Issue 5: Evidence-Based Approaches for Induction Onto VIVITROL for Patients With Opioid Dependence: A Literature Overview

Stacy Cohen, M.D.; Brian O’Connor, M.D., F.A.S.A.M.

WITH STEERING COMMITTEE COMMENTARY

Introduction

Despite intensive efforts to combat the epidemic of opioid dependence, it persists. Clinicians continue to have many unanswered questions, including “How do we remove barriers to medication-assisted treatment (MAT)—a guideline-recommended intervention?”1

Of the available MAT options, opioid antagonist therapy stands apart because it requires the patient to be opioid-free before starting treatment.2 This requirement represents both an opportunity and a challenge: the opportunity for the patient to be free of opioids, and the challenge of how to achieve an opioid-free state safely and effectively.

This newsletter presents an overview of data from 3 recent peer-reviewed journal articles examining detoxification from opioids via the process of medically supervised withdrawal prior to initiation of the once-monthly opioid antagonist VIVITROL® (naltrexone for extended-release injectable suspension).3-5 Also included is a bibliography of additional resources that you may find helpful as you consider induction onto VIVITROL in your practice. Note that scientific and clinical evidence suggest there is no single best method for detoxification, but rather a set of pharmacologic approaches and treatment settings. These publications represent a sampling of available literature and an important step forward in our understanding of medically supervised withdrawal.

Joining me with commentary throughout this newsletter is fellow Meeting the Need Steering Committee member Dr. Stacy Cohen. We hope you find this information and our perspectives interesting. Please note that this information should not be construed as medical advice. All decisions related to any individual patient’s care should be made by the treating physician and his or her medical team.

Sincerely,
Brian O’Connor, M.D., F.A.S.A.M.

Safety Considerations for Inducting an Opioid-Dependent Patient Onto VIVITROL

Before we review the studies examining protocols for medically supervised withdrawal from opioids, we will look at some safety considerations around induction onto VIVITROL.

VIVITROL indications and contraindications

VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.2 VIVITROL should be part of a comprehensive management program that includes psychosocial support.2 Note that VIVITROL is also indicated 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 VIVITROL.2 Patients should not be actively drinking at the time of initial VIVITROL administration.2

VIVITROL is contraindicated in patients receiving opioid analgesics, patients with current physiologic opioid dependence, and patients in acute opioid withdrawal.2 VIVITROL is also contraindicated in patients who have failed the naloxone challenge test or have a positive urine screen for opioids, and who have previously exhibited hypersensitivity to naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or any other components of the diluent.2

Please see additional Important Safety Information about VIVITROL at the end of this newsletter.

Patients should be opioid-free before starting VIVITROL

Opioid-dependent and opioid-using patients, including those being treated for alcohol dependence, should be opioid-free before starting VIVITROL treatment, and they should notify healthcare providers of any recent opioid use.2 An opioid-free duration of a minimum of 7 days to 10 days is recommended to avoid precipitation of opioid withdrawal that may be severe enough to require hospitalization.2

If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed.2

A naloxone challenge test may help determine whether a patient is opioid-free.2,6 However, patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test.2 It’s important to be prepared to manage withdrawal symptomatically with non-opioid medications, because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period.2

Vulnerability to opioid overdose

After opioid detoxification, patients are likely to have a reduced tolerance to opioids.2 VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration.2 As the blockade wanes and eventually dissipates completely, use of previously tolerated doses of opioids could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.).2

Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment.2 Patients and caregivers should be told of this increased sensitivity to opioids and the risk of overdose.2

Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable.2 The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade.2 This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.2

Any attempt by a patient to overcome the VIVITROL blockade by taking opioids may lead to fatal overdose.2 Patients should be told of the serious consequences of trying to overcome the opioid blockade.2

Studied Strategies for Medically Supervised Withdrawal

Medically supervised withdrawal is broadly defined by the Substance Abuse and Mental Health Services Administration (SAMHSA) as “using an opioid agonist…in tapering doses or other medications to help a patient discontinue illicit or prescription opioids.”1 SAMHSA formerly called this term detoxification.1

SAMHSA recommends that treatment with extended-release naltrexone “always be considered to reduce the likelihood of return to [opioid] use after medically supervised withdrawal is completed and an adequate period of abstinence achieved.”1

Studied strategies for medically supervised withdrawal prior to induction onto VIVITROL have included the following pharmacologic approaches:

  • The use of low-dose oral naltrexone, with or without a short course of buprenorphine up front, along with ancillary medications3,4,7-9
  • The use of non-opioid ancillary medications alone5,10,11

Let’s look at a few studies that have examined these approaches. Note that some of these publications use the term detoxification rather than medically supervised withdrawal. For this review, we will use the authors’ preferred term. Also note that the following are brief overviews of the studies. Please refer to the journal publications for full information on each of them.

