PACKAGE INSERT
`
`DESCRIPTION:
`
`VIVITROL™ (naltrexone for extended-release injectable suspension) is supplied as a
`microsphere formulation of naltrexone for suspension, to be administered by
`intramuscular injection. Naltrexone is an opioid antagonist with little, if any, opioid
`agonist activity.
`
`Naltrexone is designated chemically as morphinan-6-one, 17-(cyclopropylmethyl)-4,5-
`epoxy-3,14-dihydroxy-(5α) (CAS Registry # 16590-41-3). The molecular formula is
`C20H23NO4 and its molecular weight is 341.41 in the anhydrous form (i.e., < 1%
`maximum water content). The structural formula is:
`
`N
`
`CH2
`
`OH
`
`HO
`
`O
`
`O
`
`
`
`Naltrexone base anhydrous is an off-white to a light tan powder with a melting point of
`168-170º C (334-338º F). It is insoluble in water and is soluble in ethanol.
`
`VIVITROL is provided as a kit containing a vial each of VIVITROL microspheres and
`diluent, one 5-mL syringe, one ½-inch 20-gauge preparation needle, and two 1½-inch
`20-gauge administration needles with safety device.
`
`VIVITROL microspheres consist of a sterile, off-white to light-tan powder that is
`available in a dosage strength of 380-mg naltrexone per vial. Naltrexone is
`incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of
`naltrexone per gram of microspheres.
`
`
`
`
`
`Page 1
`
`

`

`The diluent is a clear, colorless solution. The composition of the diluent includes
`carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for
`injection. The microspheres must be suspended in the diluent prior to injection.
`
`CLINICAL PHARMACOLOGY:
`
`Pharmacodynamics
`
`Mechanism of Action
`
`Naltrexone is an opioid antagonist with highest affinity for the mμ opioid receptor.
`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. 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 opiate use or ethanol ingestion.
`
`Pharmacokinetics
`
`
`
`
`
`Page 2
`
`

`

`Absorption
`
`VIVITROL is an extended-release, microsphere formulation of naltrexone designed to
`be administered by intramuscular (IM) gluteal injection every 4 weeks or once a
`month. After IM injection, the naltrexone plasma concentration time profile is
`characterized by a transient initial peak, which occurs approximately 2 hours after
`injection, followed by a second peak observed approximately 2 - 3 days later.
`Beginning approximately 14 days after dosing, concentrations slowly decline, with
`measurable levels for greater than 1 month.
`
`Maximum plasma concentration (Cmax) and area under the curve (AUC) for naltrexone
`and 6β-naltrexol (the major metabolite) following VIVITROL administration are dose
`proportional. Compared to daily oral dosing with naltrexone 50 mg over 28 days, total
`naltrexone exposure is 3 to 4-fold higher following administration of a single dose of
`VIVITROL 380 mg. Steady state is reached at the end of the dosing interval following
`the first injection. There is minimal accumulation (<15%) of naltrexone or 6β-naltrexol
`upon repeat administration of VIVITROL.
`
`Distribution
`
`In vitro data demonstrate that naltrexone plasma protein binding is low (21%).
`
`Metabolism
`
`Naltrexone is extensively metabolized in humans. Production of the primary
`metabolite, 6β-naltrexol, is mediated by dihydrodiol dehydrogenase, a cytosolic family
`of enzymes. The cytochrome P450 system is not involved in naltrexone metabolism.
`Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-
`methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form
`glucuronide products.
`
`
`
`
`
`Page 3
`
`

`

`Significantly less 6β-naltrexol is generated following IM administration of VIVITROL
`compared to administration of oral naltrexone due to a reduction in first-pass hepatic
`metabolism.
`
`Elimination
`
`Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal
`excretion of unchanged naltrexone.
`
`The elimination half life of naltrexone following VIVITROL administration is 5 to 10
`days and is dependent on the erosion of the polymer. The elimination half life of 6β-
`naltrexol following VIVITROL administration is 5 to 10 days.
`
`Special Populations
`
`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 PRECAUTIONS).
`
`Renal Impairment: A population pharmacokinetic analysis indicated mild renal
`insufficiency (creatinine clearance of 50-80 mL/min) had little or no influence on
`VIVITROL pharmacokinetics and that no dosage adjustment is necessary (see
`PRECAUTIONS). VIVITROL pharmacokinetics have not been evaluated in subjects
`with moderate and severe renal insufficiency (see PRECAUTIONS).
`
`Gender: In a study in healthy subjects (n=18 females and 18 males), gender did not
`influence the pharmacokinetics of VIVITROL.
`
`Age: The pharmacokinetics of VIVITROL have not been evaluated in the geriatric
`population.
`
`Race: The effect of race on the pharmacokinetics of VIVITROL has not been studied.
`
`
`
`
`
`Page 4
`
`

