Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Drugs Used for the Maintenance Treatment of Opioid or Alcohol Use Disorder (e.g., Naltrexone Implants, Probuphine Implant, Sublocade Injection, Vivitrol Injection)

Policy #:08.01.37a

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

METHADONE
Methadone maintenance therapy for the treatment of opioid addiction may be available under the member's applicable Behavioral Health Benefit. Individual benefits must be verified.

BUPRENORPHINE (PROBUPHINE®) IMPLANTS
Buprenorphine (Probuphine®) implants administered subdermally into the inner side of the upper arm as four implants for a period of six months are considered medically necessary and, therefore, covered for the maintenance treatment of opioid dependence when all of the following criteria are met:
  • Individual has a documented diagnosis of opioid use disorder, as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
  • Individual has 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 Subutex or Suboxone sublingual tablet or generic equivalent) for three months or longer without any need for supplemental dosing or adjustments
  • Individual participates in a comprehensive treatment program, which includes counseling and psychosocial support
  • Individual has not had a positive urine drug screening for illicit opioids within 90 days prior to administration of implants
  • Individual has shown compliance with scheduled and random urine drug screening

Continuation of Therapy with Buprenorphine (Probuphine®) Implants

If continued therapy is required, another set of implants are considered medically necessary and, therefore, covered when the above criteria have been met and when the implants will be administered in the opposite arm, for a maximum of 2 sets of implants per lifetime (i.e., one set of implants per arm).

Provider Requirements

Providers must be in compliance with all of the criteria outlined in the REMS program, including the completion of the required live training.

Prescribers must obtain a waiver as per the requirements in the Drug Addiction Treatment Act (DATA) of 2000. Under this Act, prescribers must have the following qualifications:
  • current, valid state medical license
  • unique drug enforcement agency (DEA) registration number with "X" waiver
  • specific credentials/training in the treatment of addiction, outlined by the US Department of Health and Human Services, Substance Abuse, and Mental Health Services Administration

BUPRENORPHINE (SUBLOCADETM) INJECTION
Buprenorphine (SublocadeTM) extended-release subcutaneous injection administered monthly (
with a minimum of 26 days between doses) is considered medically necessary and, therefore, covered for the treatment of moderate to severe opioid use disorder when all of the following criteria are met:
  • Individual has a documented diagnosis of opioid use disorder, as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
  • Individual has initiated treatment with a transmucosal buprenorphine-containing product delivering the equivalent of 8 to 24 mg of buprenorphine daily, followed by dose adjustment for a minimum of 7 days. Individual is clinically stable on this dose
  • Individual is not concurrently receiving supplemental dosing with buprenorphine products
  • Individual participates in a comprehensive treatment program, which includes counseling and psychosocial support
  • Individual has shown compliance with scheduled and random urine drug screening

Continuation of Therapy with Buprenorphine (SublocadeTM) Injection

If continued therapy is required, buprenorphine (SublocadeTM) Injection is considered medically necessary and, therefore, covered when the above criteria have been met.

Provider Requirements

Providers must be in compliance with all of the criteria outlined in the REMS program.

Prescribers must obtain a waiver as per the requirements in the Drug Addiction Treatment Act (DATA) of 2000. Under this Act, prescribers must have the following qualifications:
  • current, valid state medical license
  • unique drug enforcement agency (DEA) registration number with "X" waiver
  • specific credentials/training in the treatment of addiction, outlined by the US Department of Health and Human Services, Substance Abuse, and Mental Health Services Administration

NALTREXONE (VIVITROL®) INJECTION
Alcohol Use Disorder

Naltrexone (Vivitrol®) intramuscular (I.M.) injection administered every 4 weeks (or monthly) is considered medically necessary and, therefore, covered for the treatment of alcohol dependence in individuals able to abstain from alcohol when all of the following criteria are met:
  • Individual has a documented diagnosis of alcohol use disorder, as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
  • Individual is participating in a comprehensive treatment program which includes psychosocial support
  • Individual has abstained from alcohol prior to naltrexone (Vivitrol®) administration
  • Individual has shown compliance with scheduled and random urine drug screening

Continuation of Therapy with Naltrexone (Vivitrol®)
If continued therapy is required, naltrexone (Vivitrol®) is considered medically necessary and, therefore, covered when the above criteria have been met.

