicians with a DEA-X waiver. Methadone as a treatment for OUD requires patient enrollment in a Methadone Maintenance Program. Naltrexone does not have such prescribing restrictions.

Methadone is recommended for patients who require daily adherence and supervision or who have failed buprenorphine through an opioid treatment program or OBOT. Oral naltrexone Is associated with poor adherence and is recommended for patients only in conjunction with observed administration. Extended-release injectable naltrexone reduces non-adherence but is not completely effective at eliminating it.

ASAM guidelines recommend buprenorphine/naloxone combinations for withdrawal management and treatment of OUD (except for pregnant women).

Slow induction with buprenorphine 2 to 4 mg +/- naloxone is recommended to reduce risk of opioid withdrawal. Buprenorphine monoproducts and Suboxone® transmucosal films are the only FDA-approved induction formulations. Induction in an office setting is recommended for inexperienced patients/providers and home-based induction is only recommended for experienced patients/providers. Stability with induction is based on clinician-judgment of abstinence, treatment adherence, and psychosocial improvements. Frequent monitoring (durations not specified) for abstinence and adherence is recommended, including strategies such as urine screenings, Prescription Drug Monitoring Program assessment, and observed dosing.

Guidelines do not recommend a time limit for discontinuing buprenorphine treatment. Clinician judgment and slow tapering is recommended in light in positive psychosocial changes and sustained abstinence.

Clinical Trials

Trial Identifier & Phase

Sponsor & Status Link

A Single-Dose, Open-Label Study of Depot Buprenorphine (RBP-6000) in Opioid-Dependent Individuals (First-In-Human Study)

Phase I

NCT02765867

IndiviorCompleted

Published

https://clinicaltrials.gov/ct2/show/NCT02765867

https://doi.org/10.1007/s40262-014-

0155-0A Multicenter, Open-Label, Single Ascending-Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Depot Buprenorphine (RBP-6000) in Opioid-Dependent Subjects

Phase I

NCT03002961

IndiviorCompleted

Unpublished


Pharmacokinetics, Safety, and Tolerability of Depot Buprenorphine at Three Different Molecular Weights in Treatment-Seeking Subjects With Opioid Use Disorder

Phase I

NCT02559973

IndiviorCompleted

Unpublished

https://clinicaltrials.gov/ct2/show/study/

NCT02559973

Multiple Dose Pharmacokinetics Depot Buprenorphine in Opioid-Dependent Subjects

Phase II

NCT01738503

IndiviorCompleted

Unpublished


A Multiple-Dose Study of Blockade of Subjective Opioid Effects, Plasma Levels, and Safety of Subcutaneous Injections of Depot Buprenorphine (RBP-6000) in Subjects With Opioid Use Disorder

Phase II

NCT02044094

IndiviorCompleted

Published


NCT02044094

doi: 10.1097/JCP.0000000000

000434Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess Efficacy of Multiple Subcutaneous Injections of Depot Buprenorphine (RBP 6000) Over 24 Weeks in Treatment-Seeking Participants With Opioid Use Disorder

Phase III

NCT02357901

IndiviorCompleted

Unpublished


NCT02357901

A Randomized, Double-blind, Double-dummy, Active-drug-controlled, Parallel-group, Multicentre Acceptability and Safety Study of the Transfer From Subutex/Suboxone to RBP-6300 in

Phase III

NCT01582347

IndiviorCompleted

Unpublished


NCT01582347

Opioid-dependent SubjectsAn Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With Opioid Use Disorder

Phase III

NCT02510014

IndiviorCompleted

Unpublished


NCT02510014

An Open-Label, Depot Buprenorphine (RBP-6000) Treatment Extension Study in Subjects With Opioid Use Disorder

Phase IIINCT02896

296

IndiviorCompleted

Unpublished


Key Trial Results

Nasser AF, Greenwald MK, Vince B, et al. Sustained-Release buprenorphine (RBP-6000) blocks the effects of opioid challenge with hydromorphone in subjects with opioid use disorder. J Clin Psychopharmacol. 2016;36(1):18-26.NCT0204409412

Study TypePhase II, double-blind single-site study to assess subjective experiences of blockade against an opioid agonistN = 30 (78.9% of 39 participants randomized)

Study Population

Inclusion criteria:Adults aged 18 to 55 years with moderate to severe OUD per DSM-5, who were not seeking treatment.

