Clinical UM Guideline

 

Subject: Implantable and Extended-Release Buprenorphine-Containing Products
Guideline #: CG-DRUG-89 Publish Date:    06/22/2018
Status: New Last Review Date:    03/22/2018

Description

This document addresses the use of implantable and extended-release products containing buprenorphine, including Probuphine® and Sublocade, both of which are used to treat opioid dependence and substance abuse disorder.

Probuphine, the first buprenorphine implant, is intended for maintenance treatment of opioid use disorder in individuals who have achieved and sustained prolonged clinical stability on low-to-moderate doses of buprenorphine.

Sublocade, also known as buprenorphine extended‐release or buprenorphine XR, is an extended-release injectable form of buprenorphine.

Clinical Indications

I.  Buprenorphine implant (Probuphine)

Medically Necessary:

Initial treatment with buprenorphine implant is considered medically necessary when ALL of the following criteria have been met:

  1. The individual has been diagnosed with opioid dependence (opioid use disorder); and
  2. The individual has been treated with a stable transmucosal buprenorphine dose (of 8 mg per day or less of a sublingual tablet or its transmucosal buprenorphine product equivalent) for 3 months or longer without any need for supplemental dosing or adjustments; and
  3. The individual is currently on a maintenance dose** of 8 mg per day or less of a sublingual tablet or its transmucosal buprenorphine product equivalent to achieve sustained prolonged clinical stability on transmucosal buprenorphine; and
  4. Probuphine is used as part of a comprehensive substance use disorder treatment program to include counseling and psychosocial support.

*Initial treatment with buprenorphine implant consists of one 6-month period, involving subdermal placement of the implants in the inner side of the upper arm on one side of the body. Implants must be removed at the end of the sixth month following insertion. If indicated, a second set of implants may be placed in the contralateral arm.  The second set of implants should be removed at the end of the second 6-month treatment period.

**The FDA indications specify that maintenance dose should not be tapered to a lower dose for the sole purpose of transitioning to buprenorphine implant.

Not Medically Necessary:

Treatment with buprenorphine implant is considered not medically necessary for all other indications, including but not limited to:

  1. When the medically necessary criteria above have not been met.
  2. For new entrants to treatment.
  3. For individuals who have not achieved and sustained prolonged clinical stability while being maintained on 8 mg per day or less of a sublingual tablet or its transmucosal buprenorphine product equivalent.
  4. For individuals not enrolled in a comprehensive substance use disorder treatment program.

Treatment for longer than 12 months with buprenorphine implant is considered not medically necessary under all circumstances†.

†Individuals can be transitioned back to transmucosal buprenorphine-containing medications for continued treatment after 12 months as needed.

Retreatment with buprenorphine implant after a prior 12-month treatment period is considered not medically necessary under all circumstances.

II.  Extended‐release buprenorphine (Sublocade)

Medically Necessary:

Extended-release injectable buprenorphine is considered medically necessary when all of the following criteria have been met:

  1. The individual has been diagnosed with moderate to severe opioid dependence (opioid use disorder); and
  2. The individual has initiated treatment with buprenorphine (8-24 mg per day) by sublingual tablet or its transmucosal equivalent, followed by dose adjustment for a minimum of 7 days to clinically optimize symptoms of cravings and withdrawal; and
  3. The individual is clinically stable on buprenorphine by sublingual tablet or its transmucosal equivalent prior to initiation of injectable buprenorphine therapy; and
  4. The individual is not concurrently receiving other maintenance or supplemental dosing with buprenorphine products; and
  5. Injectable buprenorphine is being used as part of a comprehensive substance use disorder treatment program to include counseling and psychosocial support.

