Patient Information

Evaluation of efficacy and safety in opioid dependence

A 24-week, multicenter, double-blind, placebo-controlled trial of opioid-dependent (DSM-IV) outpatients, ≥18 years of age.1,2

  • Participants were randomized to receive VIVITROL® (n=126) or placebo (n=124) via intramuscular injection every 4 weeks; a total of 6 injections over 24 weeks1,2
    • Participants also received psychosocial support every other week
    • Weekly urine drug testing for opioids
  • Subjects provided additional self-report of opioid use2
  • The primary endpoint was the response profile for confirmed abstinence during weeks 5-24. Weeks 1-4 were prospectively omitted2
  • Prior to treatment initiation, patients were voluntarily seeking treatment, completing ≤30 days of inpatient opioid detoxification and not taking opioids for at least 7 days1,2

Primary endpoint: more patients remained opioid-free1,2

  • Complete abstinence was sustained by 36% (n=45) of VIVITROL patients, compared with 23% (n=28) of patients treated with placebo, during weeks 5-24 (P=0.0024)1
  • The response profile indicated that patients treated with VIVITROL had a statistically significantly greater proportion of opioid-free weeks compared with those treated with placebo (P=0.0002)2
  • The median VIVITROL patient had confirmed abstinence for 90% of the weeks in the evaluation period vs 35% for the median placebo patient (P=0.0002)2

Subjects sustaining varying percentages of opioid-free weeks1

Median proportion of opioid-free weeks for weeks 5-242

Vulnerability to opioid overdose

  • Because VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration, patients are likely to have a reduced tolerance to opioids after opioid detoxification. As the blockade dissipates, 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
  • 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

Precipitation of opioid withdrawal

  • Withdrawal precipitated by administration of VIVITROL may be severe. Some cases of withdrawal symptoms have been severe enough to require hospitalization and management in the ICU
  • To prevent precipitated withdrawal, patients, including those being treated for alcohol dependence:
    • Should be opioid-free (including tramadol) for a minimum of 7-10 days before starting VIVITROL
    • Patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for as long as two weeks
  • Patients should be made aware of the risk associated with precipitated withdrawal and be encouraged to give an accurate account of last opioid use

Secondary endpoint: self-reported opioid-free days2

  • The proportion of self-reported opioid-free days over 24 weeks was greater in the VIVITROL group compared with placebo group (P=0.0004)2

Secondary endpoint: treatment retention2

  • VIVITROL helped significantly more patients complete treatment (24 weeks; n=67, 53%) compared with placebo (n=47, 38%, P=0.0171)2
  • The median time in treatment was >168 days* in VIVITROL patients (vs 96 days with placebo)2

Median days in treatment2

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

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

Secondary endpoint: relapse to physiological opioid dependence2

  • Significantly fewer VIVITROL patients had a positive naloxone challenge2
  • For patients remaining in the study, a positive naloxone challenge (administered following a positive urine test) confirmed that they had been using opioids to a sufficient degree that physical dependence had been re-established2

Reduced relapse to physical dependence with VIVITROL and counseling2

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 IM injection, VIVITROL should be administered with caution to patients with thrombocytopenia or any coagulation disorder

Secondary endpoint: craving2

  • A statistically and clinically significant reduction in opioid craving was observed with VIVITROL vs placebo by week 8 (P=0.0048), which persisted every week through to week 24 (baseline to week 24) (P<0.0001) 2
    • Craving was assessed with a weekly, self-report visual analog scale (VAS) of "need for opioids" (scale=0-100; 0=not at all; 100=very much so)2
      • The VAS is a widely used measure of continuous subjective variables
  • Patients given VIVITROL with psychosocial support had a 50% decrease in craving from baseline to week 242
    • At baseline, which was following an average of 18 days of detox, the overall mean score on the VAS was 202
  • VIVITROL patients had a mean decrease from baseline of 10.1 points over 6 months vs a mean increase of 0.7 points over 6 months for patients in the placebo group2

Depression and suicidality

  • Opioid- and alcohol-dependent individuals, including those taking VIVITROL, should be monitored for the symptoms of depression or suicidal thinking
  • Families and caregivers of VIVITROL patients should be alerted to the need to monitor patients for such symptoms and to report their occurrence to the patient's healthcare provider

In clinical studies of opioid-dependent patients:

  • Adverse events of a suicidal nature (depressed mood, suicidal ideation, suicide attempt) were reported by 5% of patients treated with VIVITROL 380 mg (n=101) and 10% of patients treated with oral naltrexone (n=20) in an open-label, long-term safety study conducted in the United States
  • Adverse events involving depressed mood or suicidal thinking were not reported by any patient in either treatment group (VIVITROL or placebo) in the 24-week pivotal opioid dependence trial conducted in Russia



References:
1. VIVITROL [prescribing information]. Waltham, MA: Alkermes, Inc; rev Dec 2015.
2. Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506-1513.

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. 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/PRECAUTIONS

Vulnerability to Opioid Overdose: Because VIVITROL blocks the effects of exogenous opioids for approximately 28 days after administration, patients are likely to have a reduced tolerance to opioids after opioid detoxification. As the blockade dissipates, 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.

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 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: Withdrawal precipitated by administration of VIVITROL may be severe. Some cases of withdrawal symptoms have been severe enough to require hospitalization and management in the ICU. To prevent precipitated withdrawal, patients, including those being treated for alcohol dependence:

  • Should be opioid-free (including tramadol) for a minimum of 7–10 days before starting VIVITROL.
  • Patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for as long as two weeks.

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

ADVERSE REACTIONS

Serious adverse reactions that may be associated with VIVITROL therapy in clinical use include severe injection site reactions, eosinophilic pneumonia, serious allergic reactions, unintended precipitation of opioid withdrawal, accidental opioid overdose, and depression and suicidality. The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence include nausea, vomiting, injection site reactions (including induration, pruritus, nodules, and swelling), 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 also include hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

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

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.