These highlights do not include all the information needed to use VIVITROL safely and effectively. See full prescribing information for VIVITROL.VIVITROL (naltrexone for extended-release injectable suspension) Intramuscular Initial U.S. Approval: 1984

WARNING: Hepatotoxicity

Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses.

Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.

The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less. VIVITROL does not appear to be a hepatotoxin at the recommended doses.

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 [see Warnings and Precautions (5.1)]

Treatment with VIVITROL should be part of a comprehensive management program that includes psychosocial support. Opioid-dependent patients, including those being treated for alcohol dependence, must be opioid-free at the time of initial VIVITROL administration.

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.

VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification.

VIVITROL must be prepared and administered by a healthcare professional.

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 professional as an intramuscular (IM) gluteal injection, alternating buttocks for each subsequent injection, using the carton components provided [see How Supplied/Storage and Handling (16)]. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1.5 or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that needle length is adequate for intramuscular administration. Healthcare professionals should ensure that the VIVITROL injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the provided needles.

VIVITROL must not be administered intravenously or subcutaneously.

If a patient misses a dose, he/she should be instructed to receive the next dose as soon as possible.

Pretreatment with oral naltrexone is not required before using VIVITROL.

There are no data to specifically address reinitiation of treatment. Patients reinitiating treatment with VIVITROL need to be opioid-free at the time of dose administration [see Indications and Usage (1), Contraindications (4), and Warnings and Precautions (5.5)].

There are no systematically collected data that specifically address the switch from oral naltrexone to VIVITROL.

To ensure proper dosing, it is important that you follow the preparation and administration instructions outlined in this document.

VIVITROL must be suspended only in the diluent supplied in the carton and must be administered only with one of the administration needles supplied in the carton. The microspheres, diluent, preparation needle, and an administration needle with needle protection device are required for preparation and administration. Two thin-walled 1.5 inch needles with needle protection device are provided in the clinical drug cartons for intramuscular administration. In addition, longer 2 inch thin-walled needles with needle protection device have been provided as ancillary supplies. For patients with a larger amount of subcutaneous tissue overlying the gluteal muscle, the administering health care professional may utilize the supplied 2 inch needle with needle protection device to ensure that the injectate reaches the intramuscular mass. Both 1.5 and 2 inch administration needles are provided to accommodate varying patient body habitus. A spare administration needle of each size is provided in case of clogging [see How Supplied/Storage and Handling (16)]. Do not substitute any other components for the components of the carton.

Prior to preparation, allow drug to reach room temperature (approximately 45 minutes).

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. A properly mixed suspension will be milky white, will not contain clumps, and will move freely down the wall of the vial [see Directions for Use, illustration below].

Product to be prepared and administered by a healthcare professional.

Keep out of reach of children.

Prepare and administer the VIVITROL suspension using aseptic technique.

WARNING: To reduce the risk of a needlestick:

THE CARTON SHOULD NOT BE EXPOSED TO TEMPERATURES EXCEEDING 25 °C (77 °F).

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

Parenteral products should be visually inspected for particulate matter and discoloration prior to administration.

NEEDLE-PRO and the color orange applied to the needle protection device are trademarks of the Smiths Medical family of companies.

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.

THE SUSPENSION IS NOW READY FOR IMMEDIATE ADMINISTRATION.

VIVITROL must NOT be given intravenously or subcutaneously.

After the injection is administered, cover the needle by pressing the needle protection device against a flat surface using a one-handed motion away from self and others. (see Figure I)

Visually confirm needle is fully engaged into the needle protection device. (See Figure J)

DISPOSE OF USED AND UNUSED ITEMS IN PROPER WASTE CONTAINERS.

VIVITROL is an injectable suspension for single use. VIVITROL contains 380 mg of naltrexone in a microsphere formulation per vial (337 mg of naltrexone per gram of microspheres) and 4 mL diluent.

VIVITROL is contraindicated in:

Naltrexone has the capacity to cause hepatocellular injury when given in excessive doses. Naltrexone is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects.

The margin of separation between the apparently safe dose of naltrexone and the dose causing hepatic injury appears to be only five-fold or less. VIVITROL does not appear to be a hepatotoxin at the recommended doses.

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.

VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema, bruising, or pruritus; however, in some cases injection site reactions may be very severe. In the clinical trials, one patient developed an area of induration that continued to enlarge after 4 weeks, with subsequent development of necrotic tissue that required surgical excision. In the postmarketing period, additional cases of injection site reaction with features including induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported. Some cases required surgical intervention, including debridement of necrotic tissue. Some cases resulted in significant scarring. The reported cases occurred primarily in female patients.