Opioid Use Disorder

Naltrexone (Vivitrol®) intramuscular (I.M.) injection administered every 4 weeks (or monthly) is considered medically necessary and, therefore, covered for the prevention of relapse to opioid dependence (following opioid detoxification) when all of the following criteria are met:
  • Individual has a documented diagnosis of opioid use disorder, as per Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
  • Individual is participating in a comprehensive treatment program which includes psychosocial support
  • Individual has abstained from alcohol prior to naltrexone (Vivitrol®) administration
  • Individual has abstained from opioids at least 7-10 days prior to and on the day of naltrexone (Vivitrol®) administration
  • Individual has shown compliance with scheduled and random urine drug screening

Continuation of Therapy with Naltrexone (Vivitrol®)
If continued therapy is required, naltrexone (Vivitrol®) is considered medically necessary and, therefore, covered when the above criteria have been met.

EXPERIMENTAL/INVESTIGATIONAL

All other uses than those described above for buprenorphine (Probuphine®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics. Examples of uses considered experimental/investigational include, but are not limited to the following:
  • Individual is a new entrant to buprenorphine treatment
  • Individual has already had one set of implants administered into each arm
  • Individual has not achieved and sustained prolonged clinical stability while being maintained on buprenorphine 8 mg per day or less of a buprenorphine (Subutex) or buprenorphine and naloxone (Suboxone®) sublingual tablet or generic equivalent
  • Individual has been tapered to a lower dose of buprenorphine for the sole purpose of transitioning to buprenorphine (Probuphine®)
  • Individual is currently receiving other opioids

All other uses than those described above for buprenorphine (SublocadeTM) injection are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

All other uses than those described above for naltrexone (Vivitrol®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics. Examples of uses considered experimental/investigational include, but are not limited to the following:
  • Individual is receiving opioid analgesics
  • Individual currently has physiologic opioid or alcohol dependence, including the use of partial agonists
  • Individual is in acute opioid or alcohol withdrawal
  • Individual has failed the naloxone challenge or has a positive urine screen for opioids

Naltrexone Implants are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

DRUG ADMINISTRATION

The following information was derived from the United States Food and Drug Administration (FDA)--approved prescribing information:

BUPRENORPHINE (PROBUPHINE®) IMPLANTS
Buprenorphine (Probuphine®) -- New implants may be inserted subdermally in an area of the inner side of either upper arm that has not been previously used at the time of removal, if continued treatment is desired. If new implants are not inserted on the same day as the removal of implants, maintain patients on their previous dosage of transmucosal buprenorphine (i.e., the dose from which they were transferred to buprenorphine [Probuphine®] treatment) prior to additional buprenorphine (Probuphine®) treatment.

After one insertion in each arm, most patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment. There is no experience with inserting additional implants into other sites in the arm to recommend an approach to a second insertion into a previously-used arm. Neither re-insertion into previously-used administration sites, nor into sites other than the upper arm, has been studied. It is important to avoid previously-implanted sites because the effect of scarring and fibrosis in previously-used insertion sites on either the effectiveness of buprenorphine (Probuphine®) or the safety of insertion have not been evaluated. After one insertion in each arm, additional cycles of treatment should only be considered if the potential benefits of continuing buprenorphine (Probuphine®) outweigh the potential risks of additional insertion and removal procedures, taking into account the experience of the healthcare provider with buprenorphine (Probuphine®) procedures and related procedures, and the clinical need of the patient for ongoing treatment with subdermal medication. In most cases, patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment.

Patients should not be tapered to a lower dose for the sole purpose of transitioning to buprenorphine (Probuphine®).

Examples of acceptable doses of transmucosal buprenorphine include:
  • Subutex (buprenorphine) sublingual tablet (generic equivalent) 8 mg or less
  • Suboxone® (buprenorphine and naloxone) sublingual tablet (generic equivalent) 8 mg/2 mg or
  • less
  • Bunavail (buprenorphine and naloxone) buccal film 4.2 mg/0.7 mg or less
  • Zubsolv® (buprenorphine and naloxone) sublingual tablets 5.7 mg/1.4 mg or less

Consider the following factors in determining clinical stability and suitability for buprenorphine (Probuphine®) treatment:
  • period free from illicit opioid drug use
  • stability of living environment
  • participation in a structured activity/job
  • consistency in participation in recommended behavioral therapy/peer support program
  • consistency in compliance with clinic visit requirements
  • minimal to no desire or need to use illicit opioids
  • period without episodes of hospitalizations (addiction or mental health issues), emergency room visits, or crisis interventions
  • social support system

BUPRENORPHINE (SUBLOCADETM) INJECTION
The following information was derived from the United States Food and Drug Administration (FDA)--approved prescribing information:

Patients appropriate for SUBLOCADE are adults who have initiated treatment on a transmucosal buprenorphine-containing product delivering the equivalent of 8 to 24 mg of buprenorphine daily. The patient may only be transitioned to SUBLOCADE after a minimum of 7 days.