Exclusion criteria: BMI outside of the 18–33.0 kg/m2 range Pregnancy Another diagnosis treated with prescription opioids Risk factors for Torsades de Pointes or prolonged QTc interval (methadone-

associated safety risk) Substance use disorder (other than opioids, cocaine, nicotine, or caffeine) History of suicidal ideations, moderate to severe depression, or uncontrolled

psychiatric illness Positive urine drug screen or self-reported use within 30-days of barbiturates,

benzodiazepines, methadone, or buprenorphine AIDS, acute hepatitis B/C infection Peak “Drug Liking” VAS score <40 mm after administration of 18 mg

hydromorphone during the baseline hydromorphone challenge

Baseline Characteristics:The mean age was 34.8 years (range, 20 to 55 years) and the highest proportion of subjects were men (89.7%) and white (65.8%). The mean body

mass index was 25.35 kg/m2 (range, 20.7–31.5 kg/m2).

Treatment Groups

The study consisted of 3 periods:1) Hydromorphone challenge at baseline (Week –3)2) Induction: Buprenorphine/naloxone sublingual (SL) titrated to 8 to 24 mg/day (Week –1)3) Treatment with buprenorphine 300 mg SQ on Days 1 and 29 (Weeks 1–12)

Once stabilized, subjects received hydromorphone challenges and 6 Visual Analog Scale (VAS) assessments and the drug versus money choice task were conducted, as detailed above, on each of the 3 days preceding administration of RBP-6000 (days –3 to –1 during week – 1).

Hydromorphone challenges were administered during the induction and treatment phases. The challenge consisted of random assignment of placebo IM, hydromorphone 6 mg IM, or hydromorphone 18 mg IM on three consecutive days until 8 weeks after the second injection of buprenorphine.

Primary Endpoint Results

Six Drug Liking Visual Analog Scale (VAS) assessments were conducted during the challenges. The question “Do you like the drug (hydromorphone/placebo)?”) was measured on a 0-100 mm scale, where 0 = “not at all” and 100 = “extremely”. Significant blockade was defined as the upper bound of the 95% confidence interval (CI) ≤11 mm (non-inferiority margin). Baseline hydromorphone challenge: the least squares mean difference

(LSMD) from VAS was 45 mm (95% CI, 37.2–53.6) for placebo vs. hydromorphone 6 mg IV and 61 mm (95% CI, 52.3–68.9) for placebo vs. hydromorphone 18 mg.

Overall, VAS scores decreased with induction and over time. At Week 12, with SUBLOCADE™, participants’ response to hydromorphone was noninferior to placebo (participants did not like hydromorphone at either dose significantly more than the placebo challenge). LSMD was −0.03 mm (95% CI, −2.19 to 2.12) for placebo vs. hydromorphone 6 mg IV and 2.78 (95% CI, 0.61– 4.96) for placebo vs. hydromorphone 18 mg IV.

Secondary Endpoint Results

Drug versus money choice tests was conducted were participants decided between clicking (using a mouse) hydromorphone/placebo dose or money, where the preset number of clicks required increased across trials for twelve trials. The breakpoint value was defined as the highest number of clicks completed to receive the drug. This endpoint assessed the reinforcing efficacy of each challenge.

Breakpoint values for both doses of hydromorphone decreased after treatment with SUBLOCADE™ compared to baseline.

At Week 12, reinforcing effects for hydromorphone were noninferior to placebo.

Hydromorphone 18 mg vs. placebo challenge ratio, LSM 4.90 (95% CI: 1.65 to 14.44)

Hydromorphone 6 mg vs. placebo challenge ratio, LSM 1.80 (0.57 to 5.81)

Log-transformed breakpoint values were 0.6 (95% CI, −0.573 to 1.8) for placebo vs. hydromorphone 6 mg IV and 1.6 (95% CI, 0.50–2.7) for placebo vs. hydromorphone 18 mg IV.*

*For the reinforcing effects transformed breakpoint value, non-inferiority was defined a 95% CI containing zero.

Adverse Events

The two doses of buprenorphine 300 mg SQ during the 12-month study period were overall well tolerated. Treatment emergent adverse events (TEAEs) that occurred in ≥10% of participants included sedation (10.3%), nausea (12.8%), constipation (30.8%), and injection site reactions (79.5%, overall mild with 3 severe cases).