`

`Pediatrics: The pharmacokinetics of VIVITROL have not been evaluated in a
`pediatric population.
`
`Drug-Drug Interactions
`
`Clinical drug interaction studies with VIVITROL have not been performed.
`
`Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and
`cold remedies, antidiarrheal preparations and opioid analgesics (see
`PRECAUTIONS).
`
`CLINICAL STUDIES:
`
`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.
`
`
`
`
`
`Page 5
`
`

`

`INDICATIONS AND USAGE:
`
`VIVITROL is indicated for the treatment of alcohol dependence in patients who are
`able to abstain from alcohol in an outpatient setting prior to initiation of treatment with
`VIVITROL.
`
`Patients should not be actively drinking at the time of initial VIVITROL administration.
`
`Treatment with VIVITROL should be part of a comprehensive management program
`that includes psychosocial support.
`
`CONTRAINDICATIONS:
`
`VIVITROL is contraindicated in:
`
`• Patients receiving opioid analgesics (see PRECAUTIONS).
`
`• Patients with current physiologic opioid dependence (see WARNINGS).
`
`• Patients in acute opiate withdrawal (see WARNINGS).
`
`• Any individual who has failed the naloxone challenge test or has a positive
`urine screen for opioids.
`
`• Patients who have previously exhibited hypersensitivity to naltrexone, PLG,
`carboxymethylcellulose, or any other components of the diluent.
`
`
`
`
`
`Page 6
`
`

`

`WARNINGS:
`
`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.
`
`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. Should a person receiving
`VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of eosinophilic
`pneumonia should be considered (see ADVERSE REACTIONS). 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.
`
`Unintended Precipitation of Opioid Withdrawal
`
`To prevent occurrence of an acute abstinence syndrome (withdrawal) in
`patients dependent on opioids, or exacerbation of a pre-existing subclinical
`
`
`
`
`
`Page 7
`
`

`

`abstinence syndrome, patients 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.
`
`Opioid Overdose Following an Attempt to Overcome Opiate Blockade
`
`VIVITROL is not indicated for the purpose of opioid blockade or the treatment of
`opiate dependence. 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. Indeed, 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 INFORMATION FOR
`PATIENTS).
`
`There is also the possibility that a patient who had been treated with VIVITROL will
`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 (see
`INFORMATION FOR PATIENTS).
`
`PRECAUTIONS:
`
`General
`
`
`
`
`
`Page 8
`
`

`

`When Reversal of VIVITROL Blockade Is Required for Pain Management
`
`In an emergency situation in patients receiving VIVITROL, a suggested plan for pain
`management is regional analgesia, conscious sedation with a benzodiazepine, and
`use of non-opioid analgesics or general anesthesia.
`
`In a situation requiring opioid analgesia, the amount of opioid required may be greater
`than usual, and the resulting respiratory depression may be deeper and more
`prolonged.
`
`A rapidly acting opioid analgesic which minimizes the duration of respiratory
`depression is preferred. The amount of analgesic administered should be titrated to
`the needs of the patient. Non-receptor mediated actions may occur and should be
`expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction),
`presumably due to histamine release.
`
`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.
`
`Depression and Suicidality
`
`In controlled clinical trials of VIVITROL, adverse events of a suicidal nature (suicidal
`ideation, suicide attempts, completed suicides) were infrequent overall, but were more
`common in VIVITROL-treated patients 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 VIVITROL-treated (~1%) than in placebo-treated patients
`(0).
`
`
`
`
`
`Page 9
`
`

`

`In the 24-week, placebo-controlled pivotal trial, 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.
`
`Alcohol 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 health care provider.
`
`Injection Site Reactions
`
`VIVITROL injections may be followed by pain, tenderness, induration, or pruritus. 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. Patients should be informed that any concerning injection site reactions
`should be brought to the attention of the physician (see INFORMATION FOR
`PATIENTS).
`
`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.
`
`Alcohol Withdrawal
`
`Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.
`
`
`
`
`
`Page 10
`
`