Evidence-Based Approach: Buprenorphine Taper and/or Low-Dose Oral Naltrexone

Sullivan et al. (2017): Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine

DESIGN

This study was a prospective, randomized, open-label, parallel-group, outpatient clinical trial.3 The objective was to examine the efficacy of 2 methods of outpatient opioid detoxification for induction onto extended-release injectable naltrexone.3

The 150 enrolled patients were stratified by the severity of their opioid dependence.3 Included in this study were opioid-dependent individuals aged 18 years to 60 years who were seeking treatment for heroin or prescription opioid dependence, met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for current opioid dependence of at least 6 months’ duration, and were able to give informed consent.3 Exclusion criteria included the presence of unstable medical or psychiatric conditions; physiologic dependence on alcohol or sedative-hypnotics; accidental overdose in the past 3 years; treatment with opioids for chronic pain; and regular use of methadone or buprenorphine.3

Patients were randomized 2:1, respectively, to oral naltrexone–assisted detoxification along with a non-opioid, standing ancillary medication regimen; or to buprenorphine-assisted detoxification along with a non-opioid, as-needed ancillary medication regimen.3 A more detailed look at the protocol is shown in Table 1. Both groups also received behavioral therapy.3 The primary outcomes assessed in the study were the odds of successful induction onto extended-release naltrexone and the odds of receiving a second injection at Week 5 (not discussed in this newsletter).3

Table 1. Sullivan et al. (2017), Outpatient Opioid Detoxification Regimens3
Protocol dayOral NTX-assisted
detoxification*
BUP-assisted
detoxification*
1Ancillary medications to support abstinence
2BUP 2 mg sublingually every 1-2 hours, up to 8 mg
3[Washout]BUP 6 mg
4Oral NTX 1 mgBUP 4 mg
5Oral NTX 3 mgBUP 4 mg
6Oral NTX 12 mgBUP 2 mg
7Oral NTX 25 mgBUP 1 mg
8XR-NTX 380 mg intramuscularly 
15 XR-NTX 380 mg intramuscularly

*Ancillary medications offered included clonidine, clonazepam, prochlorperazine, trazodone, and zolpidem.
BUP, buprenorphine; NTX, naltrexone; XR-NTX, extended-release naltrexone.
Reprinted with permission from The American Journal of Psychiatry (Copyright ©2017). American Psychiatric Association. All rights reserved.

RESULTS

The mean age of the 150 study patients was about 35 years.3 The population was 86% male and 64% Caucasian.3 The most common route of opioid administration was intranasal, and the majority of patients were primarily illicit opioid users and used a mean of about 8 bags of heroin a day.3

Successful induction onto extended-release naltrexone (primary endpoint): In this outpatient study, a greater percentage of patients in the oral naltrexone group were successfully inducted onto extended-release naltrexone, compared with patients in the buprenorphine group, and the difference was statistically significant (Figure 1).3

Figure 1. Sullivan et al (2017), Successful Induction Onto Extended-Release Naltrexone3

BUP, buprenorphine; NTX, naltrexone.

Withdrawal outcomes (secondary endpoints): The percentage of patients with at least mild opioid withdrawal, defined as a Clinical Opiate Withdrawal Scale (COWS) score of 5 or higher on average, decreased from Day 2 to Day 7.3 The authors also looked at the percentage of patients with at least one report of moderate-to-severe withdrawal, defined as a COWS score of 12 or greater.3 They found that the initial decrease in moderate-to-severe withdrawal scores was faster in the buprenorphine group, but the proportion of patients with moderate-to-severe withdrawal was low and not significantly different between study groups from Day 2 to Day 5 (Figure 2).3

Figure 2. Sullivan et al. (2017), Withdrawal Outcomes3

*Mild or greater withdrawal = COWS score of ≥5.
†Moderate-to-severe withdrawal = COWS score of ≥12.
BUP, buprenorphine; COWS, Clinical Opiate Withdrawal Scale; NTX, naltrexone.
Reprinted with permission from The American Journal of Psychiatry (Copyright ©2017). American Psychiatric Association. All rights reserved.