NNT/NNH N/A

Trial Limitations

Small sample size: thirty subjects completed the study in the ITT analysis (78.9%). Exclusion criteria are extensive: 303 subjects were excluded based on these criteria. Patients with moderate to severe psychiatric comorbidities and those who did not like (<40 mm on a 100-m VAS, where 0 indicates not liking the drug at all) hydromorphone 18 mg IV at baseline.

Clinically significant differences in drug versus money choice tests were not explained.

ConclusionParticipants with moderate to severe OUD on buprenorphine 300 mg SQ did not report significant differences in drug liking for hydromorphone 6 mg or 18 mg IV compared to placebo.

Randomized, double-blind, placebo-controlled, multicenter study to assess efficacy of multiple subcutaneous injections of depot buprenorphine (RBP 6000) over 24 weeks in treatment-seeking participants with opioid use disorder. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02357901. Published July 31, 2017. Accessed January 29, 2018.NCT0235790110

Study Type Phase III, randomized, double-blind, placebo-controlled, multicenter study.N = 504 (201 for SUBLOCADETM 300 / 300 mg, 203 for SUBLOCADE™ 300 / 100

mg, and 100 for placebo)

Study Population

Inclusion Criteria:Adults ages 18-65 years with moderate or severe OUD seeking MAT, who have not received MAT within the last 90 days, and within a BMI range of 18-35.

Exclusion Criteria: Another diagnosis treated with prescription opioids Substance use disorder (other than opioids, cocaine, tobacco, or alcohol) History of suicidal ideations Positive urine drug screen or self-reported use within 30-days of barbiturates,

benzodiazepines, methadone, or buprenorphine

Baseline Characteristics: The majority of participants were male (65% to 67%). The mean age was approximately 40 years old among the study. Most participants were white (68% to 78%) followed by African-American (20%

to 29%). The majority of participants had severe OUD (66% to 74%) with a mean duration

of opioid use of 11 years. Injectable opioid users represented 40% to 50% of participants in each group.

The majority of participants had comorbid substance use disorders with tobacco (~90%) and alcohol (~80%) and history of drug use of illicit non-opioids (~50%).

A smaller proportion of participants had a medical history of depression (~13%) or anxiety (~10%).

Among all groups, approximately 36% of participants were employed at baseline.

Treatment Groups

For a two-week run-in period, all participants received induction with buprenorphine/naloxone sublingual film, in order to assess tolerability and prevent withdrawal. Outcome measurement began at Week 5, to allow for treatment stabilization and opioid use during this period was not included in efficacy analyses.

All patients received individual drug counseling in conjunction with buprenorphine subcutaneous depot. All patients were initiated on a 300 mg dose (high-dose) or placebo for the first two monthly injections (Month 1 to 2). Then, participants received four additional monthly injections of high or low doses or placebo (Month 3 to 6). The total study duration was six months with six doses of treatment. Patients were randomized 4:4:1:1 to the following treatments:

1) SUBLOCADETM 300 mg SQ for six doses (300/300-mg group)

2) SUBLOCADETM 300 mg SQ for two doses and buprenorphine 100 mg SQ for four additional doses (300/100-mg group)

3) Volume-matched placebo for the 300/300-mg group4) Volume-matched placebo for the 300/100-mg group

The two placebo groups were pooled into once group for statistical comparisons.


Cumulative distribution function (CDF) of the percent abstinence of collected from illicit opioid use from Week 5 through Week 24. Abstinence is defined as urine drug screening (UDS) results AND self-reports negative for illicit opioid use. Distribution ranges included 0%, 1% to <20%, 20% to <40%, 40% to <60%, 60% to <80%, 80% to 100% weeks of abstinence. The CDF for percent of weeks abstinent from Weeks 5 to 12 were reported for no abstinence (0%), ≥50%, ≥80%, and complete abstinence (100%).

Both 300/300-mg and 300/100-mg SUBLOCADE™ groups demonstrated significant CDF % abstinence compared to the placebo group (p < 0.0001 for 300/300-mg vs. placebo and 300/100-mg group vs. placebo).

The majority of patients in the placebo group did not achieve abstinence. For placebo group, the CDFs were 84% for no abstinence, 4% for ≥50% abstinence, 2% for ≥80% abstinent, 1% for complete abstinence, respectively.