`

`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).
`
`Information for Patients
`
`Physicians should discuss the following issues with patients for whom they prescribe
`VIVITROL:
`
`• Patients should be advised to carry documentation to alert medical personnel
`to the fact that they are taking VIVITROL (naltrexone for extended-release
`injectable suspension). This will help to ensure that the patients obtain
`adequate medical treatment in an emergency.
`
`• Patients should be advised that administration of large doses of heroin or any
`other opioid while on VIVITROL may lead to serious injury, coma, or death.
`
`• Patients should be advised that because VIVITROL can block the effects of
`opiates and opiate-like drugs, patients will not perceive any effect if they
`attempt to self-administer heroin or any other opioid drug in small doses while
`on VIVITROL. Also, patients on VIVITROL may not experience the same
`effects from opioid containing analgesic, antidiarrheal, or antitussive
`medications.
`
`• Patients should be advised that if they previously used opioids, they may be
`more sensitive to lower doses of opioids after VIVITROL treatment is
`discontinued.
`
`• Patients should be advised that VIVITROL may cause liver injury in people who
`develop liver disease from other causes. Patients should immediately notify
`their physician if they develop symptoms and/or signs of liver disease.
`
`
`
`
`
`Page 11
`
`

`

`• Patients should be advised that VIVITROL may cause an allergic pneumonia.
`Patients should immediately notify their physician if they develop signs and
`symptoms of pneumonia, including dyspnea, coughing or wheezing.
`
`• Patients should be advised that a reaction at the site of VIVITROL injection
`may occur. Reactions include pain, tenderness, induration, and pruritus.
`Rarely, serious injection site reactions may occur. Patients should be advised
`to seek medical attention for worsening skin reactions, particularly if the
`reaction does not improve one month following the injection.
`
`• Patients should be advised that they may experience nausea following the
`initial injection of VIVITROL. These episodes of nausea tend to be mild and
`subside within a few days post-injection. Patients are less likely to experience
`nausea in subsequent injections.
`
`• Patients should be advised that because VIVITROL is an intramuscular
`injection and not an implanted device, once VIVITROL is injected, it is not
`possible to remove it from the body.
`
`• Patients should be advised that VIVITROL has been shown to treat alcohol
`dependence only when used as part of a treatment program that includes
`counseling and support.
`
`• Patients should be advised to notify their physician if they:
`
`• become pregnant or intend to become pregnant during treatment with
`VIVITROL.
`
`• are breast-feeding.
`
`• experience respiratory symptoms such as dyspnea, coughing, or wheezing
`when taking VIVITROL.
`
`• experience significant pain or redness at the site of injection, particularly if
`the reaction does not improve one month following the injection.
`
`• experience other unusual or significant side effects while on VIVITROL
`therapy.
`
`
`
`
`
`Page 12
`
`

`

`Drug Interactions
`
`Patients taking VIVITROL may not benefit from opioid-containing medicines (see
`PRECAUTIONS, Pain Management).
`
`Because naltrexone is not a substrate for CYP drug metabolizing enzymes, inducers
`or inhibitors of these enzymes are unlikely to change the clearance of VIVITROL. No
`clinical drug interaction studies have been performed with VIVITROL to evaluate drug
`interactions, therefore prescribers should weigh the risks and benefits of concomitant
`drug use.
`
`The safety profile of patients treated with VIVITROL concomitantly with
`antidepressants was similar to that of patients taking VIVITROL without
`antidepressants.
`
`Carcinogenesis, mutagenesis, impairment of fertility
`
`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 rats, there were small increases in the
`numbers of testicular mesotheliomas in males and tumors of vascular origin in males
`and females. The clinical significance of these findings is not known.
`
`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.
`
`Naltrexone given orally caused a significant increase in pseudopregnancy and a
`decrease in pregnancy rates in rats at 100 mg/kg/day (600 mg/m2/day). There was no
`
`Page 13
`
`
`
`
`

