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.

2.1 Important Dosage and Administration Information

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 (2.6)].

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 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.

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.

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.

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration.
	Remove the carton from refrigeration. Prior to preparation, allow drug to reach room temperature (approximately 45 minutes). To ease mixing, firmly tap the VIVITROL microspheres vial on a hard surface, ensuring the powder moves freely. (see Figure B) Remove flip-off caps from both vials. DO NOT USE IF FLIP-OFF CAPS ARE BROKEN OR MISSING. Wipe the vial tops with an alcohol swab. 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.
	Immediately after suspension, withdraw 4.2 mL of the suspension into the syringe using the same preparation needle. (see Figure E) Select the appropriate needle for an intramuscular injection based on patient's body habitus: 1 1/2-inch TERUMO® Needle 2-inch TERUMO® Needle
	Remove the preparation needle and replace with appropriately selected administration needle for immediate use. 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) Seat the needle firmly on the needle protection device with a push and clockwise twist.
	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. 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
	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. 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) 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. 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)
	Visually confirm needle is fully engaged into the needle protection device. (see Figure J) DISPOSE OF USED AND UNUSED ITEMS IN PROPER WASTE CONTAINERS.

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 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)].

5.2 Injection Site Reactions

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 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. 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.

5.5 Depression and Suicidality

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.

5.6 When Reversal of VIVITROL Blockade Is Required for Pain Management

In an emergency situation in patients receiving VIVITROL, suggestions for pain management include regional analgesia or use of non-opioid analgesics. If opioid therapy is required as part of anesthesia or analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

Irrespective of the drug chosen to reverse VIVITROL blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.

5.7 Eosinophilic Pneumonia

In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with antibiotics and corticosteroids. Similar cases have been reported in postmarketing use. Should a person receiving VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of eosinophilic pneumonia should be considered [see Adverse Reactions (6)]. Patients should be warned of the risk of eosinophilic pneumonia, and advised to seek medical attention should they develop symptoms of pneumonia. Clinicians should consider the possibility of eosinophilic pneumonia in patients who do not respond to antibiotics.

5.8 Hypersensitivity Reactions Including Anaphylaxis

Cases of urticaria, angioedema, and anaphylaxis have been observed with use of VIVITROL in the clinical trial setting and in postmarketing use. Patients should be warned of the risk of hypersensitivity reactions, including anaphylaxis. In the event of a hypersensitivity reaction, patients should be advised to seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis. The patient should not receive any further treatment with VIVITROL.

5.9 Intramuscular Injections

As with any intramuscular injection, VIVITROL should be administered with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia and severe hepatic failure).

5.10 Alcohol Withdrawal

Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.

5.11 Interference with Laboratory Tests

VIVITROL may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine. For further information, reference to the specific immunoassay instructions is recommended.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In all controlled and uncontrolled trials during the premarketing development of VIVITROL, more than 1100 patients with alcohol and/or opioid dependence have been treated with VIVITROL. Approximately 700 patients have been treated for 6 months or more, and more than 400 for 1 year or longer.

6.2 Postmarketing Experience

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of VIVITROL have not been established in the pediatric population. The pharmacokinetics of VIVITROL have not been evaluated in a pediatric population.

8.5 Geriatric Use

In trials of alcohol-dependent subjects, 2.6% (n=26) of subjects were >65 years of age, and one patient was >75 years of age. Clinical studies of VIVITROL did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. No subjects over age 65 were included in studies of opioid-dependent subjects. The pharmacokinetics of VIVITROL have not been evaluated in the geriatric population.

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

8.6 Renal Impairment

Pharmacokinetics of VIVITROL are not altered in subjects with mild renal insufficiency (creatinine clearance of 50-80 mL/min). Dose adjustment is not required in patients with mild renal impairment. VIVITROL pharmacokinetics have not been evaluated in subjects with moderate and severe renal insufficiency. Because naltrexone and its primary metabolite are excreted primarily in the urine, caution is recommended in administering VIVITROL to patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The pharmacokinetics of VIVITROL are not altered in subjects with mild to moderate hepatic impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required in subjects with mild or moderate hepatic impairment. VIVITROL pharmacokinetics were not evaluated in subjects with severe hepatic impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Naltrexone is an opioid antagonist with highest affinity for the mu opioid receptor. Naltrexone has little or no opioid agonist activity.

12.2 Pharmacodynamics

Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.

The administration of VIVITROL is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, VIVITROL will precipitate withdrawal symptomatology.

Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. It markedly attenuates or completely blocks, reversibly, the subjective effects of exogenous opioids. The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood. However, involvement of the endogenous opioid system is suggested by preclinical data.

Naltrexone blocks the effects of opioids by competitive binding at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor-mediated symptoms such as histamine release.

VIVITROL is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opioid use or ethanol ingestion.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies have not been conducted with VIVITROL.

Carcinogenicity studies of oral naltrexone hydrochloride (administered via the diet) have been conducted in rats and mice.

In a two-year carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of testicular mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (3-times the human exposure based on an AUC(0-28d) comparison) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day was 4% but only the incidence in females was increased compared with a maximum historical control incidence of 2% (3 and 32 times the human exposure based on an AUC(0-28d) comparison in males and females, respectively). There was no evidence of carcinogenicity in a 2-year dietary study with naltrexone in male and female mice (12 and 3 times the human exposure based on an AUC(0-28d) comparison, respectively). The clinical significance of these findings is not known.