In contrast, the majority of patients on SUBLOCADE™ did achieve some duration of absence. For 300/300 mg, the CDF was 30%, 42%, 29% and 12%, respectively. For the 300/100-mg group, the CDF for abstinence was 25%, 44%, 28%, and 13%, respectively.


Secondary endpoints patient-reported outcomes for opioid use disorder included COWS (Clinical Opiate Withdrawal Scale) and Opioid Craving VAS (Visual Analog Scale).

Control of withdrawal symptoms is signified by a total score COWS ≤ 12 (on a 0-48 scale). Almost all patients (99%) in both SUBLOCADE™ and placebo (97%) groups had a COWS ≤ 12 from Week 5 through Week 24.

Control of opioid cravings was defined as an Opioid Craving VAS ≤ 5 mm (0-100 mm scale). More participants on SUBLOCADE™ reported an Opioid Craving VAS ≤ 5 mm compared to placebo (81% vs. 48%, respectively).

More participants on SUBLOCADETM treatment were employed by the end of the study period, with an increase in employment from baseline (300/300 mg +15% and 300/100 mg: +10%) compared to placebo, with a decrease in

employment status (-5%).

Among IVDU, rates of abstinence were approximately two-times greater in 300 mg maintenance group (34%) compared to the 100 mg group (18%) during weeks 8 to 12.

Adverse Events

Drop-out rates due to adverse events were highest in the 300/300 group 5.0%, compared to 300 / 100 (3.0%) and placebo 2.0%.

Participants on SUBLOCADETM experience greater incidence (~25%) of gastrointestinal adverse events (e.g., constipation, nausea, vomiting) compared to placebo (12%) and nervous system adverse events (e.g., headache, sedation and somnolence) with 12.4% buprenorphine 300/300 mg, 17.2% buprenorphine 300/100, and 7% in placebo groups. There were no cases of liver toxicity in this study, but elevated liver enzymes (ALT greater than 3x the upper limit of normal) were greater with buprenorphine 300/300 (12.4%) compared to 100/100 mg (5.4%) and placebo (4.0%).

The majority of injection site reactions were mild or moderate. Adverse events related to systemic effects of buprenorphine were consistent with safety profiles of transmucosal buprenorphine.

NNT/NNH N/A, primary endpoint was not binary.

Trial Limitations

Per pre-specified analysis, if participants prematurely discontinued the study, missing data was imputated with positive results drug screenings. There was greater premature discontinuation rates by the end of the study in the placebo group (66%) compared to the treatment groups (36-38%). This greater discontinuation in the placebo group may have underestimated the efficacy of placebo, if drop-outs were unrelated to treatment effectiveness.

Conclusion

Both SUBLOCADETM 300/300 mg and 300/100 mg were significantly superior to placebo in achieving abstinence and reducing opioid cravings among patients with moderate-to-severe opioid use disorder. SUBLOCADETM was overall well tolerated, although there were greater incidences of adverse events in the high-dose SUBLOCADETM compared to the low-dose group.

An open-label, long-term safety and tolerability study of depot buprenorphine (RBP-6000) in treatment-seeking subjects with opioid use disorder. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02510014. Published July 31, 2017. Accessed January 29, 2018.NCT0251001413

Study Type Phase 3, open-label, multicenter, long-term safety and tolerability study

N = 669 (412 newly enrolled, 257 roll-over from either arm of the Phase III double-blind placebo controlled study NCT02357901)

Study Population

Roll-over and newly enroll participants met the inclusion/exclusion criteria from NCT02357901.

Baseline Characteristics: N/A

Treatment Groups

For a two-week run-in period, all participants received induction/reinduction with buprenorphine/naloxone SL and an initial dose of 300 mg SUBLOCADETM.

Roll-over participants

Received an additional six months treatment (total of 12 months) with open label high dose buprenorphine (300 mg) or an adjustment to low dose (100 mg) SUBLOCADETM per investigator judgment (flex-dosing).

Newly-enrolled participants

Received a total of 12 months of high dose or flex-dosed SUBLOCADETM.


Number of participants with adverse events, serious adverse events, discontinuation due to adverse events during the 12-month study period, andInjection site tolerability per injection site pain scores on a VAS.

No results available: interim analysis by manufacturer reported that abstinence rates were comparable to the Phase III double-blind placebo controlled study NCT02357901.


