` 1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` 2 These highlights do not include all the information needed to use VIVITROL®
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`3
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`safely and effectively. See full prescribing information for VIVITROL.
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`4
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`5 VIVITROL® (naltrexone for extended-release injectable suspension)
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`6
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`Intramuscular
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`7
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`Initial U.S. Approval: 1984
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`8
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`9 __________________RECENT MAJOR CHANGES _________________
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`10 Boxed Warning
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`Removed 7/2013
`11 Dosage and Administration,
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`12
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` 7/2013
`Switching from Buprenorphine and Methadone (2.3)
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` 13 Contraindications—Acute Hepatitis or Liver Failure
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` Removed 7/2013
`14 Warnings and Precautions
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`15
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`Vulnerability to Opioid Overdose (5.1)
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` 7/2013
`16
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`Injection Site Reaction (5.2)
` 7/2013
`17
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`Precipitation of Opioid Withdrawal (5.3)
` 7/2013
`18
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`Hepatotoxicity (5.4)
` 7/2013
`19
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`20 __________________ INDICATIONS AND USAGE
`_________________
`
`
` 21 •
`VIVITROL is indicated for the treatment of alcohol dependence in
`
`22
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`patients who are able to abstain from alcohol in an outpatient setting
`23
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`prior to initiation of treatment with VIVITROL. Patients should not be
`
` 24
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` actively drinking at the time of initial VIVITROL administration (1.1).
` 25 •
`
`VIVITROL is indicated for the prevention of relapse to opioid
`
`
` 26
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` dependence, following opioid detoxification (1.2).
`
` 27 •
` VIVITROL should be part of a comprehensive management program
`
`
`28
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` that includes psychosocial support (1).
`29
`
`
`______________
`_______________
`30
`
`DOSAGE AND ADMINISTRATION
`
`31 The recommended dose of VIVITROL is 380 mg delivered intramuscularly
`
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`32 every 4 weeks or once a month. The injection should be administered by a
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`33 healthcare provider as an intramuscular (IM) gluteal injection, alternating
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`34 buttocks for each subsequent injection, using the carton components provided
`
`35
`
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`(2 and 16.1).
`36
`
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`37 Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7–10
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`38 days is recommended for patients, to avoid precipitation of opioid withdrawal
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`39
`
`
`that may be severe enough to require hospitalization (5.3).
`40
`
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`41 VIVITROL must not be administered intravenously or subcutaneously.
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`42 The entire dose pack should be stored in the refrigerator (2-8°C, 36-46°F) (2.3
`
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`43 and 16.1).
`
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`44 Do not expose the product to temperatures above 25°C (77°F). VIVITROL
`
`45 should not be frozen (2.4).
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`46
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`_____________
`47 ______________ DOSAGE FORMS AND STRENGTHS
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`48 VIVITROL is an injectable suspension containing 380 mg of naltrexone in a
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`49 microsphere formulation and 4 mL diluent (3).
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`50 ____________________ CONTRAINDICATIONS ___________________
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`51
`
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`52 VIVITROL is contraindicated in:
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`
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` 53 •
`Patients receiving opioid analgesics (5.3).
`
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` 54 •
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` Patients with current physiologic opioid dependence (5.3).
`
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` 55 •
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`Patients in acute opioid withdrawal (5.3).
`
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` 56 •
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`Any individual who has failed the naloxone challenge test or has a
`
`
`57
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`positive urine screen for opioids (4).
`
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` 58 •
`Patients who have previously exhibited hypersensitivity to naltrexone,
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`
`
` 59
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` polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other
`
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`60
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` components of the diluent (4).
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`61
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`62 _______________ WARNINGS AND PRECAUTIONS _______________
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` 63 •
`Vulnerability to Opioid Overdose: Following VIVITROL treatment
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`64
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`opioid tolerance is reduced from pretreatment baseline, and patients are
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` 65
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` vulnerable to potentially fatal overdose at the end of a dosing interval,
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` 66
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` after missing a dose, or after discontinuing VIVITROL treatment.