`

`effect on male fertility at this dose level. The relevance of these observations to
`human fertility is not known.
`
`Pregnancy Category C
`
`Reproduction and developmental studies have not been conducted for VIVITROL.
`Studies with naltrexone administered via the oral route have been conducted in
`pregnant rats and rabbits.
`
`Teratogenic Effects: Oral naltrexone has been shown to increase the incidence of
`early fetal loss in rats administered ≥ 30 mg/kg/day (180 mg/m2/day) and rabbits
`administered ≥ 60 mg/kg/day (720 mg/m2/day).
`
`There are no adequate and well-controlled studies of either naltrexone or VIVITROL in
`pregnant women. VIVITROL should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`
`Labor and Delivery
`
`The potential effect of VIVITROL on duration of labor and delivery in humans is
`unknown.
`
`Nursing Mothers
`
`Transfer of naltrexone and 6β-naltrexol into human milk has been reported with oral
`naltrexone. Because of the potential for tumorigenicity shown for naltrexone in animal
`studies, and because of the potential for serious adverse reactions in nursing infants
`from VIVITROL, a decision should be made whether to discontinue nursing or to
`discontinue the drug, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`
`The safety and efficacy of VIVITROL have not been established in the pediatric
`population.
`
`
`
`
`
`Page 14
`
`

`

`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.
`
`ADVERSE REACTIONS
`
`In all controlled and uncontrolled trials during the premarketing development of
`VIVITROL, more than 900 patients with alcohol and/or opioid dependence have been
`treated with VIVITROL. Approximately 400 patients have been treated for 6 months
`or more, and 230 for 1 year or longer.
`
`Adverse Events Leading to Discontinuation of Treatment
`
`In controlled trials of 6 months or less, 9% of VIVITROL-treated patients discontinued
`treatment due to an adverse event, as compared to 7% of the patients treated with
`placebo. Adverse events in the VIVITROL 380-mg group that led to more dropouts
`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.
`
`Common Adverse Events
`
`The table lists all adverse events, 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 VIVITROL-treated patients
`in clinical studies had adverse events with a maximum intensity of “mild” or
`“moderate.”
`
`
`
`
`
`Page 15
`
`

`

`Common Adverse Events (by body system and preferred term/high level group
`term) in ≥ 5% of patients treated with VIVITROL
`
`Body system
`
`Adverse
`Event/Preferred
`Term
`
`Placebo
`
`N = 214
`
`Naltrexone for extended-release injectable
`suspension
`
`400 mg
`N = 25
`
`380 mg
`N = 205
`
`190 mg
`N = 210
`
`All
`N = 440
`
`Gastrointestinal
`disorders
`
`Nausea
`
`Vomiting NOS
`
`Diarrhea1
`
`N
`
`24
`
`12
`
`21
`
`%
`
`11
`
`6
`
`10
`
`8
`
`N
`
`8
`
`3
`
`3
`
`4
`
`%
`
`32
`
`12
`
`12
`
`16
`
`N
`
`68
`
`28
`
`27
`
`23
`
`%
`
`33
`
`14
`
`13
`
`11
`
`N
`
`53
`
`22
`
`27
`
`23
`
`%
`
`25
`
`10
`
`13
`
`11
`
`N
`
`129
`
`53
`
`57
`
`50
`
`%
`
`29
`
`12
`
`13
`
`11
`
`Abdominal pain2
`
`Dry mouth
`
`Infections and
`infestations
`
`Upper respiratory
`tract infection–Other3
`
`Pharyngitis4
`
`Psychiatric
`disorders
`
`Insomnia, sleep
`disorder
`
`17
`
`9
`
`28
`
`23
`
`25
`
`4
`
`13
`
`11
`
`12
`
`
`
`Anxiety5
`
`17
`
`8
`
`6
`
`0
`
`0
`
`2
`
`2
`
`24
`
`0
`
`0
`
`8
`
`8
`
`10
`
`27
`
`22
`
`29
`
`5
`
`13
`
`11
`
`14
`
`8
`
`25
`
`35
`
`27
`
`4
`
`12
`
`17
`
`13
`
`24
`
`12
`
`16
`
`8
`
`24
`
`52
`
`57
`
`58
`
`42
`
`24
`
`5
`
`12
`
`13
`
`13
`
`10
`
`5
`
`
`
`General
`disorders and
`administration
`site conditions
`
`Depression
`
`Any ISR
`
`Injection site
`tenderness
`
`Injection site
`induration
`
`Injection site pain
`
`9
`
`106
`
`83
`
`18
`
`16
`
`4
`
`50
`
`39
`
`8
`
`7
`
`0
`
`22
`
`18
`
`7
`
`0
`
`0
`
`88
`
`72
`
`28
`
`0
`
`32
`
`17
`
`142
`
`92
`
`71
`
`34
`
`30
`
`8
`
`69
`
`45
`
`35
`
`17
`
`15
`
`7
`
`121
`
`89
`
`52
`
`22
`
`16
`
`3
`
`58
`
`42
`
`25
`
`10
`
`8
`
`285
`
`199
`
`130
`
`56
`
`54
`
`65
`
`45
`
`30
`
`13
`
`12
`
`Other ISR (primarily
`nodules, swelling)
`
`Injection site pruritus
`
`Injection site
`ecchymosis
`
`Asthenic conditions6
`
`Arthralgia, arthritis,
`joint stiffness
`
`Back pain, back
`stiffness
`
`8
`
`0
`
`11
`
`26
`
`11
`
`10
`
`4
`
`0
`
`5
`
`12
`
`5
`
`5
`
`8
`
`0
`
`0
`
`3
`
`1
`
`1
`
`
`Page 16
`
`0
`
`0
`
`12
`
`4
`
`4
`
`Musculoskeletal
`and connective
`tissue disorders
`
`
`
`
`21
`
`14
`
`47
`
`24
`
`7
`
`23
`
`12
`
`12
`
`6
`
`10
`
`13
`
`6
`
`4
`
`19
`
`6
`
`7
`
`34
`
`23
`
`90
`
`37
`
`27
`
`8
`
`5
`
`20
`
`9
`
`6
`
`9
`
`40
`
`12
`
`14
`
`