Adverse events: Table 2 presents the adverse events reported by at least 5% of the patients who completed detoxification.3 About 56% of patients in the oral naltrexone group had at least one adverse event, compared with about 77% of patients in the buprenorphine group.3 There were no significant between-group differences in the reported adverse event rates.3

Table 2. Sullivan et al. (2017), Adverse Events Reported by ≥5% of Patients Who Completed Detoxification3
 Oral NTX-assisted
detoxification (N=54)
BUP-assisted
detoxification (N=17)
Adverse eventN%N%
At least 1 adverse event3055.61376.5
Mood changes1222.2847.1
Insomnia1018.5741.2
Nausea/vomiting713.0317.7
Diarrhea713.015.9
Bone/joint aches611.115.9
Fatigue/drowsiness47.4211.8
Chills/cold sweats59.3211.8
Decreased appetite47.4211.8

Reported adverse events were not significantly different between treatment groups.
BUP, buprenorphine; NTX, naltrexone.
Reprinted with permission from The American Journal of Psychiatry (Copyright ©2017). American Psychiatric Association. All rights reserved.

STUDY LIMITATIONS

Limitations of this study included an open-label, pragmatic design that attempted to mirror real-world practice.3 The staff participating in the study were trained and motivated to help all patients undergo induction onto extended-release naltrexone regardless of randomization assignment.3 The study patients had a greater frequency and duration of clinic visits than is likely outside a clinical trial setting.3 Also, patients were paid for their participation, which may have encouraged attendance at clinic visits.3 Lastly, the low doses of oral naltrexone used in this study are not approved by the U.S. Food and Drug Administration (FDA) or commercially available.3

AUTHORS' CONCLUSION

The authors concluded that the study results support the feasibility of ascending low doses of oral naltrexone—in combination with an initial dose of buprenorphine and a non-opioid, standing ancillary medication regimen—as an outpatient regimen for opioid detoxification and induction onto extended-release naltrexone.3

Disclaimer: Alkermes provided the medication used in this study, and the lead author continued her work on this publication after becoming an Alkermes employee.

Evidence-Based Approach: Buprenorphine Taper and/or Low-Dose Oral Naltrexone

Bisaga et al. (2018): Outpatient transition to extended-release naltrexone for patients with opioid use disorder: a phase 3 randomized trial

DESIGN

The objective of this study was to examine the efficacy and safety of low-dose oral naltrexone, combined with a brief buprenorphine taper and a standing ancillary medication regimen, for detoxification and induction onto extended-release naltrexone.4 The study was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial.4

A total of 378 patients were randomized, stratified by primary short-acting opioid-of-use, to 1 of 3 regimens: low-dose oral naltrexone plus a 3-day buprenorphine taper, low-dose oral naltrexone plus placebo buprenorphine, or placebo oral naltrexone plus placebo buprenorphine.4 All of the study groups also received psychoeducational counseling and ancillary medications.4 Additional detail on the dosing regimens is shown in Table 3.

Table 3. Bisaga et al. (2018), Outpatient Opioid Detoxification Regimens4
 Patients randomized 1:1:1 to:
Protocol dayNTX/BUPNTX/PBO-BPBO-N/PBO-B
Oral NTX*BUPOral NTX*PBO-BPBO-N*PBO-B
10.25 mg + 0.25 mg2 mg +
2 mg +
2 mg
0.25 mg + 0.25 mgPBO + PBO + PBOPBO + PBOPBO + PBO + PBO
20.25 mg + 0.25 mg2 mg0.25 mg + 0.25 mgPBOPBO + PBOPBO
30.5 mg + 0.5 mg2 mg0.5 mg + 0.5 mgPBOPBO + PBOPBO
41.5 mg + 1.5 mg1.5 mg + 1.5 mgPBO + PBO
53 mg +
3 mg
3 mg +
3 mg
PBO + PBO
67.5 mg + 7.5 mg7.5 mg + 7.5 mgPBO + PBO
715 mg +
15 mg
15 mg +
15 mg
PBO + PBO
8/8aNaloxone challenge

*Each day, second dose given ≥1 hour after first dose.
†Optional third dose at home.
BUP, buprenorphine; NTX, naltrexone; PBO-B, placebo buprenorphine; PBO-N, placebo naltrexone.