Assessment of urine drug screening for opioids or other substance use from Months 6 to 12 (results not available)Self-reported opioid or other substance use from Months 6 to 12 (results not available)

Adverse Events

No statistics available: interim analysis by manufacturer reported that treatment emergent adverse events (TEAEs) were similar between newly enrolled and roll-over groups. TEAE rates were similar between the roll-over group and previous Phase III double-blind study.

NNT/NNH N/A, no results availableTrial Limitations

Although the open-label study is complete, results are unpublished and summaries were derived from manufacturer presentations to the FDA.

ConclusionThe efficacy and safety profiles of SUBLOCADETM (300/300 mg or 300/100 mg) were similar in an open-label 12-month study compared to the Phase III double-blind study.

Evidence Preview

Medical congress abstracts, posters, presentations, and reviews, clinical expert opinions

Melville N. Second injectable buprenorphine product shows promise. Medscape. http://www.medscape.com/viewarticle/890463. Published December 21, 2017. Accessed February 16, 2018.14

Discusses CAM2038, the second once-monthly injectable buprenorphine formulation, and competitor to SUBLOCADETM. CAM2038 would not have to be refrigerated unlike SUBLOCADETM.

Relevant peer-reviewed publications (clinical)

Management of opioid dependence-resource #340106. TRC Pharmacist Letter. January 2018.15

Class review of OUD treatment options, administration, costs, and comparative effectiveness

Listed pros for SUBLOCADETM:o Long-lasting (minimum of 26 days between doses)o Fewer drug interactions compared to methadoneo Depot can be surgically removed in emergencieso Can use in patients requiring up to 24 mg/day of

buprenorphine Listed cons for SUBLOCADETM:

o Patients must be clinically stable on transmucosal buprenorphine (8 to 24 mg daily) for at least seven days

o Injection site liable to tamperingo Restricted access (only REMS providers)

Potentially several drug-drug interactions with CYP3A4 inhibitors/inducers, serotonergic, and QT-prolonging medications

Clinical commentary/opinions

Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326. doi:10.1097/ADM.0000000000000045.16

Discusses factors associated with the buprenorphine diversion and misuse, including the PK/PD of various buprenorphine formulations, availability and access to treatment, and public policies regarding the opioid treatment services

OBOT is rapidly expanding, which increases opportunities for diversion

Reasons for diversion while in OBOT include peer pressure, intent to assist addicted friends/family, and financial pressures

Overall Value Impression

In a Phase III clinical trial and unpublished interim long-term, open label, safety study, the adverse events profile of SUBLOCADETM were similar to that of systemic buprenorphine, along with mild injection site reactions.10,13 The standard of care in moderate to severe OUD is flexible, daily dosing of buprenorphine/naloxone in an outpatient opioid treatment program.11 Probuphine, a six-month buprenorphine implant, is a competitor but is more invasive compared to an injection and not yet widely used.17

Diversion with SUBLOCADETM would inherently be less than with transdermal or oral buprenorphine products, because SUBLOCADETM is a subcutaneous injection formulation that requires office-based administration with a DATA-waived provider.1 There is potential risk of tampering with the injection depot, but this was not reported in clinical trials. All buprenorphine-containing products, including SUBLOCADETM require REMS.1 SUBLOCADETM is administered through a Risk Evaluation and Mitigation Strategy (REMS), which requires prescriber letters, prescriber checklists, pharmacist letters, and medication guide. The prescriber checklist requires for assessment of appropriateness of therapy and patient monitoring.

In a Phase III, double-blind study, both SUBLOCADETM 300/300 mg and 300/100 mg were significantly superior to placebo in achieving abstinence and reducing opioid cravings among patients with moderate-to-severe opioid use disorder.10 SUBLOCADETM was overall well tolerated, although there were greater incidences of adverse events in the high-dose SUBLOCADETM compared to the low-dose buprenorphine group. In a Phase II opioid challenge study, participants with moderate to severe OUD on buprenorphine 300 mg SQ did not report significant differences in drug liking for hydromorphone 6 mg or 18 mg IV compared to placebo.