VIVITROL is administered as an intramuscular gluteal injection, and inadvertent subcutaneous injection of VIVITROL may increase the likelihood of severe injection site reactions. The needles provided in the carton are customized needles. VIVITROL must not be injected using any other needle. The needle lengths (either 1.5 inches or 2 inches) may not be adequate in every patient because of body habitus. Body habitus should be assessed prior to each injection for each patient to assure that the proper needle is selected and that the needle length is adequate for intramuscular administration. Healthcare professionals 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 professional [see Patient Counseling Information (17)]. Patients exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be eva luated by a physician to determine if referral to a surgeon is warranted.

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.

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.

To prevent occurrence of an acute abstinence syndrome (withdrawal) in patients dependent on opioids, or exacerbation of a pre-existing subclinical abstinence syndrome, opioid-dependent patients, including those being treated for alcohol dependence, must be opioid-free for a minimum of 7–10 days before starting VIVITROL treatment. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge test should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of VIVITROL. Patients treated for alcohol dependence with VIVITROL should 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 dependence on opioids.

After opioid detoxification, patients are likely to have reduced tolerance to opioids. Although VIVITROL blocks the effects of exogenous opioids for 28 days after administration, cases of opioid overdose with fatal outcomes have been reported in patients who used opioids at the end of a dosing interval or when missing a dose. Patients who have been treated with VIVITROL may respond to lower doses of opioids than previously used. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.). Patients should be aware that they may be more sensitive to lower doses of opioids after VIVITROL treatment is discontinued. Reduced tolerance is especially of concern at the end of a dosing interval, that is, near the end of the month after 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. 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 very dangerous and may lead to fatal overdose. Injury may arise because the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. As a consequence, the patient may be in immediate danger of suffering life-endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse). Patients should be told of the serious consequences of trying to overcome the opioid blockade [see Patient Counseling Information (17)].

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 professional.

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 which 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).

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).

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.

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

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.

Serious adverse reactions that may be associated with VIVITROL therapy in clinical use include: severe injection site reactions, eosinophilic pneumonia, serious allergic reactions, unintended precipitation of opioid withdrawal, accidental opioid overdose and depression and suicidality.

The adverse events seen most frequently in association with VIVITROL therapy for alcohol dependence (ie, 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.

The adverse events seen most frequently in association with VIVITROL therapy in opioid-dependent patients (ie, those occurring in ≥2% and at least twice as frequently with VIVITROL than placebo) were hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.

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.

Adverse Events Leading to Discontinuation of Treatment

Alcohol Dependence

In controlled trials of 6 months or less in alcohol-dependent patients, 9% of alcohol-dependent patients treated with VIVITROL discontinued treatment due to an adverse event, as compared to 7% of the alcohol-dependent patients treated with placebo. Adverse events in the VIVITROL 380 mg group that led to more dropouts than in the placebo-treated group were injection site reactions (3%), nausea (2%), pregnancy (1%), headache (1%), and suicide-related events (0.3%). In the placebo group, 1% of patients withdrew due to injection site reactions, and 0% of patients withdrew due to the other adverse events.

Opioid Dependence

In a controlled trial of 6 months, 2% of opioid-dependent patients treated with VIVITROL discontinued treatment due to an adverse event, as compared to 2% of the opioid-dependent patients treated with placebo.

Common Adverse Reactions

Alcohol Dependence

Table 1 lists all treatment-emergent clinical adverse reactions, regardless of causality, occurring in ≥5% of patients with alcohol dependence, for which the incidence was greater in the combined VIVITROL group than in the placebo group. A majority of patients treated with VIVITROL in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Opioid Dependence

In the open-label, long-term safety study conducted in the US, the commonly-reported adverse reactions among the opioid-dependent patients in the study were similar to those commonly observed events in the alcohol-dependent populations in VIVITROL clinical trials as displayed in Table 1, above. For example, injection site reactions of all types, nausea and diarrhea occurred in more than 5% of patients on VIVITROL in the open-label study. In contrast, 48% percent, of the opioid-dependent patients had at least one adverse event in the “Infections and Infestations” Body System. Adverse Reactions/Preferred Terms of nasopharyngitis, upper respiratory tract infection, urinary tract infection, and sinusitis were most commonly reported.

In the placebo-controlled study in opioid-dependent patients conducted in Russia, the overall frequency of adverse events was lower than in the U.S. population described above. Table 2 lists treatment-emergent clinical adverse events, regardless of causality, occurring in ≥2% of patients with opioid dependence, for which the incidence was greater in the VIVITROL group than in the placebo group. All adverse events were assessed as having a maximum intensity of “mild” or “moderate”.