Inclusion criteria were patients ages 18 years to 60 years voluntarily seeking opioid withdrawal and transition to extended-release naltrexone; a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnosis of moderate or severe opioid use disorder confirmed by the Mini-International Neuropsychiatric Interview; patient report of consistent use of opioids for at least 3 months; a positive urine opioid test at screening; and at least mild withdrawal symptoms—or a COWS score of 6 or higher—on Day 1.4

Exclusion criteria consisted of testing positive for, or having recent use of, buprenorphine or methadone within 7 days or 14 days prior to randomization, respectively; use of extended-release naltrexone within 90 days prior to screening; a history of seizures, schizoaffective disorder, or bipolar disorder; unstable major depressive disorder; physiologic dependence on any psychoactive substances; more than 3 previous unsuccessful attempts at opioid detoxification; or accidental overdose in the past 3 years.4

RESULTS

The baseline patient characteristics were similar across all 3 groups.4 The study population was 66% male and 74% white.4 The overall median craving score was 80, the median COWS score was 9, and the median Subjective Opiate Withdrawal Scale score was 28.4 Among enrolled patients, 36% primarily used prescription opioids and 64% used heroin.4

Percentage of patients receiving and tolerating extended-release naltrexone (primary endpoint): In this outpatient study, comparable percentages of patients in each group received and tolerated the first dose of extended-release naltrexone.4 Numerical differences between the groups were not significant (Figure 3).4

Figure 3. Bisaga et al. (2018), Percentage of Patients Receiving and Tolerating Extended-Release Naltrexone4

*Demonstrated by mild (COWS ≤12 or SOWS ≤10) opioid withdrawal symptoms following XR-NTX administration.
†PBO-N/PBO-B used as a reference group in logistic regression that also included randomization stratification by prior drug use (heroin vs prescription opioids) as variables.
BUP, buprenorphine; COWS, Clinical Opiate Withdrawal Scale; NTX, naltrexone; PBO-B, placebo buprenorphine; PBO-N, placebo naltrexone; SOWS, Subjective Opiate Withdrawal Scale; XR-NTX, extended-release naltrexone.

Adverse events: Among patients completing detoxification (Days 1 to 7), adverse events were reported in about 35% of patients in the oral naltrexone/buprenorphine group, about 25% of patients in the oral naltrexone/placebo buprenorphine group, and about 38% of patients in the placebo oral naltrexone/placebo buprenorphine group (Table 4).4

Most adverse events were consistent with symptoms of opioid withdrawal.4 Four adverse events led patients to discontinue the study—2 cases of nausea and one case each of opioid withdrawal and anxiety.4 Adverse events determined to be serious occurred in 5 patients and included acute confusion after administration of clonidine, clonazepam, and oral naltrexone; panic attack; alcohol use; somnolence; and dehydration.4 There were no overdoses or deaths in this study.4

Table 4. Bisaga et al. (2018), Adverse Events4

NTX/BUP
(n=126) 
NTX/PBO-B
 (n=126) 
 PBO-N/PBO-B
 (n=126)
 
 Total
(N=378)
Any treatment-emergent AE, %34.924.6 38.132.5 
Treatment-emergent AEs by severity, %
  Mild18.39.511.913.2
  Moderate13.510.319.8 14.6 
  Severe3.24.8 6.3 4.8
AE leading to discontinuation, %0.81.6 0.8 1.1
Any serious adverse drug reaction, %00.8 0 0.3

AE, adverse event; BUP, buprenorphine; NTX, naltrexone; PBO-B, placebo buprenorphine;
PBO-N, placebo naltrexone.
Reprinted from Drug and Alcohol Dependence, Vol 187, Bisaga et al., “Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: a phase 3 randomized trial,” Pages 171-178. Copyright 2018, with permission from Elsevier.

STUDY LIMITATIONS

The authors noted several limitations of their study, including that trial sites were heterogeneous with respect to their prior experience in conducting outpatient detoxification; the frequency and duration of study visits were greater than what is typically seen in clinical practice; payment of patients may have encouraged study visits; the validity of these data may not be generalizable to real-world patients with acute psychiatric needs, several failed opioid detoxification attempts, or a positive urine drug screen for methadone or buprenorphine at screening, as these patients were excluded; and low-dose oral naltrexone is not FDA approved or commercially available.4

AUTHORS' CONCLUSION

Bisaga and colleagues concluded that a 7-day detoxification protocol with naltrexone alone or with naltrexone and buprenorphine yielded rates of induction onto extended-release naltrexone that were similar to those with placebo.4 They further concluded that a fixed-dose standing ancillary medication regimen was well tolerated and ameliorated withdrawal symptoms during opioid detoxification in successfully inducted patients.4

Disclaimer: Financial support for this research and publication was provided by Alkermes.