Initiation of treatment with transmucosal buprenorphine-containing products should be based on instructions in their appropriate product label. One Suboxone® (buprenorphine and naloxone) 8 mg/2 mg sublingual tablet provides equivalent buprenorphine exposure to:
  • one Subutex (buprenorphine) 8 mg sublingual tablet, or
  • one Bunavail® (buprenorphine and naloxone) 4.2mg/0.7 mg buccal film, or
  • one Zubsolv® (buprenorphine and naloxone) 5.7 mg/1.4 mg sublingual tablet

Buprenorphine (SublocadeTM) is only approved for subcutaneous injection. Serious harm or death could result if administered intravenously. Buprenorphine (SublocadeTM) Injection forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, buprenorphine (Probuphine®), buprenorphine (SublocadeTM), and naltrexone (Vivitrol®) are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

Subject to the terms and conditions of the applicable benefit contract, naltrexone implants are not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Buprenorphine (Probuphine®) was approved by the FDA on May 26, 2016 for the maintenance treatment of opioid dependence in patients who have 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 Subutex or Suboxone sublingual tablet equivalent or generic equivalent).

Buprenorphine (SublocadeTM) was approved by the FDA on November 30, 2017 for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

Naltrexone Implants are compounded implantable pellets that are not approved by the FDA.

Naltrexone (Vivitrol®) was approved by the FDA on April 30, 2006 for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with naltrexone (Vivitrol®). Supplemental approvals for naltrexone (Vivitrol®) have since been issued by the FDA.

PEDIATRIC USE

The safety and effectiveness of buprenorphine (Probuphine®) have not been established in children or adolescents less than 16 years of age.

The safety and effectiveness of buprenorphine (SublocadeTM) have not been established in children.

The safety, efficacy, and pharmacokinetics of naltrexone (Vivitrol®) have not been established in the pediatric population.

Description

OVERVIEW

The Substance Abuse and Mental Health Services Administration (SAMHSA) published the results from Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health. They reported that in 2014, over a period of 12 months, approximately 21.5 million people aged 12 or older had a substance use disorder (SUD), including 17 million people with an alcohol use disorder, 7.1 million with an illicit drug use disorder, and 2.6 million who had both an alcohol use and an illicit drug use disorder.

The American Society of Addiction Medicine (ASAM) describes the impact of opioid use disorder as a chronic, relapsing disease which has significant economic, personal, and public health consequences. ASAM has reported that drug overdose is a national epidemic and is the leading cause of accidental death in the US, with 52,404 lethal drug overdoses in 2015. Opioid addiction is driving this epidemic, with 20,101 overdose deaths related to prescription pain relievers, and 12,990 overdose deaths related to heroin in 2015 (Rudd et al 2016). In a 2014 survey of people being treated for opioid addiction, 94% of respondents said they chose to use heroin because prescription opioids were “far more expensive and harder to obtain” (Cicero et al 2014).

Opioid and alcohol use disorders are initially treated with psychosocial support, counseling, and pharmacologic agents (oral or sublingual agents). Those unable to comply with daily dosing may be able to transition to longer-acting agents. Once the individual is stabilized on the appropriate dose, they may be transitioned to longer-acting drugs, such as buprenorphine (Probuphine®) implant, buprenorphine (SublocadeTM) subcutaneous injection, or naltrexone (Vivitrol®) intramuscular (IM) injection. These drugs are used as a part of a comprehensive treatment program which includes psychosocial support and counseling.

BUPRENORPHINE (PROBUPHINE®) IMPLANTS AND (SUBLOCADETM) INJECTION

Buprenorphine is a Schedule III controlled substance and a partial agonist at the mu-opioid receptor. Buprenorphine has low intrinsic activity, so when it binds to the mu-opioid receptors, it activates the receptors to a lesser degree than full agonists (e.g., morphine, heroin, methadone) causing a lower potential for opioid effects, such as euphoria or sedation. Since buprenorphine has a high affinity for receptors, it cannot be displaced by full agonists; it also displaces full agonists already bound to receptors. Buprenorphine produces a physical dependence on the drug and also has a high potential for abuse which can result in overdose or death; these risks increase when individuals are also receiving other drugs that act on the central nervous system, such as benzodiazepines or alcohol. As an FDA-classified Schedule III Controlled substance, there is potential for abuse, dependence, overdose, and death.

The Drug Addiction Treatment Act of 2000 (DATA 2000) permits the prescribing and dispensing of certain narcotic schedule III, IV, or V medications, such as buprenorphine to be used as opioid replacement therapy in an office- or clinic-based setting. The provider must apply for a waiver and receive additional training. Qualifications for a DATA 2000 waiver include a current, valid state medical license and a unique drug enforcement agency (DEA) registration number. Furthermore, the provider must meet at least one criteria outlined by the US Department of Health and Human Services, Substance Abuse, and Mental Health Services Administration, where the provider must have certain credentials/training in the treatment of addiction.