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` 67
` Attempts to overcome blockade may also lead to fatal overdose (5.1).
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` 68 •
`
`Injection Site Reactions: In some cases, injection site reactions may be
`
`
` 69
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` very severe. Some cases of injection site reactions required surgical
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` 70
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`intervention (5.2).
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` 71 •
`Precipitation of Opioid Withdrawal: Opioid-dependent and opioid
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` 72
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` using patients, including those being treated for alcohol dependence,
`73
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`should be opioid-free before starting VIVITROL treatment, and should
`74
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`notify healthcare providers of any recent opioid use. An opioid-free
`
` 75
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` duration of a minimum of 7-10 days is recommended for patients to
`76
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`avoid precipitation of opioid withdrawal that may be severe enough to
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` 77
` require hospitalization. (5.3).
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` 78 • Hepatotoxicity: Cases of hepatitis and clinically significant liver
`
`
`
` 79
` dysfunction were observed in association with VIVITROL treatment
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`80
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`during the clinical development program and in the postmarketing
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` 81
` period. Discontinue use of VIVITROL in the event of symptoms or
`
`
` 82
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` signs of acute hepatitis (5.4).
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` 83 •
`Depression and Suicidality: Monitor patients for the development of
`
`
` 84
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` depression or suicidal thinking (5.5).
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` 85 • When Reversal of VIVITROL Blockade Is Required for Pain
`
`
` 86
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` Management: In an emergency situation in patients receiving
`
` 87
` VIVITROL, suggestions for pain management include regional
`
`
`88
` analgesia or use of non-opioid analgesics (5.6).
`
`89
`
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`____________________ADVERSE REACTIONS____________________
`90
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`91 The adverse events seen most frequently in association with VIVITROL
`
`
`92
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`therapy for alcohol dependence (i.e, those occurring in ≥5% and at least twice
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`93 as frequently with VIVITROL than placebo) include nausea, vomiting,
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`
`94
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`injection site reactions (including induration, pruritus, nodules and swelling),
`95 muscle cramps, dizziness or syncope, somnolence or sedation, anorexia,
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`96 decreased appetite or other appetite disorders (6).
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`
`97
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`98 The adverse events seen most frequently in association with VIVITROL
`
`
`99
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`therapy in opioid-dependent patients (i.e., those occurring in ≥2% of patients
`100
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`treated with VIVITROL and at least twice as frequently with VIVITROL than
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`101 placebo) were hepatic enzyme abnormalities, injection site pain,
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`102 nasopharyngitis, insomnia, and toothache (6).
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`103 To report SUSPECTED ADVERSE REACTIONS, contact Alkermes,
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`104
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`Inc. at 1-800-VIVITROL (1-800-848-4876) and/or email:
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`105 usmedinfo@alkermes.com or FDA at 1-800-FDA-1088
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` 106 or www.fda.gov/medwatch.
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`____________________DRUG INTERACTIONS____________________
`107
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`108 Naltrexone antagonizes the effects of opioid-containing medicines, such as
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`
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`109 cough and cold remedies, antidiarrheal preparations, and opioid analgesics (7).
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`110 _______________
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` USE IN SPECIFIC POPULATIONS _______________
`
`111
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` 112 •
`VIVITROL pharmacokinetics have not been evaluated in subjects with
`
`
` 113
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` severe hepatic impairment (8.7).
`
` 114 •
`Caution is recommended in administering VIVITROL to patients with
`
`
` 115
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` moderate to severe renal impairment (8.6).