Not Medically Necessary:

Extended-release injectable buprenorphine is considered not medically necessary for all other indications, including but not limited to:

  1. When the medically necessary criteria above have not been met; or
  2. For individuals with contraindications to injectable buprenorphine, such as a pre-existing severe or moderate hepatic impairment or history of hypersensitivity to buprenorphine; or
  3. For individuals not enrolled in a comprehensive substance use disorder treatment program.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CPT

 

 

11981

Insertion, non-biodegradable drug delivery implant [when specified as insertion of Probuphine implant]

 

11983

Removal with reinsertion, non-biodegradable drug delivery implant [when specified as insertion of Probuphine implant]

 

 

 

 

HCPCS

 

 

G0516

Insertion of non-biodegradable drug delivery implants, 4 or more (services for subdermal rod implant)

 

G0517

Removal of non-biodegradable drug delivery implants, 4 or more (services for subdermal implants)

 

G0518

Removal with reinsertion, non-biodegradable drug delivery implants, 4 or more (services for subdermal implants)

 

J0570

Buprenorphine implant, 74.2 mg [Probuphine]

 

J3490

Unclassified drugs [when specified as extended-release injectable buprenorphine (Sublocade)]

 

Q9991

Injection, buprenorphine extended-release (Sublocade), less than or equal to 100 mg [Note: code effective 07/01/2018]

 

Q9992

Injection, buprenorphine extended-release (Sublocade), greater than 100 mg [Note: code effective 07/01/2018]

 

 

 

 

ICD-10 Diagnosis

 

F11.10-F11.99

Opioid related disorders

Discussion/General Information

Opioid use disorder is a chronic relapsing illness associated with significant morbidity and mortality.  In 2014, 21.5 million Americans 12 years and older were diagnosed with opioid use disorder and 1.9 million of them are users of prescription pain drugs.  Drug overdose is the leading cause of accidental death in the United States and opioid addiction is the driving force behind this trend.  Individuals with opioid use disorder who achieve abstinence often require long-term maintenance therapy to prevent relapses.  Current therapies for the maintenance of opioid withdrawal, frequently with substitution drugs such as methadone and buprenorphine, have issues with non-adherence, and abuse and diversion potentials.  Furthermore, there are complications related to such maintenance therapy, such as risk of lethal overdose.

Buprenorphine is a partial opioid agonist with lower abuse potential than methadone.  It is available for maintenance treatment of opioid use disorder as a single agent for induction or in combination with naloxone for maintenance.  The advantages of administering buprenorphine via implant may include reducing abuse and diversion potential and improving adherence.

Buprenorphine Implant (Probuphine)

The U.S. Food and Drug Administration (FDA) approved Probuphine on May 26, 2016, as the first buprenorphine implant for the maintenance treatment of opioid use disorder in individuals who have achieved and sustained prolonged clinical stability on low-to-moderate doses of buprenorphine (for example, doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).  Probuphine is designed to be implanted subcutaneously into the inside of the upper arm and is formulated to provide 6 months of consistent low-dose buprenorphine therapy without the need for daily oral administration, which is intended to eliminate adherence issues. 

The FDA-approved package insert (PI) for Probuphine provides guidance regarding selection criteria for individuals who may be considered candidates for Probuphine treatment.  The approved indications specify that the individual have “achieved and sustained prolonged clinical stability on transmucosal buprenorphine.”  The following are provided in the PI as examples of acceptable doses of transmucosal buprenorphine demonstrating sable maintenance doing:

Additionally, the PI includes the following factors in determining clinical stability and suitability for Probuphine treatment:

All healthcare providers prescribing or inserting Probuphine must enroll and successfully complete a live training program and meet the requirements set forth in the PI. 