Any professional provider can prescribe/insert/remove the implants, as long as the appropriate licensure is held and relevant training is obtained. Examples of provider types may include: Addiction Psychiatrists, Board-Certified Addiction Specialists, Primary Care Providers, etc.

BUPRENORPHINE (PROBUPHINE®) IMPLANTS
Buprenorphine (Probuphine®) implant was approved by the United States Food and Drug Administration (FDA) on 05/26/2016 for the 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 (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent) for three months or longer without any need for supplemental dosing or adjustment. It is not indicated for new entrants to buprenorphine treatment. Buprenorphine (Probuphine®) is available as kit containing four subdermal implants (each containing 74.2 mg of buprenorphine) that are inserted into the inner side of the upper arm for six months of treatment, and then are removed.

The FDA initiated a Risk Evaluation and Mitigation Strategy (REMS) program due to the risk of complications of migration, protrusion, expulsion, and nerve damage associated with the insertion and removal of buprenorphine (Probuphine®) and the risks of accidental overdose, misuse, and abuse that may occur if an implant protrudes from the skin. REMS provides education to the provider and instructs them to communicate to the patient about these complications that can arise with the insertion and removal of the implants. Components of the REMS program include:
  • Certification for professional providers who prescribe buprenorphine (Probuphine®): enrollment, live training, patient counseling on the risks listed above, and other requirements.
  • Certification and annual recertification for professional providers who insert/remove buprenorphine (Probuphine®): enrollment, live training, patient counseling on the risks listed above, attesting to the performance of a surgical procedure in the three months immediately preceding enrollment in this REMS program, and other requirements.
  • Maintenance and monitoring of the restricted distribution program for the implants by the pharmaceutical company.

Peer-Reviewed Literature for Buprenorphine (Probuphine®) Implants

Summary
A non-inferiority trial was designed to study the safety and effectiveness of buprenorphine (Probuphine®) implants compared to daily sublingual buprenorphine in the maintenance treatment of opioid dependence. This study was a randomized, double-blind, active-controlled, double-dummy study performed over 24 weeks. Participants were clinically stable, opioid-dependent individuals receiving sublingual buprenorphine maintenance therapy of 8 mg or less who were randomized to receive either:
  • Group 1: Four buprenorphine (Probuphine®) implants and placebo sublingual tablets (n=87)
  • Group 2: placebo implants and sublingual buprenorphine tablets (n=89).

Urine samples were obtained monthly for 6 months, plus an additional 4 random urine screens were obtained during that time. The primary endpoint was the difference in proportion of responders, defined as participants with at least 4 of 6 months without evidence of opioid use (based on urine test and self-report composites) by treatment group. In the buprenorphine implant group, 81 of 84 participants (96.4%) were responders, while in the sublingual buprenorphine group, 78 of 89 participants (87.6%) were responders. The Pvalue was <0.001 which signifies non-inferiority. Safety evaluation showed that 48.3% of those in Group 1 had at least one non-implant-site related adverse event, compared to 52.8% in Group 2. Twenty-three percent of those in Group 1 had at least one implant-site related adverse event, compared to 13.5% in Group 2. The authors concluded that the use of buprenorphine (Probuphine®) implants were non-inferior when compared to sublingual buprenorphine tablets (Rosenthal 2016).

BUPRENORPHINE (SUBLOCADETM) INJECTION
Buprenorphine (SublocadeTM) subcutaneous injection was approved by the United States Food and Drug Administration (FDA) on November 30, 2017 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. Buprenorphine (SublocadeTM) is administered subcutaneously into the abdomen by a professional provider as a monthly dose with a minimum of 26 days between doses.

The FDA initiated a Risk Evaluation and Mitigation Strategy (REMS) program due to the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense buprenorphine (SublocadeTM) directly to a healthcare provider for administration by a health care provider. Components of the REMS program include:
  • Healthcare Settings and Pharmacies that order and dispense buprenorphine (SublocadeTM) must be certified in the SUBLOCADE REMS Program
  • Certified Healthcare Settings and Pharmacies must establish processes and procedures to verify buprenorphine (SublocadeTM) is provided directly to a healthcare provider for administration by a healthcare provider, and the drug is not dispensed to the patient
  • Certified Healthcare Settings and Pharmacies must not distribute, transfer, loan, or sell buprenorphine (SublocadeTM)