Evidence-Based Approach: A Non-Opioid, Benzodiazepine-Free Protocol for Medically Supervised Withdrawal

Rudolf et al. (2017): A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment

DESIGN

The objective of this study was to assess the clinical feasibility of a non-opioid and benzodiazepine-free medically supervised opioid withdrawal protocol prior to transition to subsequent relapse-prevention strategies.5 This study was a retrospective chart review that included 84 DSM-IV–diagnosed opioid-dependent patients who underwent medically supervised withdrawal via the protocol.5 All patients were treated at a single inpatient facility.5

Inclusion criteria were diagnosis of opioid dependence by DSM-IV, urine drug test, and International Classification of Diseases, Ninth Revision; voluntary participation; documented need of medical management of opioid withdrawal; English language proficiency; and age 20 years to 55 years at the time of admission.5 Exclusion criteria were active use of and expected physiologic dependence on substances other than opioids; pregnancy or lactation; unstable medical or psychiatric conditions at admission; and planned use of buprenorphine for maintenance treatment.5

As part of a 4-day regimen, all patients received tizanidine, gabapentin, and hydroxyzine each day as shown in Table 5.5 As-needed ancillary medications included dicyclomine, acetaminophen, naproxen, loperamide, clonidine, trazodone, and quetiapine.5 Patients who tolerated an oral naltrexone challenge after receiving the 4-day regimen were inducted onto extended-release naltrexone.5 All patients received routine counseling during their hospital stay.5

The primary endpoints of the study were the completion of medically supervised withdrawal and successful initiation of extended-release naltrexone treatment prior to discharge.5

Table 5. Rudolf et al. (2017), Inpatient Regimen for Medically Supervised Withdrawal5
Protocol day4-day regimen (plus routine counseling)*
1Tizanidine 8 mg every 6 hours; gabapentin 1500 mg total; hydroxyzine 100 mg every 4 hours
2Repeat Day 1 regimen
3Repeat Day 1 regimen
4Repeat Day 1 regimen

*As-needed ancillary medication regimen included dicyclomine, acetaminophen, naproxen, loperamide, clonidine, trazodone, and quetiapine.
NTX, naltrexone; XR-NTX, extended-release naltrexone.

RESULTS

The 84 patients who received this 4-day, non-opioid protocol were an average of 27 years old, and 62% were male.5 About 26% of patients suffered from chronic pain.5 Most had severe physiologic dependence on opioids, with half dependent on heroin alone.5 More than half had a family history of addiction.5

Percentage of subjects completing treatment and successfully initiated onto extended-release naltrexone prior to discharge (primary endpoints): Seventy-nine of the 84 patients successfully completed the 4-day, inpatient medically supervised withdrawal protocol (Figure 4). Five patients left against medical advice.5 Two of these patients had a history of heroin use and 3 had a history of oxycodone use.5 Seventy-one of the 84 patients were discharged with arrangements to receive inpatient or outpatient treatment for substance use disorder.5

Of the 84 patients, 27 elected to pursue treatment with extended-release naltrexone (Figure 4).5 Of those 27 patients, 24 actually received the injection before hospital discharge.5 Two patients did not move forward with the injection, for unclear reasons, and one had withdrawal symptoms after challenge with oral naltrexone.5

The mean length of hospital stay per patient (a secondary endpoint) was
3.6 days.5

Figure 4. Rudolf et al. (2017), Percentage of Subjects Who5:

*Among 27 of 84 subjects (32%) who chose to pursue transition to XR-NTX.
XR-NTX, extended-release naltrexone.