Other requirements and cautions in the PI include:

Approval of Probuphine was based on the results of a randomized, double-blind, active-control study in 173 adult subjects with an opioid use disorder diagnosis who were clinically stable on sublingual buprenorphine 8 mg or less for at least 6 months (Rosenthal, 2016).  The primary efficacy endpoint evaluated response rate to therapy.  A positive response was defined as no evidence of opioid use during the 6 month period.  Subjects were randomized in a 1:1 fashion to receive either Probuphine plus oral placebo (n=84) or treatment as usual with their pre-randomization dose of sublingual buprenorphine and placebo implant (controls, n=89).  Subjects were seen monthly for 6 months and were also required to provide four randomly scheduled urine samples for toxicology.  Efficacy was evaluated through urine toxicology screening and subject self-report to detect opioid use over the 6-month treatment period.  Supplemental dosing with open-label sublingual buprenorphine/naloxone tablets was permitted as clinically indicated.  Missing samples were considered to be evidence of opioid use, and only subjects with no evidence of opioid use were adjudicated as maintaining stability.  The use of supplemental buprenorphine in subjects on Probuphine, which cannot be titrated, may be interpreted to indicate that the dose of buprenorphine provided by Probuphine was inadequate for that subject to maintain stability.  Subjects who required supplemental dosing were not included in the data as successfully maintained, even if they did not have evidence of opioid use.  At the end of the study, 84 (94.4%) controls and 81 (96.4%) Probuphine subjects had completed the trial.  Of the subjects receiving Probuphine, 81 (96.4%) were responders vs. 78 (87.6%) of control subjects, for an 8.8% difference (p<0.001 for noninferiority).  Over 6 months, 72 (85.7%) of the Probuphine subjects and 64 (71.9%) of the controls maintained opioid abstinence (hazard ratio [HR], 13.8; p=0.03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of Probuphine subjects and in 52.8% and 13.5% of control subjects, respectively. The final data indicated no significant difference between groups with regard to the primary endpoint.  The authors noted that the control group had an exceptionally high response rate, and further studies are needed in broader populations to assess the efficacy in other settings.

The results from additional randomized double-blind, placebo-controlled trials have also been published.  The first, by Ling (2010), involved 163 subjects assigned in a 2:1 fashion to receive buprenorphine implants (n=108) or placebo implants (n=55).  Subjects were placed on a fixed dose of 12 to 16 mg/day of sublingual buprenorphine-naloxone tablets for 3 days prior to Probuphine implantation.  Supplemental buprenorphine-naloxone tablet use was allowed if significant withdrawal symptoms were encountered.  An additional implant was provided for subjects if they required supplemental medications for 3 or more consecutive days in 2 consecutive weeks.  Urine samples were collected 3 times a week for the full 6 months of the study for each subject.  Implants were removed at a mean of 24 weeks for the Probuphine group and 16.6 weeks in the control group.  Additional implants were received in 20.3% of Probuphine subjects and 58.2% of controls.  During weeks 1-16, 59% of Probuphine subjects and 91% of controls required supplemental medications.  During weeks 17-24, these numbers changed to 12% and 20%, respectively.  The primary outcome, percentage of negative urine samples out of the total collected between 1 and 16 weeks, was reported to be 40.4% in the Probuphine group and 28.3% in the control group (p=0.04).  For the secondary outcome, the same outcome for the period between 17 and 24 weeks, no specific data were provided other than that the difference remained significant (p<0.001).  For the overall study period, the percentage of subjects with negative urine samples was 36.6% and 22.4%, respectively.  The overall loss to follow-up was not provided, but for weeks 1-16, 18.5% of the Probuphine subjects and 49.1% of the controls were lost.  Significant differences were noted between groups with regard to results on the Clinical Opiate Withdrawal Scale (p<0.0001), Clinical Global Impressions (CGI) tool severity measure (p<0.001), and the CGI improvement scale (p<0.001).  The authors concluded that among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples.