`116
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`117 See 17 for PATIENT COUNSELING INFORMATION and FDA
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` 118 approved Medication Guide
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`119
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`Revised: July 2013
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`2
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Alcohol Dependence
`
`
`1.2 Opioid Dependence
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Reinitiation of Treatment in Patients Previously Discontinued
`
`2.2
`Switching From Oral Naltrexone
`
`
`2.3
`Switching from Buprenorphine, Buprenorphine/Naloxone, or
`
`Methadone
`
`
`2.4 Directions for Use
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Vulnerability to Opioid Overdose
`
`
`5.2
`Injection Site Reactions
`
`
`
`Precipitation of Opioid Withdrawal
`5.3
`
`
`5.4 Hepatotoxicity
`
`
`5.5 Depression and Suicidality
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`5.6 When Reversal of VIVITROL Blockade Is Required for Pain
`
`
`Management
`
`5.7 Eosinophilic Pneumonia
`
`
`
`5.8 Hypersensitivity Reactions Including Anaphylaxis
`
`5.9
` Intramuscular Injections
`
`
`5.10 Alcohol Withdrawal
`
`
`5.11
`Interference with Laboratory Tests
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`
`6.2
`Postmarketing Reports
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`6
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`7
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`8
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`Reference ID: 3348450
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`Pregnancy
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`8.1
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`8.2 Labor and Delivery
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`8.3 Nursing Mothers
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`8.4
`Pediatric Use
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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`10 OVERDOSAGE
`
`
`11
`DESCRIPTION
`
`
`12
`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`NONCLINICAL TOXICOLOGY
`13
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`
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`CLINICAL STUDIES
`14
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`16.1 Storage and Handling
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`
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`PATIENT COUNSELING INFORMATION
`17
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`17.1 Patient Information
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`
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`17.2 Frequently Asked Questions About Administering VIVITROL
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`*Sections or subsections omitted from the full prescribing information
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`are not listed.
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`Reference ID: 3348450
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`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`Treatment with VIVITROL should be part of a comprehensive management program that
`includes psychosocial support.
`
`
`Alcohol Dependence
`1.1
`VIVITROL is 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.
`Patients should not be actively drinking at the time of initial VIVITROL administration.
`
`Opioid Dependence
`1.2
`VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid
`detoxification.
`
`DOSAGE AND ADMINISTRATION
`2
`
`VIVITROL must be prepared and administered by a healthcare provider.
`Prior to initiating VIVITROL, an opioid-free duration of a minimum of 7–10 days is
`recommended for patients, to avoid precipitation of opioid withdrawal that may be severe
`enough to require hospitalization [see Warnings and Precautions (5.3)].
`
`The recommended dose of VIVITROL is 380 mg delivered intramuscularly every 4 weeks or
`once a month. The injection should be administered by a healthcare provider as an intramuscular
`(IM) gluteal injection, alternating buttocks for each subsequent injection, using the carton
`components provided [see How Supplied/Storage and Handling (16)]. The needles provided in
`the carton are customized needles. VIVITROL must not be injected using any other needle. The
`needle lengths (either 1.5 or 2 inches) may not be adequate in every patient because of body
`habitus. Body habitus should be assessed prior to each injection for each patient to assure that
`needle length is adequate for intramuscular administration. For patients with a larger amount of
`subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may
`utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate
`reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate
`to prevent the needle contacting the periosteum. Either needle may be used for patients with
`average body habitus. Healthcare providers should ensure that the VIVITROL injection is given
`correctly, and should consider alternate treatment for those patients whose body habitus
`precludes an intramuscular gluteal injection with one of the provided needles.
`VIVITROL must not be administered intravenously or subcutaneously.
`If a patient misses a dose, he/she should be instructed to receive the next dose as soon as
`possible.
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`Reference ID: 3348450
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`Pretreatment with oral naltrexone is not required before using VIVITROL.
`
`Reinitiation of Treatment in Patients Previously Discontinued
`2.1
`There are no data to specifically address reinitiation of treatment. Patients reinitiating treatment
`with VIVITROL should be opioid-free at the time of dose administration [see Indications and
`Usage (1), Contraindications (4), and Warnings and Precautions (5.3)].
