`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Injection Site Reactions: VIVITROL must be prepared and administered
`
`
`by a healthcare provider. 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).
`
`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
`(5.7).
`
`Hypersensitivity Reactions Including Anaphylaxis: Cases of urticaria,
`angioedema, and anaphylaxis have been observed with the use of
`
`VIVITROL (5.8).
`
`____________________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 _______________
`
`
`Caution is recommended in administering VIVITROL to patients with
`
`moderate to severe renal impairment (8.6).
`
`VIVITROL pharmacokinetics have not been evaluated in subjects with
`severe hepatic impairment (8.7).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide
`
`
`Revised: 09/2022
`
`
`
`
` 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), for
`intramuscular use
`
`Initial U.S. Approval: 1984
`
`
`
` __________________RECENT MAJOR CHANGES _________________
`
`09/2022
`Dosage and Administration (2.1)
`
`09/2022
`Dosage and Administration (2.6)
`
`Warnings and Precautions (5.2)
`09/2022
`
`
` ___________________________________ INDICATIONS AND USAGE
`
`VIVITROL contains naltrexone, an opioid antagonist, and 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
`
`
`
`
`VIVITROL must be prepared and administered by a healthcare provider
`
`
`(2.1, 2.6).
`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 (2.1).
`The recommended dose of VIVITROL is 380 mg delivered
`intramuscularly (deep) as a gluteal injection, every 4 weeks or once a
`month, alternating buttocks for each subsequent injection, using the
`carton components provided (2.1).
`
`VIVITROL must ONLY be administered as a deep intramuscular gluteal
`
`injection (2.1).
`
`See Full Prescribing Information for complete Directions for Use (2.6).
`
`
`_____________
`______________ DOSAGE FORMS AND STRENGTHS
`VIVITROL is an injectable suspension containing 380 mg of naltrexone in a
`
`
`microsphere formulation in a single-dose vial (3).
`
` ____________________
`CONTRAINDICATIONS
`VIVITROL is contraindicated in:
`
`Patients receiving opioid analgesics (4).
`
`
`Patients with current physiologic opioid dependence (4).
`
`
`Patients in acute opioid withdrawal (4).
`
`
`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.
`
`Strongly consider prescribing naloxone for the emergency treatment of
`
`opioid overdose (5.1).
`
`
`
`
`
`
`
`
`
`
`
`
`
`___________________
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5053937
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`7
`
`8
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2 Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`DESCRIPTION
`11
`
`
`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 Frequently Asked Questions About Administering VIVITROL:
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Alcohol Dependence
`
`
`1.2 Opioid Dependence
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Important Dosage and Administration Information
`
`Patient Access to Naloxone for the Emergency Treatment of
`2.2
`
`Opioid Overdose
`
`
`2.3 Reinitiation of Treatment in Patients Previously Discontinued
`
`
`Switching From Oral Naltrexone
`2.4
`
`
`2.5
`Switching from Buprenorphine, Buprenorphine/Naloxone, or
`
`
`
`Methadone
`
`
`2.6 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
`
`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 Trials Experience
`
`
`
`Postmarketing Experience
`6.2
`
`
`6
`
`
`
`
`
`
`
`
`
`Reference ID: 5053937
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`Treatment with VIVITROL should be part of a comprehensive management program that
`includes psychosocial support.
`
`1.1
`Alcohol Dependence
`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.
`
`1.2
`Opioid Dependence
`VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid
`detoxification.
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`Important Dosage and Administration Information
`2.1
`
` VIVITROL must be prepared and administered by a healthcare provider.
`VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
`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 Dosage
`
`and Administration (2.6)].
`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 (deep) as a gluteal
`injection every 4 weeks or once a month, 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
`
`
`
`Reference ID: 5053937
`
`1
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`patients whose body habitus precludes an intramuscular gluteal injection with one of the
`provided needles.
`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.
`
`2.2
`Patient Access to Naloxone for the Emergency Treatment of Opioid
`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.
`Because patients being treated for opioid use disorder have the potential for relapse, putting them
`at risk for opioid overdose after VIVITROL treatment is discontinued, at the end of the
`VIVITROL dosing interval (i.e., near the end of the month that VIVITROL was administered),
`or after a dose of VIVITROL is missed, strongly consider prescribing naloxone for the
`emergency treatment of opioid overdose [see Warnings and Precautions (5.1)].
`Inform patients and caregivers of their options for obtaining naloxone as permitted by individual
`state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription,
`directly from a pharmacist, or as part of a community-based program) [see Patient Counseling
`
` Information (17)].
`
`2.3
`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)].
`
`2.4
`Switching From Oral Naltrexone
`There are no systematically collected data that specifically address the switch from oral
`naltrexone to VIVITROL.
`
`2.5
`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.
`
`2.6
`Directions for Use
` VIVITROL must be prepared and administered by a healthcare provider.
`
`VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
`
`
`
`Reference ID: 5053937
`
`2
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`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].
`
`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 °C to 8 °C, 36 °F to 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.
`
`
`
`Reference ID: 5053937
`
`3
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`Parenteral products should be visually inspected for particulate matter and discoloration prior
`to administration.
`
`
`
`
`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)
`
`
`
`
`
`
`
`Reference ID: 5053937
`
`4
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`Reference ID: 5053937
`
`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.
`
`
`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 a deep
`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.
`
`
`
`
`
`
`
`5
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`Reference ID: 5053937
`
`
`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 ONLY be administered as a deep
`
`intramuscular gluteal injection.
`
`6
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`Reference ID: 5053937
`
`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)
`
`Visually confirm needle is fully engaged into the needle
`protection device. (see Figure J)
`DISPOSE OF USED AND UNUSED ITEMS IN
`
`PROPER WASTE CONTAINERS.
`
`
`
`
`
`7
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`VIVITROL is an off-white to light tan powder for injectable suspension in a 5 mL single-dose
`vial.
`VIVITROL contains 380 mg of naltrexone in a microsphere formulation per vial (337 mg of
`naltrexone per gram of microspheres).
`
`
`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)].
`
`
`
`
` WARNINGS AND PRECAUTIONS
`5
`
`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
`
`
`
`Reference ID: 5053937
`
`8
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
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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)].
`
`Patient Access to Naloxone for the Emergency Treatment of Opioid 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.
`Because of the risks for opioid overdose described above, discuss with the patient and caregiver
`the importance of having access to naloxone for the emergency treatment of opioid overdose.
`Inform patients and caregivers of the options for obtaining naloxone as permitted by individual
`state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription,
`directly from a pharmacist, or as part of a community-based program). Strongly consider
`prescribing naloxone for the emergency treatment of opioid overdose.
`Educate patients and caregivers on how to recognize the signs and symptoms of an opioid
`overdose and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance
`of calling 911 or getting emergency medical help in all cases of known or suspected opioid
`
` overdose, even if naloxone is administered [see Patient Counseling Information (17)].
`
`5.2
`Injection Site Reactions
` VIVITROL must be prepared and administered by a healthcare provider.
`
`VIVITROL must ONLY be administered as a deep intramuscular gluteal injection.
`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 a deep 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 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 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
`the needle contacting the periosteum. Either needle may be used for patients with average body
`
`
`
`Reference ID: 5053937
`
`9
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`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.
`
`5.3
`Precipitation of Opioid Withdrawal
`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
`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.
`
`5.4
`Hepatotoxicity
`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.
`
`
`
`Reference ID: 5053937
`
`10
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`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
`