Peer-Reviewed Literature for Buprenorphine (SublocadeTM) Injection

Summary
The safety and effectiveness of buprenorphine (SublocadeTM) Injection was established in a Phase 3 randomized, double-blind, placebo-controlled multicenter trials over a 24-week period in treatment-seeking individuals (N=504) who met the DSM-5 criteria for moderate or severe opioid use disorder. All participants were stabilized on buprenorphine/naloxone sublingual film prior to the first dose, and received psychosocial support in addition to one of the following dosing arms: 6 once-monthly 300 mg doses, 2 once-monthly 300 mg doses followed by 4 once-monthly 100 mg doses, or 6 once-monthly SC injections of placebo (randomized 4:4:1:1 [203 subjects in the 300 mg/100 mg group, 201 patients in the 300 mg/300 mg group and 100 patients in the placebo group [2 groups of volume-matched placebo)]. The primary efficacy endpoint was the cumulative distribution function (CDF) of the percentage of opioid-free weeks at Week 24 based on weekly urine drug screens combined with self-reported use of illicit opioid use. It was determined, regardless of dose, that buprenorphine (SublocadeTM) was superior to the placebo group with statistical significance.
Participants with ≥80% opioid-free weeks was statistically significantly higher in both groups receiving buprenorphine (SublocadeTM) compared to the placebo group (28.4% [300 mg/100 mg], 29.1% [300 mg/300mg], 2% [placebo]).

NALTREXONE IMPLANTS AND (VIVITROL®) INJECTION

Naltrexone is an opioid antagonist which binds to and blocks the mu-opioid receptor, thereby preventing the receptor from being activated by full agonists, such as morphine, heroin, and methadone. Without activation of the receptor, there are no opioid effects such as euphoria or sedation.

NALTREXONE IMPLANTS
Naltrexone Implants are compounded pellets using a bulk powder formulation of naltrexone. As per FDA guidance, "Compounded drugs are not FDA-approved. This means that FDA does not review these drugs to evaluate their safety, effectiveness, or quality before they reach patients." Although there have been randomized trials and systematic reviews for naltrexone implants, the evidence is limited in quantity and quality.

Peer-Reviewed Literature for Naltrexone Implants

Summary
The National Health and Medical Research Council (NHMRC) guidance on the use of naltrexone implant in 2010 concluded that "while naltrexone implant treatment may show some efficacy as part of an integrated program, more research is needed. Naltrexone implants are an experimental product and as such should only be used in the context of a well conducted RCT with sufficient sample size, appropriate duration of treatment and follow up, regular robust monitoring, provision of a comprehensive psychosocial treatment program, and with comparison to current best practice. Until these trials have occurred and the relevant data are available and validated, the efficacy of the treatment, alone or in comparison to conventional first line treatments, cannot be determined."

As summarized in the The World Federation of Societies of Biological Psychiatry Guidelines, the majority of evidence for naltrexone implants have been trials in countries outside of the United States, including Russia and Australia. They stated "naltrexone implants cannot yet be recommended for clinical use because although there are promising efficacy data for them, safety concerns remain and require further evaluation" (Soyka et al 2011).

Krupitsky et al 2012 conducted a randomized, double-dummy, double-blind, 24-week trial in 306 individuals in Russia. There were three study arms to compare efficacy:
  • bimonthly naltrexone implant and daily oral placebo
  • bimonthly placebo implant and daily oral naltrexone
  • bimonthly placebo implant and daily oral placebo
The primary outcome was retention without relapse. At 6 months, those with the naltrexone implant (52.9%) remained in treatment without relapse, compared to oral naltrexone (15.7%) or placebo (10.8%) at 6 months; however there was loss to follow-up at 9 and 12 months. Longer-term studied are required in order to make final efficacy determinations.

A systematic review and meta-analysis was performed by Larney et al 2014. Five randomised controlled trials (576 patients) and four non-randomised studies (8,358 patients) were included in the review. The quality of evidence reviewed was classified as moderate to low. They summarized that “The evidence on safety, efficacy, and effectiveness of naltrexone implants was limited in quantity and quality, and the evidence had little clinical use in settings where effective treatments for opioid dependence (such as opioid substitution therapy) were available. Naltrexone implants were significantly more effective in suppressing opioid use than placebo or oral naltrexone.”

Kelty et al 2017 conducted a retrospective cohort study in Australia to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent individuals treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose. They reviewed opioid dependent individuals treated with methadone (n = 3515), buprenorphine (n = 3250) or implant naltrexone (n = 1461) between 2001 and 2010, were matched against state mortality and hospital data. They concluded there was no significant difference between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses.