`
`Switching From Oral Naltrexone
`2.2
`There are no systematically collected data that specifically address the switch from oral
`naltrexone to VIVITROL.
`
`2.3
`
` Switching from Buprenorphine, Buprenorphine/Naloxone, or
`Methadone
` There are no systematically collected data that specifically address the switch from
`
`buprenorphine or methadone to VIVITROL; however, review of postmarketing case reports have
`indicated that some patients may experience severe manifestations of precipitated withdrawal
`when being switched from opioid agonist therapy to opioid antagonist therapy [see Warnings
`and Precautions (5.3)]. Patients transitioning from buprenorphine or methadone may be
`
`vulnerable to precipitation of withdrawal symptoms for as long as 2 weeks. Healthcare providers
`should be prepared to manage withdrawal symptomatically with non-opioid medications.
`
`Directions for Use
`2.4
`To ensure proper dosing, it is important that you follow the preparation and administration
`instructions outlined in this document.
`VIVITROL must be suspended only in the diluent supplied in the carton and must be
`
`administered only with one of the administration needles supplied in the carton. The
`microspheres, diluent, preparation needle, and an administration needle with needle protection
`device are required for preparation and administration. Two thin-walled 1.5-inch needles with
`needle protection device and two 2-inch thin-walled needles with needle protection device have
`been provided to accommodate varying patient body habitus. For patients with a larger amount
`of subcutaneous tissue overlying the gluteal muscle, the administering healthcare provider may
`utilize the supplied 2-inch needle with needle protection device to help ensure that the injectate
`reaches the intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate
`to prevent the needle contacting the periosteum. Either needle may be used for patients with
`average body habitus. A spare administration needle of each size is provided in case of clogging
`[see How Supplied/Storage and Handling (16)]. Do not substitute any other components for the
`components of the carton.
`Prior to preparation, allow drug to reach room temperature (approximately 45 minutes).
`Parenteral products should be visually inspected for particulate matter and discoloration prior to
`administration whenever solution and container permit. A properly mixed suspension will be
`milky white, will not contain clumps, and will move freely down the wall of the vial [see
`Directions for Use, illustration below].
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`2
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`Reference ID: 3348450
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`Product to be prepared and administered by a healthcare provider.
`
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` Keep out of reach of children.
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`Prepare and administer the VIVITROL suspension using aseptic technique.
`
` WARNING: To reduce the risk of a needlestick:
`
`
`• Do not intentionally disengage the needle protection device.
`
`• Discard bent or damaged needle into a sharps container and use the spare needle
`
`provided. Do not attempt to straighten the needle or engage needle protection device
`if the needle is bent or damaged.
`• Do not mishandle the needle protection device in a way that could lead to protrusion
`
`of the needle.
`
`• Do not use free hand to press sheath over needle.
`
`THE CARTON SHOULD NOT BE EXPOSED TO TEMPERATURES EXCEEDING
`25 °C (77 °F).
`The entire carton should be stored in the refrigerator (2-8°C, 36-46°F). Unrefrigerated,
`VIVITROL microspheres can be stored at temperatures not exceeding 25°C (77°F) for no more
`than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above
`25°C (77°F). VIVITROL should not be frozen.
`
`
`
`Parenteral products should be
`visually inspected for particulate
`matter and discoloration prior to
`administration.
`
`
`
`
`
`
` NEEDLE-PRO® and the color orange applied to the needle protection device are trademarks
`
`
`
`
` of the Smiths Medical family of companies.
`
`
`
`
`
`1. Remove the carton from refrigeration. Prior to preparation,
`allow drug to reach room temperature (approximately 45
`minutes).
`2. To ease mixing, firmly tap the VIVITROL microspheres vial
`on a hard surface, ensuring the powder moves freely. (see Figure
`B)
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`Reference ID: 3348450
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` 3. Remove flip-off caps from both vials. DO NOT USE IF FLIP-OFF CAPS ARE BROKEN OR
`MISSING.