Adverse events: No serious adverse events and no medication-related events resulting in treatment discontinuation or transfer to a higher-acuity unit were recorded in this study.5 All patients had adequate oral intake and hydration, and none reported dry mouth or urinary retention.5 Forty-four percent of patients had documented asymptomatic bradycardia during sleep.5 No symptomatic bradycardia was observed.5 Twenty-six percent of patients had documented asymptomatic hypotension, and 8% of patients had hypotension with symptoms of lightheadedness and weakness or fatigue while resting in bed.5 About 2% of patients indicated that they experienced episodic sedation from the scheduled medications.5

STUDY LIMITATIONS

Rudolf and colleagues noted the following limitations of this study: its retrospective design and lack of a control group; reported misuse of gabapentin in recent literature; the relatively young age of the study population, which may not represent the typical treatment population; and limited generalizability due to the exclusion of a significant number of participants (patients with any other active, physiologic substance dependence), resulting in smaller sample size.5

AUTHORS' CONCLUSION

The authors concluded that this retrospective chart review suggests the feasibility of this non-opioid, non-benzodiazepine inpatient protocol to provide effective and well-tolerated medically supervised withdrawal from opioids and transition to relapse prevention strategies, including injectable extended-release naltrexone.5

Disclaimer: The authors reported no conflicts of interest.

Bibliography of Additional Resources

Additional publications are available regarding medically supervised withdrawal prior to induction onto VIVITROL. These resources also may be helpful as you consider induction onto VIVITROL in your practice.

  • Bisaga A, Mannelli P, Sullivan MA, et al. Antagonists in the medical management of opioid use disorders: historical and existing treatment strategies. Am J Addict. 2018;27(3):177-187.
  • Bisaga A, Sullivan MA, Glass A, et al. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence. J Subst Abuse Treat. 2014;46(5):546-552.
  • Bisaga A, Sullivan MA, Glass A, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone. Drug Alcohol Depend. 2015;154:38-45.
  • Dakwar E, Kleber HD. Naltrexone-facilitated buprenorphine discontinuation: a feasibility trial. J Subst Abuse Treat. 2015;53:60-63.
  • Mannelli P, Wu LT, Peindl KS, Swartz MS, Woody GE. Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial. Drug Alcohol Depend. 2014;138:83-88.
  • Mogali S, Khan NA, Drill ES, et al. Baseline characteristics of patients predicting suitability for rapid naltrexone induction. Am J Addict. 2015;24(3):258-264.
  • Providers’ Clinical Support System for Medication Assisted Treatment.
    XR-Naltrexone: A Step-by-Step Guide. https://pcssnow.org/resource/naltrexone-step-step-guide. Accessed June 12, 2019.
  • Sigmon SC, Bisaga A, Nunes EV, O’Connor PG, Kosten T, Woody G. Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice. Am J Drug Alcohol Abuse. 2012;38(3):187-199.

More information about medically supervised withdrawal prior to induction onto VIVITROL is available from your VIVITROL representative. To request a representative, visit VIVITROLHCP.com.

References

  1. Substance Abuse and Mental Health Services Administration. Medications for Opioid Use Disorder. For Healthcare and Addiction Professionals, Policymakers, Patients, and Families. Treatment Improvement Protocol (TIP) Series, No. 63. HHS Publication No. (SMA) 18-5063FULLDOC. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2018.
  2. VIVITROL [prescribing information]. Waltham, MA: Alkermes, Inc; rev July 2019.
  3. Sullivan M, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry. 2017;174(5):459-467.
  4. Bisaga A, Mannelli P, Yu M, et al. Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: a phase 3 randomized trial. Drug Alcohol Depend. 2018;187:171-178.
  5. Rudolf G, Walsh J, Plawman A, et al. A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment. Am J Drug Alcohol Abuse. 2018;44(3):302-309.
  6. Providers’ Clinical Support System for Medication Assisted Treatment. XR-Naltrexone: A Step-by-Step Guide. https://pcssnow.org/resource/naltrexone-stepstep-guide. Accessed June 12, 2019.
  7. Mannelli P, Wu LT, Peindl KS, Swartz MS, Woody GE. Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial. Drug Alcohol Depend. 2014;138:83-88.
  8. Dakwar E, Kleber HD. Naltrexone-facilitated buprenorphine discontinuation: a feasibility trial. J Subst Abuse Treat. 2015;53:60-63.
  9. Mogali S, Khan NA, Drill ES, et al. Baseline characteristics of patients predicting suitability for rapid naltrexone induction. Am J Addict. 2015;24(3):258-264.
  10. Bisaga A, Sullivan MA, Glass A, et al. The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone. Drug Alcohol Depend. 2015;154:38-45.
  11. Bisaga A, Sullivan MA, Glass A, et al. A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence. J Subst Abuse Treat. 2014;46(5):546-552.