Pharmacodynamics and pharmacokinetic (PK/PD) studies have established efficacy thresholds to correlate buprenorphine serum concentrations and treat opioid withdrawal.18 PK/PD analyses demonstrate that SUBLOCADETM maintains therapeutic serum concentrations to support its efficacy.12

Studies have compared daily dosing of buprenorphine-containing products to other OUD treatments. A meta-analysis compared buprenorphine-containing daily formulations to methadone for in treatment retention and abstinence among heroin users.19 This study showed that buprenorphine-containing oral products at medium to high fixed-doses, but not at low, flexible-doses, had comparable efficacy to methadone treatment.

Extended-release naltrexone (Vivitrol®), also a once-monthly injectable, requires detoxification prior to initiation, which is a major barrier to treatment retention. A recently published randomized, comparative effectiveness trial demonstrated that Vivitrol® was comparable to daily Suboxone® in efficacy in abstinence at six months and safety, only after successful induction of both therapies.20 However, investigators noted difficulty in initiating patients on Vivitrol® (72% induction) vs. Suboxone® (92%) (p < 0.0001), and in intent-to-treat analyses, Suboxone® was superior to Vivitrol® in efficacy. Another study with Norwegian participants demonstrated that Vivitrol® was non-inferior to flex-dosed Suboxone®.21

SUBLOCADETM is significantly more expensive at $1,896 per month AWP compared to generic buprenorphine-containing daily dosing products, which is standard of care for MAT.22 Below are the monthly costs based on AWP of other competitor OUD treatments and their formulations. Buprenorphine products indicated for pain management were not included in as competitors (i.e. Belbuca buccal, Buprenex injection, and Butrans transdermal patch).

Table: Comparison of buprenorphine formulations for OUD and other OUD treatment products (adapted)17

BrandDrug Manufacturer

Description Use in OUD Dosing Regimen AWP (1 month)22

Generic (several) Buprenorphine/naloxone sublingual tablet

Induction and maintenance

Same as brand $224

Generic (several) Buprenorphine sublingual tablet Induction and maintenance

Same as brand $255

BunavailBioDelivery Sciences International

Buprenorphine/naloxone buccal film

Induction and maintenance

Daily maintenance treatment

$559

ProbuphineTitan Pharmaceuticals/Braeburn Pharmaceuticals

Buprenorphine subdermal implant

Maintenance after stability on low-to-moderate doses of transmucosal buprenorphine-containing product

Four subdermal implants every 6 months

$915 per month

($5,940 for 6 months)

SuboxoneIndivior, Inc.

Buprenorphine/naloxone sublingual film for sublingual or buccal use

Induction/Maintenance


$587

ZubsolvOrexo US, Inc.

Buprenorphine/naloxone sublingual tablet

Induction/Maintenance


$597

VivitrolAlkermes

Extended-release naltrexone Maintenance after stability on low-to-moderate doses of transmucosal buprenorphine-containing product and detoxification

Monthly injection

$1,571

P&T Considerations

Key questions to consider when evaluating the SUBLOCADETM’s clinical and economic value for potential formulary and reimbursement coverage:

Q1. What is the current formulary status for comparator drugs?23

Comparator drugs are other buprenorphine formulations and extended-release naltrexone. Daily transmucosal buprenorphine-combinations have the most coverage (~50% of HMOs/MCOs) as Tier 2 preferred or Tier 3 non-preferred brands. The current formulary status of SUBLOCADE™ is unknown. Its extended release competitors have significantly less coverage. Probuphine has 16% coverage and is Tier 2 or 3 when on formulary. Vivitrol® has the greatest coverage of non-oral OUD treatments at 38%, of which 7% is covered as a specialty medication.

Bunavail® 51% covered

Zubsolv® 50% covered

Probuphine 16% covered

Vivitrol® 38% covered

Q2. What are the cost implications of adverse events of SUBLOCADETM in comparison to comparator drugs?

The safety profile of SUBLOCADETM is comparable to other systemic buprenorphine formulations, with the exception of rare injection site reactions.10,13

Q3. What are the quality of life measures (QoL) for Opioid Use Disorder?