`
`4. Wipe the vial tops with an alcohol swab.
`5. Place the 1-inch preparation needle on the syringe and
`withdraw 3.4 mL of the diluent from the diluent vial. Some
`
` diluent will remain in the diluent vial. (see Figure B)
`
`
`
`
`
`
`
`Inject the 3.4 mL of diluent into the VIVITROL microsphere
`vial. (see Figure C)
`
`
`
`
`
`
`Mix the powder and diluent by vigorously shaking the vial
`for approximately 1 minute. (see Figure D)
`Ensure that the dose is thoroughly suspended prior to
`proceeding to Step E.
`A PROPERLY MIXED SUSPENSION WILL BE
`MILKY WHITE, WILL NOT CONTAIN CLUMPS,
`AND WILL MOVE FREELY DOWN THE WALLS O F
`
`THE VIAL.
`
`
`
`
`1. Immediately after suspension, withdraw 4.2 mL of the
`suspension into the syringe using the same preparation
`needle. (see Figure E)
`2. Select the appropriate needle for an intramuscular
`injection based on patient’s body habitus:
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`4
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`Reference ID: 3348450
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` a. 1.5-inch TERUMO® Needle
`b. 2-inch NEEDLE-PRO® Needle
`
`
`1. Remove the preparation needle and replace with
`appropriately selected administration needle for immediate use.
`2. Peel the blister pouch of the selected administration needle
`open halfway. Grasp sheath using the plastic pouch. Attach the
`
` luer connection to the syringe with an easy clockwise twisting
`motion. (see Figure F)
`3. Seat the needle firmly on the needle protection device with a
`push and clockwise twist.
`
`
`
`
`
`1. Pull the sheath away from the needle -do not twist the sheath
`
` because it could result in loosening the needle.
`2. Prior to injecting, tap the syringe to release any air bubbles,
`then push gently on the plunger until 4 mL of the suspension
`
`remains in the syringe. (see Figure G)
`
`THE SUSPENSION IS NOW READY FOR IMMEDIATE
`
`ADMINISTRATION.
`
`
`
`1. Using a circular motion, clean the injection site with the
`alcohol swab. Let the site dry before injecting. Do not touch
`the site again before giving injections.
`2. Administer the suspension by deep intramuscular (IM)
`injection into a gluteal muscle, alternating buttocks per
`monthly injection. Remember to aspirate for blood
`before injection. (see Figure H)
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`3. If blood aspirates or the needle clogs, do not inject.
`Change to the spare needle provided in the carton and
`administer into an adjacent site in the same gluteal region,
`again aspirating for blood before injection.
`4. Inject the suspension in a smooth and continuous motion.
`VIVITROL must NOT be given intravenously or
`subcutaneously.
`
`
`
`
`After the injection is administered, cover the needle by pressing
`the needle protection device against a flat surface using a one-
`handed motion away from self and others. (see Figure I)
`
`
`
`
`
`
`
`
`
`
`Visually confirm needle is fully engaged into the needle
`protection device. (see Figure J)
`
`DISPOSE OF USED AND UNUSED ITEMS IN PROPER
`WASTE CONTAINERS.
`
`
`
`6
`
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`VIVITROL is an injectable suspension for single use. VIVITROL contains 380 mg of
`naltrexone in a microsphere formulation per vial (337 mg of naltrexone per gram of
`microspheres) and 4 mL diluent.
`
`
`
` CONTRAINDICATIONS
`4.
`VIVITROL is contraindicated in:
`• Patients receiving opioid analgesics [see Warnings and Precautions (5.3)].
`
`• Patients with current physiologic opioid dependence [see Warnings and Precautions
`
`(5.3)].
`• Patients in acute opioid withdrawal [see Warnings and Precautions (5.3)].
`
`• Any individual who has failed the naloxone challenge test or has a positive urine
`
`screen for opioids [see Warnings and Precautions (5.3)].