Mutagenesis: Naltrexone was negative in the following in vitro genotoxicity studies: bacterial reverse mutation assay (Ames test), the heritable translocation assay, CHO cell sister chromatid exchange assay, and the mouse lymphoma gene mutation assay. Naltrexone was also negative in an in vivo mouse micronucleus assay. In contrast, naltrexone tested positive in the following assays: Drosophila recessive lethal frequency assay, non-specific DNA damage in repair tests with E. coli and WI-38 cells, and urinalysis for methylated histidine residues.

Impairment of Fertility: Daily oral administration of naltrexone caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (75 times the human exposure based on an AUC(0-28d) comparison). There was no effect on male fertility at this dose level (6 times the human exposure based on an AUC(0-28d) comparison). The relevance of these observations to human fertility is not known.

Alcohol Dependence

The efficacy of VIVITROL in the treatment of alcohol dependence was evaluated in a 24-week, placebo-controlled, multi-center, double-blind, randomized trial of alcohol-dependent (DSM-IV criteria) outpatients. Subjects were treated with an injection every 4 weeks of VIVITROL 190 mg, VIVITROL 380 mg or placebo. Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. Psychosocial support was provided to all subjects in addition to medication.

Subjects treated with VIVITROL 380 mg demonstrated a greater reduction in days of heavy drinking than those treated with placebo. Heavy drinking was defined as self-report of 5 or more standard drinks consumed on a given day for male patients and 4 or more drinks for female patients. Among the subset of patients (n=53, 8% of the total study population) who abstained completely from drinking during the week prior to the first dose of medication, compared with placebo-treated patients, those treated with VIVITROL 380 mg had greater reductions in the number of drinking days and the number of heavy drinking days. In this subset, patients treated with VIVITROL were also more likely than placebo-treated patients to maintain complete abstinence throughout treatment. The same treatment effects were not evident among the subset of patients (n=571, 92% of the total study population) who were actively drinking at the time of treatment initiation.

Opioid Dependence

The efficacy of VIVITROL in the treatment of opioid dependence was evaluated in a 24-week, placebo-controlled, multi-center, double-blind, randomized trial of opioid-dependent (DSM-IV) outpatients, who were completing or had recently completed detoxification. Subjects were treated with an injection every 4 weeks of VIVITROL 380 mg or placebo. Oral naltrexone was not administered prior to the initial or subsequent injections of study medication. Standardized, manual-based psychosocial support was provided on a biweekly basis to all subjects in addition to medication.

Figure 1, below, displays the cumulative percentage of subjects with opioid-free weeks ranging from no visits (0%) to all visits (100%). An opioid-free week was one in which urine drug test results were negative for opioids and self-reported opioid use was also zero. An initial period of engagement in treatment was permitted during which opiate use, if it occurred, was not considered in the analysis. Subjects discontinuing from the trial were assumed to have had opioid-use weeks for the weeks after dropout.

The cumulative percentage of subjects achieving each observed percentage of opioid-free weeks was greater in the VIVITROL group compared to the placebo group. Complete abstinence (opioid-free at all weekly visits) was sustained by 23% of subjects in the placebo group compared with 36% of subjects in the VIVITROL group from Week 5 to Week 24.

Figure 1: Subjects Sustaining Varying Percentages of Opioid-Free Weeks

A greater percentage of subjects in the VIVITROL group remained in the study compared to the placebo group.

16.1 Storage and Handling

The entire dose pack should be stored in the refrigerator (2 °C to 8 °C, 36 °F to 46 °F). Unrefrigerated, VIVITROL can be stored at temperatures not exceeding 25 °C (77 °F) for no more than 7 days prior to administration. Do not expose the product to temperatures above 25 °C (77 °F). VIVITROL should not be frozen.

Keep out of Reach of Children.

17.1 Frequently Asked Questions About Administering VIVITROL:

1. Can I prepare the suspension prior to my patient's arrival?
   No. You may remove the carton from the refrigerator prior to the patient's arrival, but once the diluent is added to the VIVITROL microspheres, the dose should be mixed and the suspension administered immediately. It is very important to use proper aseptic technique when preparing the suspension [see Dosage and Administration (2.6)].
2. How much time do I have between preparing and administering the dose?
   It is recommended that the suspension be administered immediately once the product has been suspended and transferred into the syringe. If a few minutes' delay occurs after suspension but before transfer into the syringe [see Dosage and Administration (2.6; Figure D)], the vial can be inverted a few times to resuspend and then transferred into the syringe for immediate use [see Dosage and Administration (2.6)].
3. Can I use needles other than those provided in the carton?
   No. The needles in the carton are specially designed for administration of VIVITROL. Do not make any substitutions for components of the carton [see Dosage and Administration (2.6)].
4. The suspension is milky white upon mixing with the diluent. Is this normal?
   Yes. VIVITROL microspheres will form a milky suspension when mixed with the provided diluent [see Dosage and Administration (2.6)].
5. What if a needle clog occurs during administration of the product?
   If a clog occurs during administration, the needle should be withdrawn from the patient, capped with the attached needle protection device, and replaced with the spare administration needle. Gently push on the plunger until a bead of the suspension appears at the tip of the needle. The remainder of the suspension should then be administered into an adjacent site in the same gluteal region [see Dosage and Administration (2.6)].

For additional information, visit www.vivitrol.com or call 1-800-848-4876

Manufactured and marketed by:
Alkermes, Inc.
852 Winter Street
Waltham, MA 02451-1420

©2021 Alkermes. All rights reserved.
ALKERMES® and VIVITROL® are registered trademarks of Alkermes, Inc.
Printed in U.S.A.
REV: March 2021

US Patent No. 7,919,499