`
`
`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 _________________
`
`
`
`Dosage and Administration (2.5)
`09/2019
`
`
`
`
`Warnings and Precautions (5.2)
`09/2019
`
`
` _________________
`
`__________________ 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, 2.5).
`
`
`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 (IM) 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 not be administered intravenously or subcutaneously
`(2.1).
`
`See Full Prescribing Information for complete Directions for Use (2.5).
`
`
`
`
`
`•
`
`______________ 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,
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`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
`
`
`2.2 Reinitiation of Treatment in Patients Previously Discontinued
`
`
`
`2.3
`Switching From Oral Naltrexone
`
`
`2.4
`Switching from Buprenorphine, Buprenorphine/Naloxone, or
`
`
`Methadone
`
`
`2.5 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: 4605456
`
`after missing a dose, or after discontinuing VIVITROL treatment.
`
`
`
`Attempts to overcome blockade may also lead to fatal overdose (5.1).
`
`
`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).
`
`
`____________________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: 05/2020
`
`
`6
`
`
`
`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
`
`
`
`6.2
`Postmarketing Experience
`
`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
`
`
`
`7
`
`8
`
`
`
`
`13
`
`
`17
`
`
`
`
` 12
`
`
`
` CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14
`CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`16.1 Storage and Handling
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1 Frequently Asked Questions About Administering VIVITROL:
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`Reference ID: 4605456
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1
` INDICATIONS AND USAGE
`
`
` 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.
`
` Opioid Dependence
`
`
` 1.2
`
` 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.
`
` 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 (2.5)].
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
`
` 1
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
` 2.2
` 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)].
`
`
`
`
`
`
`
` 2.3
` Switching From Oral Naltrexone
` There are no systematically collected data that specifically address the switch from oral
`
` naltrexone to VIVITROL.
`
` 2.4
` 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
`
`
` 2.5
`
`
` VIVITROL must be prepared and administered by a healthcare provider.
` 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
`
` 2
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Parenteral products should be visually inspected for particulate matter and discoloration prior to
`
`administration.
`
`
`
`
`
`
`Reference ID: 4605456
`
`
`
` 3
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
`
`
`
` 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.
`
`
`
`
`
` 4
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
` 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.
`
`
`
`
`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
`
`
`
`
`
` 5
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`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)
`
`
`
` 6
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
` 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
`
`
`
`
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
` 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).
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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,
`
`
` carboxymethylcellulose, or any other components of the diluent [see Warnings and
`
` Precautions (5.8)].
`
`
`
`
`
`
` 5
`
`
` WARNINGS AND PRECAUTIONS
` 5.1
` Vulnerability to Opioid Overdose
`
`
`
`
` 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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`
`
`Reference ID: 4605456
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` 8
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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 must be prepared and administered by a healthcare provider.
`
` VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema,
`
` bruising, or pruritus; however, in some cases injection site reactions may be very severe. In the
`
`
` clinical trials, one patient developed an area of induration that continued to enlarge after
`
`
`
`
` 4 weeks, with subsequent development of necrotic tissue that required surgical excision. 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 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 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
`
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`
`Reference ID: 4605456
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`
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` 9
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`
` 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.
`
`
`
`
`
`
`
`
`Reference ID: 4605456
`
`
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` 10
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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 respi