`• Patients who have previously exhibited hypersensitivity to naltrexone, PLG,
`
`carboxymethylcellulose, or any other components of the diluent [see Warnings and
`Precautions (5.8)].
`
`
`5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`Vulnerability to Opioid Overdose
`5.1
`
`After opioid detoxification, patients are likely to have reduced tolerance to opioids. VIVITROL
`blocks the effects of exogenous opioids for approximately 28 days after administration.
`However, as the blockade wanes and eventually dissipates completely, patients who have been
`treated with VIVITROL may respond to lower doses of opioids than previously used, just as they
`would have shortly after completing detoxification. This could result in potentially life-
`
`threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the
`patient uses previously tolerated doses of opioids. 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 should be alerted that they may be more sensitive to opioids, even at lower doses, after
`VIVITROL treatment is discontinued, especially at the end of a dosing interval (i.e., near the end
`of the month that VIVITROL was administered), or after a dose of VIVITROL is missed. It is
`important that patients inform family members and the people closest to the patient of this
`increased sensitivity to opioids and the risk of overdose [see Patient Counseling Information
`
` (17)].
`There is also the possibility that a patient who is treated with VIVITROL could overcome the
`opioid blockade effect of VIVITROL. Although VIVITROL is a potent antagonist with a
`prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The
`
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`
`7
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`Reference ID: 3348450
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`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
`antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid
`intoxication or fatal overdose. Patients should be told of the serious consequences of trying to
`
` overcome the opioid blockade [see Patient Counseling Information (17)].
`
`Injection Site Reactions
`5.2
`
`
`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. In the
`postmarketing period, additional cases of injection site reaction with features including
`induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported.
`Some cases required surgical intervention, including debridement of necrotic tissue. Some cases
`resulted in significant scarring. The reported cases occurred primarily in female patients.
`VIVITROL is administered as an intramuscular gluteal injection, and inadvertent subcutaneous
`injection of VIVITROL may increase the likelihood of severe injection site reactions. The
`needles provided in the carton are customized needles. VIVITROL must not be injected using
`any other needle. The needle lengths (either 1.5 inches or 2 inches) may not be adequate in
`every patient because of body habitus. Body habitus should be assessed prior to each injection
`for each patient to assure that the proper needle is selected and that the needle length is adequate
`for intramuscular administration. For patients with a larger amount of subcutaneous tissue
`overlying the gluteal muscle, the administering healthcare provider may utilize the supplied 2
`inch needle with needle protection device to help ensure that the injectate reaches the
`intramuscular mass. For very lean patients, the 1.5-inch needle may be appropriate to prevent
`the needle contacting the periosteum. Either needle may be used for patients with average body
`habitus. Healthcare providers should ensure that the VIVITROL injection is given correctly, and
`should consider alternate treatment for those patients whose body habitus precludes an
`intramuscular gluteal injection with one of the provided needles.
`Patients should be informed that any concerning injection site reactions should be brought to the
`attention of the healthcare provider [see Patient Counseling Information (17)]. Patients
`
`exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be evaluated by a
`physician to determine if referral to a surgeon is warranted.
`
`Precipitation of Opioid Withdrawal
`5.3
`The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation
`of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be
`severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the
`administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal
`syndrome can be severe enough to require hospitalization. Review of postmarketing cases of
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`8
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`Reference ID: 3348450
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`precipitated opioid withdrawal in association with naltrexone treatment has identified cases with
`symptoms of withdrawal severe enough to require hospital admission, and in some cases,
`management in the intensive care unit.
`To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or
`exacerbation of a pre-existing subclinical withdrawal syndrome, 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 precipitation of withdrawal symptoms
`
`
` 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.
`In every case, healthcare providers should always 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. A naloxone challenge test
`may be helpful; however, a few case reports have indicated that patients may experience
`precipitated withdrawal despite having a negative urine toxicology screen or tolerating a
`naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment).