Another randomized double-blind, placebo-controlled trial involved 287 subjects with opioid dependence who were assigned to receive one set of four buprenorphine implants (80 mg/implant) (n=114), a set of four placebo implants (n=54), or open-label buprenorphine-naloxone tablets (12-16 mg/day) (n=119) (Rosenthal, 2013).  Eligible subjects were entered into an open-label trial with Probuphine.  Those that achieved target doses of 12-16 mg/day without significant withdrawal symptoms or cravings were enrolled in the trial.  Supplemental buprenorphine-naloxone tablets were allowed.  The authors reported that the Probuphine cumulative distribution function was significantly different from that of the placebo group (p<0.0001).  Mean proportions of urine samples that were negative for opioids were 31.2% for the Probuphine group and 13.4% for the placebo group.  Probuphine subjects had a higher study completion rate relative to placebo subjects (64% versus 26%, p<0.0001), lower clinician-rated withdrawal symptoms (p<0.0001) and subject-rated withdrawal symptoms (p<0.0001), lower subject-ratings of craving (p<0.0001) and better subjects' global ratings of improvement (p=0.031) and clinicians' global ratings of improvement (p=0.022).  They concluded that Probuphine was non-inferior to treatment with buprenorphine-naloxone based on percentage of urine samples negative for opioids [mean (95% confidence interval [CI])=33.5 (27.3, 39.6); 95% CI for the difference of proportions equals (-10.7, 6.2)].

The package insert (PI) mentions two additional studies involving subjects who were new entrants to buprenorphine treatment.  While the details of these studies are not provided, the results are discussed, and suggested that Probuphine should not be used for individuals who are new entrants to buprenorphine treatment or who have not achieved and sustained prolonged clinical stability on low to moderate doses of a transmucosal buprenorphine-containing product, i.e., doses of no more than 8 mg per day of a Subutex or Suboxone sublingual tablet or generic equivalent, because the dose appears to be too low to be effective in these populations.

Extended-Release Buprenorphine (Sublocade)

On November 30, 2017 the FDA approved the first monthly injection of extended-release buprenorphine, Sublocade, “for the treatment of moderate to severe opioid use disorder in individuals who have initiated treatment with a transmucosal buprenorphine‐containing product, followed by dose adjustment for a minimum of 7 days.”  The FDA label additionally specifies that Sublocade should only be used as part of a complete treatment program that includes counseling and psychosocial support (Sublocade label, 2017).

The label for Sublocade details a Phase III, 24‐week, multicenter, randomized, double‐blind, placebo‐controlled, trial evaluating the safety and efficacy of extended-release buprenorphine in individuals who met the DSM‐5 criteria for moderate or severe opioid use disorder and were seeking treatment for it.  Study participants were randomized to one of following three dosing regimens: (1) six once‐monthly 300 mg doses of Sublocade, (2) two once‐monthly 300 mg doses of Sublocade followed by four once‐monthly 100 mg doses, or (3) six once‐monthly subcutaneous (SQ) injections of placebo.  Participants in all three study arms additionally received psychosocial support at least once a week.  Treatment with buprenorphine was initiated through a sublingual induction dose and were adjusted from 8 mg to 24 mg per day over a period of 7‐14 days; and randomization to one of the three study arms took place after cravings and withdrawal symptoms were clinically controlled by this titration.  Following randomization, supplemental dosing with Suboxone was not permitted during the study.  The study’s primary outcome was evaluation from week 5 through week 24 of illicit opioid use based on weekly urine drug screens combined with self‐reported use.  A total of 504 participants were randomized in a 4:4:1:1 fashion (203 in the first group, 201 in the second group, and 100 in the placebo group [2 groups of placebo volume‐matched to the first or second group, respectively]).  Based on the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self‐reports negative for illicit opioid use, Sublocade was statistically superior to placebo irrespective of dose.  Similarly, the proportion of participants who achieved a ‘treatment success’ (≥ 80% opioid‐free weeks) was statistically significantly higher in both groups receiving Sublocade compared to the placebo group (28.4% [300 mg/100 mg], 29.1% [300 mg/300 mg], 2% [placebo].

