Medical Policy

 

Subject: Buprenorphine Implant (Probuphine®)
Document #: DRUG.00092 Publish Date:    12/27/2017
Status: Revised Last Review Date:    02/02/2017

Description/Scope

This document addresses the use of Probuphine, the first buprenorphine implant 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.

Note: This document only addresses the use of the implantable form of buprenorphine.  Other forms of buprenorphine (e.g., tablets) are not addressed in this document.

Position Statement

Medically Necessary:

Initial treatment with Probuphine* (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 Subutex or Suboxone 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 Subutex or Suboxone 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 Probuphine 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 Probuphine.

Investigational and Not Medically Necessary:

Treatment with Probuphine is considered investigational and 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 buprenorphine 8 mg per day or less of a Subutex or Suboxone sublingual tablet or generic equivalent.
  4. For individuals not enrolled in a comprehensive substance use disorder treatment program.

Treatment for longer than 12 months with Probuphine is considered investigational and 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 Probuphine after a prior 12-month treatment period is considered investigational and not medically necessary under all circumstances.

Rationale

The Probuphine buprenorphine implant received approval from the U.S. Food and Drug Administration (FDA) on May 26, 2016 for maintenance treatment of opioid dependence in individuals who have achieved and sustained prolonged clinical stability on low to moderate doses of a transmucosal buprenorphine-containing product (for example, doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).

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.

Background/Overview

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.

The FDA approved Probuphine, 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.  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:

Coding

The following codes for treatments and procedures applicable to this document 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.

When services may be Medically Necessary when criteria are met:

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]

 

 

 

 

ICD-10 Diagnosis

 

F11.10-F11.99

Opioid related disorders

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

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. 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.
  3. 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. 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 December 7, 2016.
  2. 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 December 7, 2016.
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  December 7, 2016.
  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 December 7, 2016.
Document History
Status Date Action
  12/27/2017 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes; added G0516, G0517, and G0518.
Revised 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 01/20/2017 Behavioral Health Subcommittee review. Revised title. Made minor typographical changes in the Position Statement. Updated Description and References sections.
  01/01/2017 Updated Coding section with 01/01/2017 HCPCS changes.
New 08/04/2016 MPTAC review.
New 07/29/2016 Behavioral Health Subcommittee review. Initial document development.