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VIVITROL® (naltrexone for extended-release injectable suspension) logo
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X:BOT: AN INVESTIGATIONAL
HEAD-TO-HEAD STUDY

X:bot study

Comparative effectiveness of extended-release naltrexone vs buprenorphine-naloxone for opioid relapse prevention1

X:BOT: A MULTICENTER, OPEN-LABEL, RANDOMIZED CONTROLLED TRIAL


x:bot study design1

A US-based, 24-week, multicenter, open-label, randomized clinical trial of opioid use disorder (DSM-5 criteria) outpatients aged ≥18 years

  • 772 participants were recruited and screened during voluntary, usual care, inpatient detoxification admissions
  • Participants had used non-prescribed opioids in the previous 30 days
  • 570 participants were randomized to receive either daily sublingual self-administered BUP-NX 8 to 24 mg/d (n=287), or XR-NTX 380 mg, prepared and administered by an HCP intramuscularly every fourth week (n=283)
    • XR-NTX treatment could be initiated and administered by an HCP after complete detoxification (≥3 days from last opioid use), opioid-negative urine drug test (UDT), and a negative naloxone challenge. Criteria were not met by 79 participants
    • BUP-NX treatment could be initiated once withdrawal symptoms emerged. Criteria were not met by 17 participants
  • Exclusion criteria included the presence of serious medical, psychiatric, or substance use disorders; liver function tests >5x the upper limit of normal; those who were suicidal or homicidal; had allergy or sensitivity to XR-NTX or BUP-NX; were not able to have safe intramuscular XR-NTX treatment; had methadone maintenance; had chronic pain requiring opioids; had a legal status precluding study completion; or women who were or could become pregnant or were breastfeeding

STUDY LIMITATIONS1

  • The study design, particularly the acute detoxification setting, flexible randomization, and varied induction protocols, limits interpretation and generalizability
  • Site differences in detoxification protocols and lengths of stay contributed to induction and relapse events, and showed substantial variability in standard opioid detoxification approaches. Ease of induction is a well-known limitation of XR-NTX
  • An open-label, real-world effectiveness study such as this includes more sources of bias than a tightly controlled efficacy study, including the absence of placebo control or masking

POPULATIONS:

  • The intention-to-treat (ITT) population included all randomized participants
  • The per-protocol population included only the participants who successfully began study medication
Chart describing study populations Chart describing study populations

Participants who were randomized but unable to initiate treatment were considered induction failures and excluded from the per-protocol population.

202 individuals were excluded because they dropped out of treatment, did not meet eligibility criteria, completed screening but were not eligible, or other reasons.1
*217 participants were randomized early, within 72 hours of last opioid use, including opioids used for detoxification. 353 participants were randomized late, or more than 72 hours after last opioid use. 353 participants were randomized late, or more than 72 hours after last opioid use. †Includes 1 participant with induction failure who nevertheless completed the study.

Demographics and baseline clinical characteristics1

itt population per-protocol
population
XR-NTX
(n=283)
BUP-NX
(n=287)
XR-NTX
(n=204)
BUP-NX
(n=270)
Age (years) 34.0 (9.5) 33.7 (9.8) 33.7 (9.3) 33.7 (9.8)
Male 195 (69%) 206 (72%) 138 (68%) 193 (71%)
White 206 (73%) 215 (75%) 157 (77%) 201 (74%)
Duration of opioid use (years) 12.8 (9.0) 12.2 (9.0) 12.9 (9.1) 12.3 (9.1)
Primary opioid used in the 7 days
before detoxification admission
Buprenorphine 6 (2%) 2 (1%) 4 (2%) 2 (1%)
Opioid analgesics 43 (15%) 47 (16%) 36 (18%) 45 (17%)
Methadone 3 (1%) 4 (1%) 3 (1%) 4 (1%)
Heroin 230 (81%) 233 (81%) 160 (78%) 218 (81%)
Data are mean (SD) or number (%).

PRIMARY Outcome measure1

  • Primary outcome measure was time to a relapse event
    • Relapse was defined as opioid use after Day 20 postrandomization: either 4 consecutive weeks with at least 1 day of non-study opioid use as measured by a weekly UDT or 7 consecutive days with self-reported opioid use

Primary endpoint: relapse rates1

The ITT population included all randomized participants. The per-protocol population included only the participants who successfully began study medication.

Opioid relapse rates, Weeks 3-24, ITT1

Opioid relapse, weeks 3-24 - intention to Treat was 65% for XR-NTX n=283 and 57% for BUP-NX n=287

Opioid relapse rates, Weeks 3-24, per protocol1

Opioid relapse, weeks 3-24 - Per-Protocol was 52% for XR-NTX n=204 and 56% for BUP-NX n=270
Relapse was defined as opioid use after Day 20 postrandomization, either 4 consecutive weeks with at least 1 day of non-study opioid use as measured by a weekly UDT or 7 consecutive days with self-reported opioid use.

SECONDARY ENDPOINT: OPIOID CRAVING SCORE IN PATIENTS ADMINISTERED XR-NTX VS BUP-NX OVER 24 WEEKS1

Graph opioid craving score over 24 weeks for both per-protocol BUP-NX (n=270) and XR-NTX (n=204)

Craving was self-reported with an opioid-craving VAS, range 0-100.