NALTREXONE (VIVITROL®) INJECTION
Naltrexone (Vivitrol®) was approved by the United States Food and Drug Administration (FDA) on April 13, 2006 for the treatment of alcohol dependence in individuals who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with naltrexone (Vivitrol®). In addition, on October 12, 2010, naltrexone (Vivitrol®) was FDA-approved for the prevention of relapse to opioid dependence, following opioid detoxification.

Naltrexone (Vivitrol®) is available as one 380 mg-vial that may be administered by a professional provider (no special training is required) via IM gluteal injection (alternating buttocks for each subsequent injection) every 4 weeks or once a month. Prior to initiating naltrexone (Vivitrol®), an opioid-free duration of a minimum of 7-10 days is recommended for individuals, to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization.

The FDA initiated a REMS program for naltrexone (Vivitrol®) to inform professional providers about the potential risk of severe injection site reactions that may occur during administration and to, additionally, counsel their patients accordingly. The communication includes a patient counseling tool and a poster that shows professional providers the “Key Techniques to Reduce Severe Injection Site Reactions.”

Peer-Reviewed Literature for Naltrexone (Vivitrol®) Injection

Summary

Garbutt et al 2005 evaluated the efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence in a six-month, randomized, double-blind, multi-center, placebo-controlled trial. Participants received monthly intramuscular injections of 380 mg of long-acting naltrexone (n=205), 190 mg of long-acting naltrexone (n=210), or a matching volume of placebo (n=209), along with biweekly psychosocial support.

The primary efficacy endpoint was the event rate, which combines the frequency and pattern of heavy drinking days over the 24 weeks of treatment. The definition of heavy drinking (5 or more drinks per day for men and 4 or more drinks per day for women). Participants who received 380 mg of long-acting naltrexone experienced approximately a 25% greater reduction in the rate of heavy drinking relative to placebo-treated patients (P=0.03). Patients treated with naltrexone 190 mg reported a 17% greater reduction in the rate of heavy drinking than placebo-treated patients (P= .07). A subset of patients with lead-in abstinence showed even greater reductions in the number of drinking days and in the number of heavy drinking days, when receiving long-acting naltrexone, compared to placebo-treated patients. These results were not seen in the subset of patients who were actively drinking at the time of treatment initiation. Long-acting injectable naltrexone was well tolerated, where the most common adverse events were nausea, headache, fatigue, and injection site reaction tenderness.

Krupitsky et al 2011 performed a double-blind, placebo-controlled, multicenter randomized (1:1) trial to evaluate the safety and effectiveness of injectable extended-release naltrexone (n=126) versus placebo (n=124) for the treatment of opioid dependence. Placebo or injectable extended-release naltrexone were administered at 380 mg intramuscularly every four weeks for 24 weeks, along with biweekly individual drug counseling sessions. After 24 weeks, all participants were offered open-label injectable extended-release naltrexone for an additional year. The primary endpoint was the response profile for confirmed abstinence during weeks 5-24, assessed by urine drug tests and self report of non-use. The median proportion of weeks of confirmed abstinence was 90% in the injectable extended-release naltrexone group compared with 35% in the placebo group (P=0.0002). Patients in the injectable extended-release naltrexone group self-reported a median of 99.2% opioid-free days compared with 60.4% for the placebo group (P=0·0004). Total abstinence (opioid-free at all weekly visits) was reported in 36% of patients in the injectable extended-release naltrexone group compared with 23% in the placebo group (P=0.0224). According to the authors, injectable extended-release naltrexone was well-tolerated with mainly mild to moderate adverse reactions.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References

References for Medically Necessary Indications


American Hospital Formulary Service (AHFS). Drug Information 2019. naltrexone (Vivitrol®). [Lexicomp Online Web site]. 09/25/17. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 15, 2019.

American Society of Addiction Medicine (ASAM). Opioid Addiction 2016 Facts & Figures. Available at: http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf . Accessed March 20, 2019.

Center for Substance Abuse Treatment. Clinical Guidelines for the use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS publication no. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration (SAMHSA); 2004. Available at: https://www.ncbi.nlm.nih.gov/books/NBK64245/ . Accessed March 20, 2019.

Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry. 2014;71(7):821-826.
Dammerman R, Bailey GL, Beebe KL, et al. Long-Term Buprenorphine Implants for Treatment of Opioid Dependence: Safety Outcomes from Two Open-Label Extension Trials. J Addict Behav Ther Rehabil. 2017; 6:1.

Elsevier’s Clinical Pharmacology Compendium. buprenorphine. Indications/Dosages (Revised: 02/13/18). Mechanism of Action (Revised: 03/22/2011). [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 18, 2019.
Elsevier’s Clinical Pharmacology Compendium. naltrexone (Vivitrol®). 12/17/2018. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 15, 2019.