Rarely is QoL measured in OUD clinical trials.25 The majority of patient-reported outcomes for OUD involve visual analog scales for withdrawal, such as the Opioid Craving VAS (Visual Analog Scale).10 Lack of QoL contrasts the burden on mental and physical health for OUD patients. Societal costs of OUD include unemployment, homelessness, incarceration, and other psychosocial stressors. In the SUBLOCADETM Phase III double-blind study, employment status

was measured as a secondary endpoint.10 More participants on SUBLOCADETM treatment were employed by the end of the study period, with an increase in employment from baseline (300/300 mg +15% and 300/100 mg: +10%) compared to placebo, with a decrease in employment status (-5%). Employment status was an outcome directly associated with patient QoL. MAT adherence is associated with reduced illicit opioid use. One study showed that risk of relapse was 10 times greater among non-adherent patients (Tkacz et al. 2012). Theoretically, medication adherence may be associated with improved psychosocial abilities and QoL.

Q4. What is the relationship between the primary clinical trial outcome and patient quality-of-life (QoL) or the patients’ ability to perform activities of daily living?

The primary clinical trial outcome for OUD studies is percent abstinence of collected from illicit opioid use.10 Abstinence is defined by negative urine drug screening (UDS) results AND self-reports negative for illicit opioid use. Theoretically, abstinence may be associated with improved psychosocial abilities and QoL, as a patients on active treatment in the Phase III double-blind SUBLOCADETM trial showed significantly greater rates of both abstinence and employment compared to placebo.10

Q5. How many patients will clinically qualify for treatment with SUBLOCADETM and what factors should be considered to prioritize access?

SUBLOCADETM is indicated for treatment of moderate to severe opioid use disorder (OUD) in patients who have initiated treatment with a transmucosal buprenorphine containing product.‐ 1 It is an option for the 1.8 million Americans with prescription OUD.4

Moderate to severe OUD: Approximately 9.7% of patients on long-term opioid therapy in their lifetime have moderate OUD and 3.5% have severe opioid use disorder.6 Therefore, approximately 237,600 individuals have moderate to severe OUD in the United States.

Seeking treatment with a Drug Addiction Treatment Act (DATA)-registered healthcare provider and initiated treatment with a transmucosal buprenorphine containing product. In‐ 2012, there were 22,715 DATA-waived physicians, with a capacity to provide 1,093,150 patients with buprenorphine MAT.

Difficulty adhering to daily dosing of MAT or high likelihood of drug diversion. Buprenorphine is within the top four diverted opioid medications.8 One-year adherence to buprenorphine daily therapy was 32% in one study.9 Therefore, an estimated 161,568 patients may be non-adherent on buprenorphine daily therapy.

Q6. What is the impact of SUBLOCADETM on patient healthcare resource utilization?

SUBLOCADETM has a restricted distribution system that requires patients to have frequent contact with healthcare providers, in order to prevent diversion. Compared to daily buprenorphine-containing products, SUBLOCADETM is a monthly injection and requires medical

administration by a DATA-waived provider, incurring excess costs. Patients also must be stabilized on transmucosal buprenorphine-containing products for at least seven days, which requires frequent follow-up with designated providers. A comparator monthly injection for OUD, Vivitrol®, requires similar administration and induction costs. The buprenorphine implant, Probuphine, also prevents diversion and is administered every six months.

SUBLOCADETM as a once monthly injection may increase adherence and decrease diversion of buprenorphine. Given the current opioid epidemic, these benefits may lower the estimated $78.5 billion burden of OUD from a societal perspective.24 As of 2013, $28.9 billion was attributed to substance abuse treatment costs for OUD. Investment in extended-release OUD treatments may increase treatment costs while improving OUD control for the potentially 161,568 Americans who are non-adherent to buprenorphine daily therapy.9

References1. SUBLOCADETM [package insert]. Indivior PLC; November 2017.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Fifth Edition.; 2013. https://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596. Accessed February 13, 2018.

3. Centers for Disease Control and Prevention. Prescribing data. Drug overdose. https://www.cdc.gov/drugoverdose/data/prescribing.html. Published August 31, 2017. Accessed February 14, 2018.

4. Substance Abuse and Mental Health Services Administration. Reports and detailed tables from the 2016 National Survey on Drug Use and Health (NSDUH). Substance Abuse and Mental Health Services Administration; 2017. https://www.samhsa.gov/samhsa-data-outcomes-quality/major-data-collections/reports-detailed-tables-2016-NSDUH. Accessed February 14, 2018.

5. CDC. Drug Overdose Death Data. CDC Injury Center. https://www.cdc.gov/drugoverdose/data/statedeaths.html. Published January 5, 2018. Accessed January 28, 2018.