`

`Skin and
`subcutaneous
`tissue disorders
`
`Nervous system
`disorders
`
`Muscle cramps7
`
`Rash8
`
`3
`
`8
`
`1
`
`4
`
`Headache9
`
`Dizziness, syncope
`
`Somnolence,
`sedation
`
`39
`
`18
`
`9
`
`2
`
`4
`
`1
`
`0
`
`3
`
`9
`
`4
`
`3
`
`0
`
`12
`
`36
`
`16
`
`12
`
`16
`
`12
`
`51
`
`27
`
`8
`
`8
`
`6
`
`25
`
`13
`
`4
`
`5
`
`10
`
`34
`
`27
`
`9
`
`2
`
`5
`
`16
`
`13
`
`4
`
`21
`
`25
`
`94
`
`58
`
`20
`
`5
`
`6
`
`21
`
`13
`
`5
`
`Metabolism and
`nutrition
`disorders
`
`6
`
`3
`
`5
`
`20
`
`30
`
`14
`
`13
`
`6
`
`48
`
`11
`
`Anorexia, appetite,
`decreased NOS,
`appetite disorder
`NOS
`1 Includes the preferred terms: diarrhea NOS; frequent bowel movements; gastrointestinal upset; loose stools
`2 Includes the preferred terms: abdominal pain NOS; abdominal pain upper; stomach discomfort; abdominal pain
`lower
`3 Includes the preferred terms: upper respiratory tract infection NOS; laryngitis NOS; sinusitis NOS
`4 Includes the preferred terms: nasopharyngitis; pharyngitis streptococcal; pharyngitis NOS
`5 Includes the preferred terms: anxiety NEC; anxiety aggravated; agitation; obsessive compulsive disorder; panic
`attack; nervousness; post-traumatic stress
`6 Includes the preferred terms: malaise; fatigue (these two comprise the majority of cases); lethargy; sluggishness
`7 Includes the preferred terms: muscle cramps; spasms; tightness; twitching; stiffness; rigidity
`8 Includes the preferred terms: rash NOS; rash papular; heat rash
`9 Includes the preferred terms: headache NOS; sinus headache; migraine; frequent headaches
`
`
`Laboratory Tests
`
`In clinical trials, subjects on VIVITROL had increases in eosinophil counts relative to
`subjects on placebo. With continued use of VIVITROL, eosinophil counts returned to
`normal over a period of several months.
`
`VIVITROL 380-mg was associated with a decrease in platelet count. Patients treated
`with high dose VIVITROL experienced a mean maximal decrease in platelet count of
`17.8 x 103/uL, compared to 2.6 x 103/uL in placebo patients. In randomized controlled
`trials, VIVITROL was not associated with an increase in bleeding related adverse
`events.
`
`In short-term, controlled trials, the incidence of AST elevations associated with
`VIVITROL treatment was similar to that observed with oral naltrexone treatment (1.5%
`each) and slightly higher than observed with placebo treatment (0.9%).
`
`
`
`
`
`Page 17
`
`