Garbutt JC, Kranzler HR, O'Malley SS, et al; Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005 Apr 6;293(13):1617-25.

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" or https://www.asam.org/resources/guidelines-and-consensus-documents/npg or https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-jam-article.pdf?sfvrsn=0 . Accessed on March 20, 2019.

Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011 Apr 30;377(9776):1506-13.

Lexi-Drugs Compendium. buprenorphine. 03/16/19. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2019.

Lexi-Drugs Compendium. naltrexone (Vivitrol®). 03/07/2019. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 15, 2019.

Ling W, Casadonte P, Bigelow G, et al. Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial. JAMA. Oct 13 2010;304(14):1576-1583.

Lobmaier P, Kornor H, Kunoe N, Bjørndal A. Sustained-Release Naltrexone For Opioid Dependence. Cochrane Database Syst Rev. 2008;(2) CD006140.

Probuphine® (buprenorphine) implant. [prescribing information]. Titan Pharmaceuticals, Inc. South San Francisco, CA; 02/2018. Available at: https://probuphine.com/. Accessed March 15, 2019.

Probuphine® (buprenorphine) implant. [Probuphine® REMS Program]. Titan Pharmaceuticals, Inc. South San Francisco, CA. Available at: https://probuphinerems.com/ . Accessed March 18, 2019.

Rosenthal RN, Ling W, Casadonte P, et al. Buprenorphine implants for treatment of opioid dependence: randomized comparison to placebo and sublingual buprenorphine/naloxone. Addiction. Dec 2013;108(12):21412149.

Rosenthal RN, Lofwall MR, Kim S, et al. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: a randomized clinical trial. JAMA. Jul 19 2016;316(3):282-290.

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:1445–1452.

Sublocade (buprenorphine) extended-release subcutaneous injection. [prescribing information 03/2018]. Indivior Inc. North Chesterfield, VA. Available at: https://www.sublocade.com/ . March 18, 2019.

Sublocade (buprenorphine) extended-release subcutaneous injection. [Sublocade REMS Program]. Indivior Inc. North Chesterfield, VA. Available at: https://www.sublocaderems.com/ . March 18, 2019.

Substance Abuse and Mental Health Services Administration (SAMHSA). Behavioral health trends in the United States: Results from the 2014 National Survey on Drug Use and Health; 2014. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf. Accessed on March 20, 2019.

Substance Abuse and Mental Health Services Administration (SAMHSA). Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Quick Guide for Physicians Based on TIP 40. 2005.

Substance Abuse and Mental Health Services Administration (SAMHSA). Programs & Campaigns » Medication-Assisted Treatment » Medication and Counseling Treatment » Naltrexone. Last Updated: 09/12/2016. Available at: https://www.samhsa.gov/medication-assisted-treatment/treatment/naltrexone . Accessed March 20, 2019.

Substance Abuse and Mental Health Services Administration (SAMHSA). Substance use disorders. 01/30/19. Available at: https://www.samhsa.gov/disorders/substance-use . Accessed March 20, 2019.

Truven Health Analytics. Micromedex® DrugDex® Compendium. buprenorphine. 03/08/19. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed March 18, 2019.

Truven Health Analytics. Micromedex® DrugDex® Compendium. naltrexone (Vivitrol®). 01/08/19. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed March 15, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. buprenorphine (Probuphine®) prescribing information and approval letter (Original 05/26/2016; Updated 02/010/2018). [FDA Web site]. Available at: http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm . Accessed March 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. buprenorphine (Probuphine®) Approved Risk Evaluation and Mitigation Strategies (REMS). Initial 05/2016; Revised 11/01/2018. [FDA Web site]. Available at: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=356 . Accessed March 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. buprenorphine (Sublocade) prescribing information and approval letter (Original 11/30/2017; Updated 03/05/2018). [FDA Web site]. Available at: http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm . Accessed March 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. naltrexone (Vivitrol®) Approved Risk Evaluation and Mitigation Strategies (REMS). Initial 03/2010; Revised 05/17/2016. [FDA Web site]. Available at: https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=67 . Accessed March 18, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. naltrexone (Vivitrol®) prescribing information and approval letter (Original: 04/13/06. Revised 12/28/2018). [FDA Web site]. Available at: http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm . Accessed March 15, 2019.

Vivitrol® (naltrexone) implant. [prescribing information]. Alkermes, Inc.; Waltham, MA. Original: 04/13/06. Revised 12/2018. Available at: https://www.vivitrol.com/opioid-alcohol-addiction-awareness?s_mcid=ppc-google-vivitrol-general-terms. Accessed March 15, 2019.

