Description
Opioid use disorder (OUD) is the diagnostic term used for a chronic neurobiological disease characterized by a problematic pattern of opioid use leading to significant impairment or distress and includes signs and symptoms that reflect compulsive, prolonged self-administration of  opioid substances for no legitimate medical purpose or, if another medical condition is present that requires opioid treatment, the opioid is used in doses  greater than the amount needed for treatment of that medical condition. OUD is a chronic relapsing illness associated with significant morbidity and mortality.

Sublocade™, also know as buprenorphine extended-release, is a drug-device combination product that utilizes buprenorphine and the Atrigel Delivery System in a pre-filled syringe. It is injected subcutaneously as a solution by a health care professional and the delivery system forms a solid deposit, or depot, containing buprenorphine. After initial formation of the depot, buprenorphine is released by the biodegradation of the depot. Sublocade provides sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Sublocade should be used as part of a complete treatment program that includes counseling and psychosocial support.

Policy
Sublocade (buprenorphine extended-release) injection, for subcutaneous use may be considered MEDICALLY NECESSARY when all the following criteria have been met:

• The patient must be 18 years of age or older.
• The patient has been diagnosed with moderate to severe opioid use disorder; AND
• The patient is part of a complete treatment program that includes counseling and psychosocial support; AND 
• The patient will not be concomitantly receiving opioid medications or Soma (Carisoprodol) while on treatment with Sublocade per the Sublocade Pharmacy Restriction Policy; AND 
  • To receive therapy with opioid medications or Soma (carisoprodol) will require attestation of sublocade discontinuation and clinical appropriateness per the Sublocade Pharmacy Restriction Policy; AND
• The patient has initiated therapy with transmucosal buprenorphine-containing product (delivering the equivalent of 8-24mg of buprenorphine daily) over a minimum 7-day period and is stable with clinically controlled cravings and withdrawal symptoms; AND 
• The patient will receive monthly treatment with Sublocade with injections no less than 26 days apart.

Sublocade is considered NOT MEDICALLY NECESSARY when the above criteria are not met.  

Policy Guidelines
Sublocade has a boxed warning that provides important safety information, including the risks of intravenous self-administration. If the product were to be administered intravenously rather than subcutaneously, the solid mass could cause occlusion, tissue damage and thrombo-embolic events, including life threatening pulmonary emboli.

Sublocade must be prescribed and dispensed as part of a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the product is not distributed directly to patients. Sublocade will be provided to health care providers through a restricted program, administered only by health care providers in a health care setting, and will require health care settings and pharmacies that dispense Sublocade to complete an enrollment form attesting that they have procedures in place to ensure that Sublocade is dispensed only to health care providers and not directly to patients.

In the event the depot must be removed, it can be surgically excised under local anesthesia within 14 days of injection. Only the most recently-injected deport can be removed. Patients who elect to discontinue treatment with Sublocade should be monitored for withdrawal signs and symptoms. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing Sublocade.

Rationale
Extended-Release Buprenorphine (Sublocade)
On Nov. 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  

1. U.S. Food and Drug Administration. Sublocade (buprenorphine extended-release) injection prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209819s000lbl.pdf
2. Indivior, Sublocade Fact Sheet. Available at: http://indivior.com/wpcontent/uploads/2017/11/SUBLOCADE-Fact-Sheet.pdf  

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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