`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use VIVITROL®
`
`
`
`
`
`safely and effectively. See full prescribing information for VIVITROL.
`
`VIVITROL® (naltrexone for extended-release injectable suspension)
`
`
`
`Intramuscular
`
`Initial U.S. Approval: 1984
`
` _________________
` _________________
`RECENT MAJOR CHANGES
`
`Dosage and Administration,
`
`
`
`
`12/2015
`Directions for Use (2.4)
` __________________
` _________________
`INDICATIONS AND USAGE
`
`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 (1.1).
`
`
`
`VIVITROL is indicated for the prevention of relapse to opioid
`
`
`dependence, following opioid detoxification (1.2).
`
`VIVITROL should be part of a comprehensive management program
`
`
`
`that includes psychosocial support (1).
`
` ______________
`
`_______________DOSAGE AND ADMINISTRATION
`
`
`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
`
`
`(2 and 16.1).
`
`
`
`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 (5.3).
`
`
`
`
`VIVITROL must not be administered intravenously or subcutaneously.
`
`
`The entire dose pack should be stored in the refrigerator (2-8°C, 36-46°F) (2.3
`
`
`and 16.1).
`
`
`
`
`Do not expose the product to temperatures above 25°C (77°F). VIVITROL
`
`
`should not be frozen (2.4).
`
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`VIVITROL is an injectable suspension containing 380 mg of naltrexone in a
`
`
`
`
`microsphere formulation and 4 mL diluent (3).
` ___________________
` ___________________
`CONTRAINDICATIONS
`
`VIVITROL is contraindicated in:
`
`
`Patients receiving opioid analgesics (5.3).
`
`•
`
`
`Patients with current physiologic opioid dependence (5.3).
`
`•
`
`
`
`Patients in acute opioid withdrawal (5.3).
`
`•
`
`
`Any individual who has failed the naloxone challenge test or has a
`
`•
`
`positive urine screen for opioids (4).
`
`
`
`
`Patients who have previously exhibited hypersensitivity to naltrexone,
`
`polylactide-co-glycolide (PLG), carboxymethylcellulose, or any other
`
`components of the diluent (4).
`
`
`
`
`
`_______________ WARNINGS AND PRECAUTIONS_______________
`Vulnerability to Opioid Overdose: Following VIVITROL treatment
`
`
`•
`
`
`opioid tolerance is reduced from pretreatment baseline, and patients are
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`vulnerable to potentially fatal overdose at the end of a dosing interval,
`
`after missing a dose, or after discontinuing VIVITROL treatment.
`
`
`Attempts to overcome blockade may also lead to fatal overdose (5.1).
`Injection Site Reactions: In some cases, injection site reactions may be
`
`
`
`
`
`very severe. Some cases of injection site reactions required surgical
`
`intervention (5.2).
`Precipitation of Opioid Withdrawal: Opioid-dependent and opioid-
`
`
`
`
`using patients, including those being treated for alcohol dependence,
`
`
`
`
`should be opioid-free before starting VIVITROL treatment, and should
`notify healthcare providers of any recent opioid use. 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. (5.3).
`
`• Hepatotoxicity: Cases of hepatitis and clinically significant liver
`
`
`
`
`
`dysfunction were observed in association with VIVITROL treatment
`
`
`
`
`
`during the clinical development program and in the postmarketing
`
`
`
`
`period. Discontinue use of VIVITROL in the event of symptoms or
`
`
`signs of acute hepatitis (5.4).
`
`Depression and Suicidality: Monitor patients for the development of
`
`
`
`depression or suicidal thinking (5.5).
`
`
`
`
`• 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 (5.6).
`
`
`
`
`___________________ ADVERSE REACTIONS ___________________
`
`The adverse events seen most frequently in association with VIVITROL
`
`
`
`
`
`therapy for alcohol dependence (i.e, 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),
`
`
`
`muscle cramps, dizziness or syncope, somnolence or sedation, anorexia,
`
`
`decreased appetite or other appetite disorders (6).
`
`
`The adverse events seen most frequently in association with VIVITROL
`
`
`
`
`therapy in opioid-dependent patients (i.e., those occurring in ≥2% of patients
`
`
`
`
`treated with VIVITROL and at least twice as frequently with VIVITROL than
`
`placebo) were hepatic enzyme abnormalities, injection site pain,
`
`
`
`nasopharyngitis, insomnia, and toothache (6).
`
`To report SUSPECTED ADVERSE REACTIONS, contact Alkermes,
`
`
`Inc. at 1-800-VIVITROL (1-800-848-4876) and/or email:
`
`
`usmedinfo@alkermes.com or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`
`
`___________________ DRUG INTERACTIONS____________________
`
`Naltrexone antagonizes the effects of opioid-containing medicines, such as
`
`
`
`
`cough and cold remedies, antidiarrheal preparations, and opioid analgesics (7).
` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`
`
`VIVITROL pharmacokinetics have not been evaluated in subjects with
`•
`
`severe hepatic impairment (8.7).
`
`
`
`Caution is recommended in administering VIVITROL to patients with
`
`moderate to severe renal impairment (8.6).
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide
`
`
`
`Revised: 12/2015
`
`
`
`2
`
`
`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
`
`
`Switching From Oral Naltrexone
`2.2
`
`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
`
`
`
`5.3
`Precipitation of Opioid Withdrawal
`
`
`5.4 Hepatotoxicity
`
`
`5.5 Depression and Suicidality
`
`Reference ID: 3857120
`
`
`6
`
`
`7
`
`8
`
`
`5.6 When Reversal of VIVITROL Blockade Is Required for Pain
`
`Management
`
`
`5.7 Eosinophilic Pneumonia
`
`
`
`5.8 Hypersensitivity Reactions Including Anaphylaxis
`
`
`Intramuscular Injections
`5.9
`
`
`
`
`5.10 Alcohol Withdrawal
`
`
`5.11
`Interference with Laboratory Tests
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`
`
`Postmarketing Reports
`6.2
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`ALKERMES EXHIBIT 2003
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 39
`
`