A study by Nasser and colleagues (2016) involved 38 subjects with moderate to severe opioid use disorder.  Subjects began the study by participating in a “baseline” phase that consisted of intramuscular (IM) injections of placebo or 6 or 18 mg of hydromorphone in one of six randomized sequences.  Subjects were assessed with a ‘Drug liking” visual analog scale (VAS) and a drug vs. money choice task.  Following the baseline period, subjects were moved into the “induction/stabilization” phase, during which they received 8 to 24 mg of Suboxone until a stable dose was established.  Once stabilization had been reached, subjects received hydromorphone challenges involving the administration of placebo, 6 mg or 18 mg of hydromorphone.  Subjects also underwent VAS assessments and drug vs. money choice tasks.  The final ‘treatment” phase of the study involved all subjects from the first two phases who continued to meet inclusion and dosing criteria.  Suboxone therapy was ceased in this phase and subjects were treated with a single 300 mg SQ injection of Sublocade at day 1 and again on day 29. Hydromorphone challenges, VAS assessments, and drug vs. money choice tasks were administered in weekly 3-day trial periods for a total of 12 weeks.  These assessments occurred in a residential setting and clinicians and subjects were blinded to the hydromorphone challenge group.  A total of 30 (78.9%) subjects completed the study.  The authors reported that at baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg vs. placebo were 61 mm (95% [CI], 52.3-68.9) and 45 mm (95% CI, 37.2-53.6), respectively. After 300 mg of Sublocade was administered, mean VAS score differences from placebo were less than 10 mm through week 12.  The reinforcing efficacy of hydromorphone decreased in a parallel manner.  No data were presented related to the drug vs. money choice tasks, and no p-values were provided for any statistical comparisons.  At least one “treatment-emergent adverse event” (TEAE) was reported by all subjects, including injection site reactions (79.5%), constipation (30.8%), nausea (12.8%), and sedation (10.3%).  Most injection site reactions were judged to be minor. 

References

Peer Reviewed Publications:

  1. Ling W, Casadonte P, Bigelow G, et al. Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial. JAMA. 2010; 304(14):1576-1583. 
  2. 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.
  3. Rosenthal RN, Ling W, Casadonte P, et al. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction. 2013; 108(12):2141-2149.
  4. Rosenthal RN, Lofwall MR, Kim S, et al.; PRO-814 Study Group. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: a randomized clinical trial. JAMA. 2016; 316(3):282-290.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Buprenorphine. In: DrugPoints® Evaluations (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 5, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.
  2. Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid withdrawal. Cochrane Database Syst Rev. 2017;(2):CD002025.
  3. 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. 2015. Available at: http://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf?sfvrsn=24#search="naltrexone". Accessed on March 22, 2018.
  4. Sublocade [Product Information Label], Indivior Inc, North Chesterfield, VA. Updated November 30, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209819s000lbl.pdf. Accessed on March 22, 2018.
  5. Substance Abuse and Mental Health Services Administration (SAMHSA) Buprenorphine Waiver Management. Available at: http://www.samhsa.gov/medication-assisted-treatment/buprenorphine-waiver-management. Accessed on March 22, 2018.
  6. United States Food and Drug Administration. Prescribing information for Probuphine (buprenorphine) implant. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204442Orig1s000lbl.pdf. Accessed on March 22, 2018.
Websites for Additional Information
  1. Injury Prevention and Control: Opioid Overdose. Centers for Disease Control and Prevention website. Available at http://www.cdc.gov/drugoverdose/index.html. Accessed March 22, 2018.
  2. Opioid addiction: 2016 facts and figures. American Society of Addiction Medicine website. Available at http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf. Accessed March 22, 2018.
Index

Buprenorphine Implant
Probuphine
Sublocade

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

03/22/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

02/23/2018

Behavioral Health Subcommittee review. Initial document development. Moved content of DRUG.00092 Buprenorphine Implant (Probuphine®) to new clinical utilization management guideline document. Revised title and scope to include extended-release buprenorphine-containing products.  Updated Coding section to include 07/01/2018 HCPCS changes, added Q9991, Q9992.