Adverse events1

Treatment-emergent adverse events XR-NTX 380 mg
(n=283)
BUP-NX
(n=287)
Participants with one or more treatment-emergent adverse event‡ 111 (54%) 141 (52%)
Number of treatment-emergent adverse events 247 334
Study medication discontinued due to adverse event 6 8
Type of treatment-emergent adverse event
Injection site reaction, mild or moderate 46 N/A
Gastrointestinal 34 59
Psychiatric disorders 30 29
Injury, poisoning, and procedural complications 23 25
Infections and infestations 22 27
Nervous system disorders 22 28
Overdose events
Participants with one or more overdose event (all) 15 8
Participants with one or more overdose event (per protocol) 9 7
Number of overdose events (all) 18 10
Number of overdose events (per protocol) 10 9
Fatal overdose events
Number of fatal overdose events (all) 2 3
Number of fatal overdose events (per protocol) 2 3
Data are n (%) or N. ‡Treatment-emergent is defined as any adverse events that occurred after induction day in those participants inducted onto study medication.
  • The proportion of participants reporting adverse events and serious adverse events did not differ between groups, with the exception of injection site reactions among the XR-NTX group that were of mild to moderate severity
    • 2 participants treated with XR-NTX and 3 participants treated with BUP-NX had fatal overdoses

Disclosure:

Funding: National Institute on Drug Abuse (NIDA) Clinical Trials Network.

XR-NTX was approved based on DSM-IV-TR criteria.

View the open-label, head-to-head study in the treatment of opioid dependence.

Download the x:bot Study

VIVITROL is not right for everyone. There are significant risks from VIVITROL treatment, including risk of opioid overdose, injection site reactions, and sudden opioid withdrawal. Strongly consider prescribing naloxone for the emergency treatment of opioid overdose. See Important Safety Information below. See Prescribing Information. Review Medication Guide with your patients.

  • What is vivitrol?
  • How does vivitrol work?
  • Alcohol Dependence Data
    • Pivotal Study
    • Post hoc analyses
  • Opioid Dependence Data
    • Pivotal Study
    • Extension study
    • Investigational
      head-to-head study: x:bot
    • Investigational
      head-to-head study: tanum
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CO-PAY SAVINGS PROGRAM

Learn how the VIVITROL® Co-pay Savings Program may assist eligible§ patients with out-of-pocket expenses for their VIVITROL prescriptions.

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Important safety information MORE

Important safety information

Important safety information

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

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.

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. Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver, at the initial VIVITROL injection and with each subsequent injection. Strongly consider prescribing naloxone for the emergency treatment of opioid 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.
  • In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision.
  • 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 opioid-dependent 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.
  • Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.

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:

  • Patients who develop dyspnea and hypoxemia should seek medical attention immediately. Consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics.

Hypersensitivity Reactions including Anaphylaxis:

  • Cases of urticaria, angioedema, and anaphylaxis have been observed with the use of VIVITROL.
  • Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis.
  • In the event of a hypersensitivity reaction, patients should be advised to seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis. The patient should not receive any further treatment with VIVITROL.

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.

Interference with Laboratory Tests:

  • VIVITROL may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine.
  • For further information, reference to the specific immunoassay instructions is recommended.

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.

Reference: 1. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318.

§Terms and Conditions

Eligibility for Alkermes-Sponsored Co-pay Savings. This offer is only available to patients 18 years or older, with a prescription consistent with the Prescribing Information and the patient is not enrolled in, or covered by, any local, state, federal or other government program that pays for any portion of medication costs, including but not limited to Medicare, including Medicare Part D or Medicare Advantage plans; Medicaid, including Medicaid Managed Care and Alternative Benefit Plans under the Affordable Care Act; Medigap; VA; DOD; TRICARE; or a residential correctional program.

Additional Terms of Use: This offer is not conditioned on any past, present, or future purchase, including refills. Alkermes reserves the right to rescind, revoke, or amend this offer, program eligibility, and requirements at any time without notice. This offer is limited to one per patient, may not be used with any other offer, is not transferable and may not be sold, purchased or traded, or offered for sale, purchase or trade. Void where prohibited by law. Program Administrator or its designee will have the right upon reasonable prior written notice, during normal business hours, and subject to applicable law, to audit compliance with this program.

As of December 8, 2015, VIVITROL® (naltrexone for extended-release injectable suspension) has new Prescribing Information (12/2015). The Dosage and Administration, Section 2.4 Directions for Use has been updated. When administering VIVITROL, please refer to Section 2.4 Directions for Use in the VIVITROL Prescribing Information that is provided in the carton you are administering.

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As of December 8, 2015, VIVITROL® (naltrexone for extended-release injectable suspension) has new Prescribing Information (12/2015). The Dosage and Administration, Section 2.4 Directions for Use has been updated. When administering VIVITROL, please refer to Section 2.4 Directions for Use in the VIVITROL Prescribing Information that is provided in the carton you are administering.

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During the evolving COVID-19 situation, we want to help patients with access to receiving their injection of VIVITROL® (naltrexone for extended-release injectable suspension). If your patients need access to alternate injection providers, please contact Vivitrol2gether℠ Patient Support Services at 1-800-VIVITROL (1-800-848-4876) for assistance in locating a healthcare provider who is providing injections or click on 'Find A Vivitrol Provider' on Vivitrol.com to get a listing of injection providers in your area. Vivitrol2gether can contact injection sites to confirm treatment availability.

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