`

`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 Storage and Handling
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`17.1 Patient Information
`
`
`17.2 Frequently Asked Questions About Administering VIVITROL
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`Reference ID: 3857120
`
`Page 2 of 39
`
`

`

`
`
`
`
`
`
` 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 1/2 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 1/2-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.
`
`Pretreatment with oral naltrexone is not required before using VIVITROL.
`
`
`
`
`
`
`
` 1
`
`
`Reference ID: 3857120
`
`Page 3 of 39
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`

`

`
`
`
`
` 2.1
`
`
`
` Reinitiation of Treatment in Patients Previously Discontinued
` 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 1/2-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 1/2-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].
`
`
`Product to be prepared and administered by a healthcare provider.
`
`
`
`
`
` 2
`
`Reference ID: 3857120
`
`Page 4 of 39
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`

`

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` Keep out of reach of children.
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
` 3
`
`
`Reference ID: 3857120
`
`Page 5 of 39
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`

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`
`
` 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)
`
`
`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 OF THE VIAL.
`
`
`
`
`
`
`
`
`Reference ID: 3857120
`
`
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` 4
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`Page 6 of 39
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`

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`
`
`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:
`a. 1 1/2-inch TERUMO® Needle
`
`
`
`
` b. 2-inch TERUMO® 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. Grip the base of the needle, not the safety sheath.
`
`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.
`
`
`
`
`
`
`
`
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`
`
`
`Reference ID: 3857120
`
`
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` 5
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`Page 7 of 39
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`Reference ID: 3857120
`
`
`
`
`1. Move the safety sheath away from the needle and toward the
` syringe barrel. 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)
`
`
`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.
`
`
`
`
`
`
`
` 6
`
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`Page 8 of 39
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`
`
`Reference ID: 3857120
`
`
`
` After the injection is administered, cover the needle by pressing
`
`
` the needle protection device against a flat surface using a one-
`
` handed technique to activate the safety mechanism away
`
`
`
`
` from self and others. (see Figure I)
`
`
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` 7
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`Page 9 of 39
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`
`
`
`
`
`
`
`
`
`
`
`
`Visually confirm needle is fully engaged into the needle protection
`
`
` device. (see Figure J)
`
`
`
`DISPOSE OF USED AND UNUSED ITEMS IN PROPER
`
`WASTE CONTAINERS.
`
` 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.
`
`
`
`
`
` 4.
`
` CONTRAINDICATIONS
` 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,
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` carboxymethylcellulose, or any other components of the diluent [see Warnings and
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` Precautions (5.8)].
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` 5
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` WARNINGS AND PRECAUTIONS
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` Vulnerability to Opioid Overdose
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`
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`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
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`
` have been reported in patients who used opioids at the end of a dosing interval, after missing a
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`
`
` scheduled dose, or after discontinuing treatment.
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`
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` 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
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`
`
`
`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)].
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`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
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`
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`prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The
`plasma concentration of exogenous opioids attained immediately following their acute
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`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
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`administering large amounts of exogenous opioids. Any attempt by a patient to overcome the
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`
`
`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)].
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`
`
` 5.2
`Injection Site Reactions
`
`
` VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema,
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` 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
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`postmarketing period, additional cases of injection site reaction with features including
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`induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported.
`
`Some cases required surgical intervention, including debridement of necrotic tissue. Some cases
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`
`resulted in significant scarring. The reported cases occurred primarily in female patients.
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`VIVITROL is administered as an intramuscular gluteal injection, and inadvertent subcutaneous
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`
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`injection of VIVITROL may increase the likelihood of severe injection site reactions. The
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`needles provided in the carton are customized needles. VIVITROL must not be injected using
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` any other needle. The needle lengths (either 1 1/2 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 1/2-inch needle may be appropriate to prevent
`
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`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
`
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`intramuscular gluteal injection with one of the provided needles.
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`
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`Patients should be informed that any concerning injection site reactions should be brought to the
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`
`
`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.
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`
`
` 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
`
`
`
`
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` 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
`
`
`
`
`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
`
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`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
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`encouraged to give an accurate account of last opioid use. Patients treated for alcohol
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` 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.
`
` 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.
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`Reference ID: 3857120
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`Page 13 of 39
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` 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 block