6. Boscarino JA, Hoffman SN, Han JJ. Opioid-use disorder among patients on long-term opioid therapy: impact of final DSM-5 diagnostic criteria on prevalence and correlates. Subst Abuse Rehabil. 2015;6:83-91. doi:10.2147/SAR.S85667

7. Jones CM, Campopiano M, Baldwin G, McCance-Katz E. National and state treatment need and capacity for opioid agonist medication-assisted treatment. Am J Public Health. 2015;105(8):e55-e63. doi:10.2105/AJPH.2015.302664

8. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. Factors contributing to the rise of buprenorphine misuse: 2008-2013. Drug Alcohol Depend. 2014;142:98-104. doi:10.1016/j.drugalcdep.2014.06.005

9. Tkacz J, Volpicelli J, Un H, Ruetsch C. Relationship between buprenorphine adherence and health service utilization and costs among opioid dependent patients. J Subst Abuse Treat. 2014;46(4):456-462. doi:10.1016/j.jsat.2013.10.014

10. Treatment seeking participants with opioid use disorders assessing tolerability of depot injections of buprenorphine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02357901. Published July 31, 2017. Accessed January 29, 2018.

11. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. J Addict Med. 2015;9(5):358-367. doi:10.1097/ADM.0000000000000166

12. Nasser AF, Greenwald MK, Vince B, et al. Sustained-release buprenorphine (RBP-6000) blocks the effects of opioid challenge with hydromorphone in subjects with opioid use disorder. J Clin Psychopharmacol. 2016;36(1):18-26. doi:10.1097/JCP.0000000000000434

13. Safety and tolerability study of depot buprenorphine in treatment seeking subjects with opioid use disorder. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02510014. Published July 31, 2017. Accessed February 8, 2018.

14. Melville N. Second injectable buprenorphine product shows promise. Medscape. http://www.medscape.com/viewarticle/890463. Published December 21, 2017. Accessed February 16, 2018.

15. Management of opioid dependence-resource #340106. January 2018.

16. Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326. doi:10.1097/ADM.0000000000000045

17. Smith L, Mosley J, Johnson J, Nasri M. Probuphine (buprenorphine) subdermal implants for the treatment of opioid-dependent patients. Pharm Ther. 2017;42(8):505-508.

18. Nasser AF, Heidbreder C, Gomeni R, Fudala PJ, Zheng B, Greenwald MK. A population pharmacokinetic and pharmacodynamic modelling approach to support the clinical development of RBP-6000, a new, subcutaneously injectable, long-acting, sustained-release formulation of buprenorphine, for the treatment of opioid dependence. Clin Pharmacokinet. 2014;53(9):813-824. doi:10.1007/s40262-014-0155-0

19. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014;(2):CD002207. doi:10.1002/14651858.CD002207.pub4

20. Lee JD, Nunes EV, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet Lond Engl. 2018;391(10118):309-318. doi:10.1016/S0140-6736(17)32812-X

21. Tanum L, Solli KK, Latif Z-H, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74(12):1197-1205. doi:10.1001/jamapsychiatry.2017.3206

22. RED BOOK Online®. MICROMEDEX®.

23. DRG Fingertip Formulary. Formulary Lookup. https://lookup.decisionresourcesgroup.com/#. Accessed June 5, 2017.

24. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care. 2016;54(10):901-906. doi:10.1097/MLR.0000000000000625

25. Bray JW, Aden B, Eggman AA, et al. Quality of life as an outcome of opioid use disorder treatment: A systematic review. J Subst Abuse Treat. 2017;76:88-93. doi:10.1016/j.jsat.2017.01.019

Contributing Authors

Michelle Vu (PharmD/MPH Candidate), Mercer UniversityIan Dilley (PharmD Candidate), Purdue University

Contributing Reviewer

Elizabeth Sampsel (PharmD, MBA, BCPS), Dymaxium Inc.

Acknowledgements

Evidex Software: evidence based data, analytics, and insights for healthcare decision makers.

DRG Fingertip Formulary: gold standard formulary data and interactive tools.

® FORMULARYDECISIONS.COM, DYMAXIUM and are registered trademarks of Dymaxium Inc. Used under license. All other brand or SUBLOCADE names are trademarks or registered marks of their respective owners.Copyright © 2017 Dymaxium Inc., All rights reserved.

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