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IMPORTANT SAFETY INFORMATION

INDICATIONS

VIVITROL is indicated for:

  • Treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration.
  • Prevention of relapse to opioid dependence, following opioid detoxification.
  • VIVITROL should be part of a comprehensive management program that includes psychosocial support.

CONTRAINDICATIONS

VIVITROL is contraindicated in patients:

  • Receiving opioid analgesics
  • With current physiologic opioid dependence
  • In acute opioid withdrawal
  • Who have failed the naloxone challenge test or have a positive urine screen for opioids
  • Who have exhibited hypersensitivity to naltrexone, polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other components of the diluent

WARNINGS AND PRECAUTIONS

Vulnerability to Opioid Overdose:

  • After opioid detoxification, patients are likely to have a reduced tolerance to opioids. VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration. As the blockade wanes and eventually dissipates completely, use of previously tolerated doses of opioids could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.).
  • Cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval, after missing a scheduled dose, or after discontinuing treatment.Patients and caregivers should be told of this increased sensitivity to opioids and the risk of overdose.
  • Although VIVITROL is a potent antagonist with a prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.
  • Any attempt by a patient to overcome the VIVITROL blockade by taking opioids may lead to fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade.

Injection Site Reactions:

  • VIVITROL must be prepared and administered by a healthcare provider.
  • VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus; however, in some cases injection site reactions may be very severe.
  • Injection site reactions not improving may require prompt medical attention, including, in some cases, surgical intervention.
  • Inadvertent subcutaneous/adipose layer injection of VIVITROL may increase the likelihood of severe injection site reactions.
  • Select proper needle size for patient body habitus, and use only the needles provided in the carton.
  • Patients should be informed that any concerning injection site reactions should be brought to the attention of their healthcare provider.

Precipitation of Opioid Withdrawal:

  • When withdrawal is precipitated abruptly by administration of an opioid antagonist to an opioiddependent patient, the resulting withdrawal syndrome can be severe. Some cases of withdrawal symptoms have been severe enough to require hospitalization, and in some cases, management in the ICU.
  • To prevent occurrence of precipitated withdrawal, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting VIVITROL treatment:
    • – An opioid-free interval of a minimum of 7–10 days is recommended for patients previously dependent on short-acting opioids.
      – Patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for as long as two weeks.
  • If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed.
  • Patients should be made aware of the risk associated with precipitated withdrawal and be encouraged to give an accurate account of last opioid use.

Hepatotoxicity:

  • Cases of hepatitis and clinically significant liver dysfunction have been observed in association with VIVITROL. Warn patients of the risk of hepatic injury; advise them to seek help if experiencing symptoms of acute hepatitis. Discontinue use of VIVITROL in patients who exhibit acute hepatitis symptoms.

Depression and Suicidality:

  • Alcohol- and opioid-dependent patients taking VIVITROL should be monitored for depression or suicidal thoughts. Alert families and caregivers to monitor and report the emergence of symptoms of depression or suicidality.

When Reversal of VIVITROL Blockade Is Required for Pain Management:

  • For VIVITROL patients in emergency situations, suggestions for pain management include regional analgesia or use of non-opioid analgesics. If opioid therapy is required to reverse the VIVITROL blockade, patients should be closely monitored by trained personnel in a setting staffed and equipped for CPR.

Eosinophilic Pneumonia:

  • Cases of eosinophilic pneumonia requiring hospitalization have been reported. Warn patients of the risk of eosinophilic pneumonia and to seek medical attention if they develop symptoms of pneumonia.

Hypersensitivity Reactions:

  • Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis.

Intramuscular Injections:

  • As with any intramuscular injection, VIVITROL should be administered with caution to patients with thrombocytopenia or any coagulation disorder.

Alcohol Withdrawal:

  • Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.

ADVERSE REACTIONS

  • The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence (ie, those occurring in ≥5% and at least twice as frequently with VIVITROL than placebo) include nausea, vomiting, injection site reactions (including induration, pruritus, nodules, and swelling), arthralgia, arthritis, or joint stiffness, muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, decreased appetite or other appetite disorders.
  • The adverse events seen most frequently in association with VIVITROL in opioid-dependent patients (ie, those occurring in ≥2% and at least twice as frequently with VIVITROL than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

You are encouraged to report side effects to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

See Prescribing Information and Medication Guide.