`

`In short-term controlled trials, more patients treated with Vivitrol 380 mg (11%) and
`oral naltrexone (17%) shifted from normal creatinine phosphokinase (CPK) levels
`before treatment to abnormal CPK levels at the end of the trials, compared to placebo
`patients (8%). In open-label trials, 16% of patients dosed for more than 6 months had
`increases in CPK. For both the oral naltrexone and Vivitrol 380-mg groups, CPK
`abnormalities were most frequently in the range of 1-2 x ULN. However, there were
`reports of CPK abnormalities as high as 4x ULN for the oral naltrexone group, and 35
`x ULN for the Vivitrol 380-mg group. Overall, there were no differences between the
`placebo and naltrexone (oral or injectable) groups with respect to the proportions of
`patients with a CPK value at least three times the upper limit of normal. No factors
`other than naltrexone exposure were associated with the CPK elevations.
`
`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.
`
`Other Events Observed During the Premarketing Evaluation of VIVITROL
`
`The following is a list of preferred terms that reflect events reported by alcohol and/or
`opiate dependent subjects treated with VIVITROL in controlled trials. The listing does
`not include those events already listed in the previous tables or elsewhere in labeling,
`those events for which a drug cause was remote, those events which were so general
`as to be uninformative, and those events reported only once which did not have a
`substantial probability of being acutely life-threatening.
`
`Gastrointestinal Disorders – constipation, toothache, flatulence, gastroesophageal
`reflux disease, hemorrhoids, colitis, gastrointestinal hemorrhage, paralytic ileus,
`perirectal abscess
`
`Infections and Infestations – influenza, bronchitis, urinary tract infection,
`gastroenteritis, tooth abscess, pneumonia, cellulitis
`
`
`
`
`
`Page 18
`
`

`

`General Disorders and Administration Site Conditions – pyrexia, lethargy, rigors,
`chest pain, chest tightness, weight decreased
`
`Psychiatric Disorders – irritability, libido decreased, abnormal dreams, alcohol
`withdrawal syndrome, agitation, euphoric mood, delirium
`
`Nervous System Disorders – dysgeusia, disturbance in attention, migraine, mental
`impairment, convulsions, ischemic stroke, cerebral arterial aneurysm
`
`Musculoskeletal and Connective Tissue Disorders – pain in limb, muscle spasms,
`joint stiffness
`
`Skin and Subcutaneous Tissue Disorders – sweating increased, night sweats,
`pruritus
`
`Respiratory, Thoracic, and Mediastinal Disorders – pharyngolaryngeal pain,
`dyspnea, sinus congestion, chronic obstructive airways disease
`
`Metabolism and Nutrition Disorders – appetite increased, heat exhaustion,
`dehydration, hypercholesterolemia
`
`Vascular Disorders – hypertension, hot flushes, deep venous thrombosis, pulmonary
`embolism
`
`Eye Disorders – conjunctivitis
`
`Blood and Lymphatic System Disorders – lymphadenopathy (including cervical
`adenitis), white blood cell count increased
`
`Cardiac Disorders – palpitations, atrial fibrillation, myocardial infarction, angina
`pectoris, angina unstable, cardiac failure congestive, coronary artery atherosclerosis
`
`Immune System Disorders – seasonal allergy, hypersensitivity reaction (including
`angioneurotic edema and urticaria)
`
`
`
`
`
`Page 19
`
`

`

`Pregnancy, Puerperium, and Perinatal Conditions – abortion missed
`
`Hepatobiliary Disorders – cholelithiasis, aspartate aminotransferase increased,
`alanine aminotransferase increased, cholecystitis acute
`
`DRUG ABUSE AND DEPENDENCE:
`
`Controlled Substance Class
`
`VIVITROL is not a controlled substance.
`
`Physical and Psychological Dependence
`
`Naltrexone, the active ingredient in VIVITROL, is a pure opioid antagonist that does
`not lead to physical or psychological dependence. Tolerance to the opioid antagonist
`effect is not known to occur.
`
`OVERDOSAGE:
`
`There is limited experience with overdose of VIVITRO