CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -8 9 7
`
`LABELING~
`
`
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -8 9 7
`
`LABELING~
`
`
`
`PACKAGE INSERT
`
`DESCRIPTION:
`
`VIVITROLT'V' (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-(50) (CAS Registry # 16590-4143). 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 4
`
`o‘
`
`Naltrexone base anhydrous is an off-white to a light tan powder with a melting point of
`
`168-170° C (334-338° F).
`
`It is insoluble in water and is soluble in ethanol.
`
`VIVITROL is provided as a kit cdntaining a vial each of VIVITROL microspheres and
`
`diluent, one 5-mL syringe, one 1/2-inch 20-gauge preparation needle, and two 11/z—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 mu 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.
`I
`
`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.
`I
`
`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 BB-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 SB-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, 6|3-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-6B-naltrexol and 2—hydroxy-3-
`
`methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form _
`
`glucuronide products.
`
`
`
`Page 3
`
`
`
`Significantly less BB-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 ofBB-
`
`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 _na|trexone
`
`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.
`
`be discontinued in the event of symptoms and/or signs of acute hepatitis.
`
`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
`
`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
`
`conseguences of tying 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:
`
`'
`
`‘ 0 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.
`
`0 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.
`
`0 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.
`
`0 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'VlVITROL.
`
`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 VlVlTROL 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
`
`I frequency assay, non-Specific DNA damage in repair tests with E. coli and Wl-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/mglday). There was no I
`
`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 VlVlTROL.
`
`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 2 30 mg/kg/day (180 mg/m2/day) and rabbits
`
`administered 2 60 mg/kg/day (720 mg/m2/day).
`
`There are no adequate and well-controlled studies of either naltrexone or VlVlTROL in
`pregnant women. VlVlTROL should be .used during pregnancy only if the potential
`
`benefit justifies the potential risk to the fetus.
`
`Labor and Delivery
`
`The potential effect of VlVlTROL 0n duration of labor and delivery in humans is
`
`unknown.
`
`Nursing Mothers
`
`Transfer of naltrexone and GB-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 VlVlTROL, 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 VlVlTROL 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 25% 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 2 5% of patients treated with VIVITROL
`
`Gastrointestinal
`disorders
`
`m 24
`Vomiting NOS -n
`--n
`
`—n-
`
`Infections and
`infestations
`
`
`
`
`tract infection—Other3
`
`Psychiatric
`disorders
`
`disorder
`
`
`
`
`
`
`
`14
`
`-A on
`
`.\ Q)
`
`28
`
`N\l
`
`[\JN
`
`NN(D\l
`
`10
`
`-—\ co
`
`53
`
`0-:\l
`
`12
`
`A o.)
`
`N\l
`
`a!(.0 IEIO
`.x N lN
`01I
`U1m
`
`NU1
`
`o)01
`
`N‘1
`
`—\ \l
`
`_\ (,0
`
`
`
` Adverse
`
`
`Body system
`Naltrexone for extended-release injectable
`
`Event/Preferred
`
`suspension
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.x.\.3.x000)N_\
`01_Ll8 _L_\OJA0)—‘N(.0OU1010
`
`Nh
`
`N
`
`CD
`
`n
`
`_1 n- 24
`1
`w
`
`an 17
`7
`01a Nl (D(I)
`..L AN
`‘1N
`A m
`
`Any lSR
`
`injection site
`tenderness
`
`m_L
`
`(0N
`
`-h(.11
`
`CD(0
`
`N
`
`Injection Site
`induration
`
`18
`
`Injection Site pain
`
`Other lSR (primarily
`nodules, swelling)
`
`lA
`
`
`
`
`
`
`General
`disorders and
`administration
`site conditions
`
`
`
`
`
`
`
`
`Injection site pruritus n
`Injection site
`11
`ecchymosis
`
`Asthenic conditions6
`
`
` Muscuioskeletai
`
`stiffness
`
`and connective
`tissue disorders
`
`
`
`
`
`
`
`Arthralgia, arthritis
`joint stiffness
`
`Back pain, back
`
`5
`
`11
`
`10
`
`1
`
`1
`
`4
`
`4
`
`
`
`
`
`Muscle cramps7
`Skin and
`subcutaneous
`tissue disorders
`
`disorders
`
`
`
`Dizziness syncope
`
`Somnolence,
`sedafion
`
`Metabolism and Anorexia, appetite,
`nutrition
`decreased NOS,
`disorders
`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; Iaryngitis 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 ainNays 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 — cholelithia‘sis, 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 VIVITROL. Single doses up to 784 mg
`
`were administered to 5' healthy subjects. There were no serious or severe adverse
`
`events. The most common effects were injection site reactions, nausea, abdominal
`
`pain, somnolence, and dizziness. There were no significant increases inhepatic
`
`enzymes.
`
`In the event of an overdose, appropriate supportive treatment should be initiated.
`
`DOSAGE AND ADMINISTRATION:
`
`VIVITROL must be administered by a health care 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 health care
`
`professional as an intramuscular (IM) gluteal injection, alternating buttocks, using the
`
`
`
`Page 20
`
`
`
`kit components provided (see HOW SUPPLIED). VIVITROL must not be
`
`administered intravenously.
`
`If a patient misses a dose, he/she should be instructed to receive the next dose as
`
`soon as possible.
`
`I
`
`Pretreatment with oral naltrexone is not required before using VIVITROL.
`
`Reinitiation of Treatment in Patients Previously Discontinued
`
`There are no data to specifically address reinitiation of treatment.
`
`Switching From Oral Naltrexone for Alcohol Dependence
`
`There are no systematically collected data that specifically address the switch from
`
`oral naltrexone to VIVITROL.
`
`Preparation of Dose
`
`VIVITROL must be suspended only in the diluent supplied in the dose kit and must be
`
`administered with
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