`Patients should be made aware of the risks associated with precipitated withdrawal and
`encouraged to give an accurate account of last opioid use. Patients treated for alcohol
`dependence with VIVITROL should also be assessed for underlying opioid dependence and for
`any recent use of opioids prior to initiation of treatment with VIVITROL. 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
`5.4
`Cases of hepatitis and clinically significant liver dysfunction were observed in association with
`VIVITROL exposure during the clinical development program and in the postmarketing period.
`Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials
`and postmarketing period. Although patients with clinically significant liver disease were not
`systematically studied, clinical trials did include patients with asymptomatic viral hepatitis
`infections. When patients presented with elevated transaminases, there were often other
` potential causative or contributory etiologies identified, including pre-existing alcoholic liver
`
`disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic
`drugs. Although clinically significant liver dysfunction is not typically recognized as a
`manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to
`systemic sequelae including acute liver injury.
`
`Patients should be warned of the risk of hepatic injury and advised to seek medical attention if
`they experience symptoms of acute hepatitis. Use of VIVITROL should be discontinued in the
`event of symptoms and/or signs of acute hepatitis.
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`9
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`Reference ID: 3348450
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`Depression and Suicidality
`5.5
`Alcohol- and opioid-dependent patients, including those taking VIVITROL, should be monitored
`for the development of depression or suicidal thinking. Families and caregivers of patients being
`treated with VIVITROL should be alerted to the need to monitor patients for the emergence of
`symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare
`provider.
` Alcohol Dependence
`
`In controlled clinical trials of VIVITROL administered to adults with alcohol dependence,
`adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were
`infrequent overall, but were more common in patients treated with VIVITROL than in patients
`treated with placebo (1% vs 0). In some cases, the suicidal thoughts or behavior occurred after
`study discontinuation, but were in the context of an episode of depression that began while the
`patient was on study drug. Two completed suicides occurred, both involving patients treated
`
` with VIVITROL.
`Depression-related events associated with premature discontinuation of study drug were also
`
`more common in patients treated with VIVITROL (~1%) than in placebo-treated patients (0).
`In the 24-week, placebo-controlled pivotal trial in 624 alcohol-dependent patients, adverse
`events involving depressed mood were reported by 10% of patients treated with VIVITROL 380
`mg, as compared to 5% of patients treated with placebo injections.
`
`Opioid Dependence
`In an open-label, long-term safety study conducted in the US, adverse events of a suicidal nature
`(depressed mood, suicidal ideation, suicide attempt) were reported by 5% of opioid-dependent
`patients treated with VIVITROL 380 mg (n=101) and 10% of opioid-dependent patients treated
`with oral naltrexone (n=20). In the 24-week, placebo-controlled pivotal trial that was conducted
`in Russia in 250 opioid-dependent patients, adverse events involving depressed mood or suicidal
`thinking were not reported by any patient in either treatment group (VIVITROL 380 mg or
`placebo).
`
`5.6
`
`When Reversal of VIVITROL Blockade Is Required for Pain
`Management
`In an emergency situation in patients receiving VIVITROL, suggestions for pain management
`include regional analgesia or use of non-opioid analgesics. If opioid therapy is required as part
`of anesthesia or analgesia, patients should be continuously monitored in an anesthesia care
`setting by persons not involved in the conduct of the surgical or diagnostic procedure. The
`opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs
`and the management of the respiratory effects of potent opioids, specifically the establishment
`and maintenance of a patent airway and assisted ventilation.
`Irrespective of the drug chosen to reverse VIVITROL blockade, the patient should be monitored
`closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary
`resuscitation.
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`Reference ID: 3348450
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` Eosinophilic Pneumonia
`5.7
`In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of
`eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with
`antibiotics and corticosteroids. Similar cases have been reported in postmarketing use. Should a
`person receiving VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of
`eosinophilic pneumonia should be considered [see Adverse Reactions (6)]. Patients should be
`warned of the risk