References for Naltrexone Implant

Kelty E, Hulse G. Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone. Int J Drug Policy. 2017; 46:54-60.

Krupitsky E, Zvartau E, Blokhina E, et al. Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. Arch Gen Psychiatry. 2012 Sep;69(9):973-81.

Larney S, Gowing L, Mattick RP, Farrell M, Hall W, Degenhardt L. A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence. Drug Alcohol Rev. 2014 ;33(2):115-28.

National Health and Medical Research Council (NHMRC). Naltrexone implant treatment for opioid dependence. 2010. Available at: https://www.nhmrc.gov.au/about-us/publications/naltrexone-implant-treatment-opioid-dependence#block-views-block-file-attachments-content-block-1 . Accessed March 20, 2019.

Soyka M, Kranzler HR, van den Brink W, et al.; WFSBP Task Force on Treatment, Guidelines for Substance Use Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence. World J Biol Psychiatry. 2011;12(3):160-187.

US Food and Drug Administration (FDA). FDA Compounding Laws and Policies. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm606881.htm . Accessed March 20, 2019.




Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

F10.20 Alcohol dependence, uncomplicated

F10.21 Alcohol dependence, in remission

F10.220 Alcohol dependence with intoxication, uncomplicated

F10.221 Alcohol dependence with intoxication delirium

F10.229 Alcohol dependence with intoxication, unspecified

F10.230 Alcohol dependence with withdrawal, uncomplicated

F10.231 Alcohol dependence with withdrawal delirium

F10.232 Alcohol dependence with withdrawal with perceptual disturbance

F10.239 Alcohol dependence with withdrawal, unspecified

F10.24 Alcohol dependence with alcohol-induced mood disorder

F10.250 Alcohol dependence with alcohol-induced psychotic disorder with delusions

F10.251 Alcohol dependence with alcohol-induced psychotic disorder with hallucinations

F10.259 Alcohol dependence with alcohol-induced psychotic disorder, unspecified

F10.26 Alcohol dependence with alcohol-induced persisting amnestic disorder

F10.27 Alcohol dependence with alcohol-induced persisting dementia

F10.280 Alcohol dependence with alcohol-induced anxiety disorder

F10.281 Alcohol dependence with alcohol-induced sexual dysfunction

F10.282 Alcohol dependence with alcohol-induced sleep disorder

F10.288 Alcohol dependence with other alcohol-induced disorder

F10.29 Alcohol dependence with unspecified alcohol-induced disorder

F11.20 Opioid dependence, uncomplicated

F11.21 Opioid dependence, in remission

F11.220 Opioid dependence with intoxication, uncomplicated

F11.221 Opioid dependence with intoxication delirium

F11.222 Opioid dependence with intoxication with perceptual disturbance

F11.229 Opioid dependence with intoxication, unspecified

F11.23 Opioid dependence with withdrawal

F11.24 Opioid dependence with opioid-induced mood disorder

F11.250 Opioid dependence with opioid-induced psychotic disorder with delusions

F11.251 Opioid dependence with opioid-induced psychotic disorder with hallucinations

F11.259 Opioid dependence with opioid-induced psychotic disorder, unspecified

F11.281 Opioid dependence with opioid-induced sexual dysfunction

F11.282 Opioid dependence with opioid-induced sleep disorder

F11.288 Opioid dependence with other opioid-induced disorder

F11.29 Opioid dependence with unspecified opioid-induced disorder




HCPCS Level II Code Number(s)


MEDICALLY NECESSARY

J0570 Buprenorphine implant, 74.2 mg

J2315 Injection, naltrexone, depot form, 1 mg

Q9991 Injection, buprenorphine extended-release (sublocade), less than or equal to 100 mg
Q9992 Injection, buprenorphine extended-release (sublocade), greater than 100 mg

EXPERIMENTAL/INVESTIGATIONAL

THE FOLLOWING CODES ARE USED TO REPRESENT NALTREXONE IMPLANTS:
J7999 Compounded drug, not otherwise classified



Revenue Code Number(s)

N/A


Misc Code

N/A:

N/A


Coding and Billing Requirements


Cross References


Policy History

Revisions from 08.01.37a
11/04/2019This policy has been updated to include the Company’s coverage position on buprenorphine (SublocadeTM) extended-release subcutaneous injection (as Medically Necessary) and naltrexone implants (as Experimental/Investigational). Policy criteria has been modified for naltrexone (Vivitrol®).

Effective 10/05/2017 this policy has been updated to the new policy template
format.
Version Effective Date: 11/04/2019
Version Issued Date: 11/04/2019
Version Reissued Date: N/A

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