CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -8 9 7
`
`MEDICAL REVIEW
`
`

`

`h FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA AND RHEUMATOLOGY PRODUCTS
`
`
`
`
`DIVISION DIRECTOR’S APPROVAL MEMO
`
`
`DATE:
`
`April 13, 2006
`
`- DRUG:
`
`VivitrolTM (naltrexone for extended—release injectable suspension)
`
`NDA:
`
`21—897
`
`NDA Code:
`
`Type 4P NDA
`
`SPONSOR:
`
`Alkermes, Inc.
`
`.
`
`For the treatment of alcohol dependence
`INDICATION:
`
`
`Alkermes, Inc. submitted NDA 21—897 in support of marketing approval for VivitrolTM
`(naltrexone for extended-release inj ectable suspension)1 on March 31, 2005. An
`approvable letter was issued on December 23, 2005. The letter noted that the sponsor
`would need to address the following issues prior to approval:
`
`0
`
`0
`
`the absence of Reproductive Toxicology and Carcinogenicity studies to support
`the clinical use of the product
`
`an absence of evidence that the product is safe and effective in patients who had
`not achieved abstinence prior to the initiation of treatment (see Division
`Director’s Approvable Memo, dated December 23,2005)
`
`The sponsor has responded to these concerns by agreeing to perform post—marketing
`studies toassess the deficiency listed in the first bullet, and by agreeing to language in
`the label that will limit the indicated use of the product to “. . . patients who are able to
`abstain from alcohol in an outpatient setting prior to initiation of treatment. . .”
`
`l VivitrolTM will be marketed in a kit.
`
`

`

`Most of the subjects in the efficacy studies achieved initial abstinence through
`participation in a treatment program or via medical detoxification. There were no
`subjects who maintained abstinence in the setting of no continued available alcohol.
`Therefore, Drs. Kashoki and Winchell have recommended that the sponsor perform a
`post—marketing study to assess the efficacy of VivitrolTM in patients who are abstinent
`“by virtue of hospitalization or other mechanism to limit access to alcohol” as these
`patients are likely to differ in regard to their motivation to stop drinking compared to
`patients who stop drinking in spite of access to alcohol. The sponsor has agreed to
`perform this study.
`'
`
`Drs. Kashoki and Winchell have reviewed the updated safety data in this submission and
`have determined that there are no new safety concerns that would impact the risk to
`benefit ratio of the product, when compared to the safety data analyzed in the initial
`application. However, they did find an increase in creatinine phophokinase (CPK) serum
`levels with prolonged exposure and have recommended addition of these data to the
`product label. No serious adverse events were associated with these CPK elevations.
`
`Discussion .-
`
`The sponsor has adequately addressed the concerns noted in the approvable letter. Of
`note, however, the absence of Reproductive Toxicology and Carcinogenicity data to fully
`cover the range of expected human exposure to naltrexone and to the polylactide—co—
`glycolide vehicle will not be fully elucidated at the time of approval and initial patient
`exposure. Nevertheless, the available data on reproductive toxicity indicates a low risk,
`the risk is certainly no more significant than the risk of fetal alcohol syndrome, and this
`risk can be mitigated by appropriate cautionary language in the product label until further
`data is available. There is also no evidence to suspect that the carcinogenic effects of the
`product are of unusual potential potency, and the absence of complete data to fully assess
`the long—term carcinogenic potential can be explicated in the label, again until further
`data isavailable. While our response to the initial application was that these studies
`should be completed prior to approval, this decision was partially based on the likelihood
`that the sponsor would be completing further clinical studies to support their proposed
`indication and, thus, the development program would allow for an adequate period of
`time to complete the preclinical studies prior to approval. However, the sponsor has
`proposed an alternate indication that we find acceptable and that will not require
`additional clinical studies. This new indication limits treatment to the subpopulation of
`alcoholic patients who will have achieved abstinence prior to treatment with VivitrolTM,
`the subpopulation that has been demonstrated to clearly benefit from treatment with this
`product. In light of this new development, and as alcoholism is a serious disease with
`significant associated morbidity and mortality, and a devastating impact on patients,
`families and the public health, we must reconsider the overall risk to benefit analysis
`upon which this application rests. VivitrolTM is likely to provide alcoholic patients with a
`higher level of compliance compared to the currently approved treatments and, thus, an
`improvement in the likelihood that they will be able to successfully maintain abstinence.
`
`NDA 21—897 Division Director’s Approvable Memo
`VivitrolTM
`
`2
`
`April 13, 2006
`
`

`

`As such, it is acceptable to garner the remaining data necessary to fully elucidate the
`toxicity of this product in the post-marketing setting.
`
`Action:
`
`Approval
`
`Bob A. Rappaport, MD.
`Director
`
`Division of Anesthesia, Analgesia and Rheumatology Products
`Office of Drug Evaluation II, CDER, FDA
`
`NDA 21-897 Division Director’s Approvable Memo
`VivitrolTM
`
`April 13, 2006
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Bob Rappaport
`4/13/2006 02:52:50 PM
`MEDICAL OFFICER
`
`

`

`'7
`
`a mi 03/ '3 7,_/
`
`h FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA, AND RHEUMATOLOGY PRODUCTS
`
`
`
`
`
`
`M E M 0 R A N D U M
`
`DATE:
`
`TO: .
`
`FROM:
`
`April 11, 2006
`
`File, NDA 21—897
`
`Celia Jaffe Winchell, MD.
`Medical Team Leader
`
`RE:
`
`NDA 21-897
`
`Response to Approvable Action
`Letter Date 2/ 14/2006
`
`% I
`
`concur with Dr. Kashoki’s reView of the resubmission of this application and her
`recommendations.
`
`In our original action letter conveying the Approvable decision on the application, we
`advised Alkermes that:
`
`You have not provided evidence of efficacy of Vivitrol in alcohol—dependent
`patients who are actively drinking at the time of treatment initiation. '5
`
`* / //
`
`//
`
`//
`
`//
`
`propose labeling to restrict the use of the product to alcohol—dependent patients
`
`who have refrained from drinking
`~ _
`. prior to treatment initiation.
`
`Note that if you elect this latter option, we would expect you to conduct a post—
`approval study to determine whether Vivitrol is effective in pateints whose pre—
`treatment abstinence is enforced (i.e. via hospitalization) rather than spontaneous
`(as was the case with the population studied in your efficacy trial, ALK21-003).
`
`In this resubmission, Alkermes has elected the option of labeling the product for patients
`abstinent at the time of treatment initiation. However, they disagreed with the
`
`

`

`requirement that a W v. and provided a
`reasonable rationale for deleting this _ __
`-r.equirement
`In addition, they
`correctly took issue with the term ' F to describe the abstinence of the study
`participants many of whom had achieved initial abstinence through participation in a
`program of treatment and/or medical detoxification. The more appropriate descriptor of
`this population was that they had maintained abstinence in an outpatient setting (i.e., with
`access to alcohol) prior to treatment initiation; indeed, this was true of all of the subjects
`in question, as confirmed by Alkermes in a submission dated 3/10/20Q6 (sequence 0044).
`
`Therefore, we have arrived at agreement regarding the appropriate description of the
`target population as “patients who are able to abstain from alcohol in an outpatient setting
`prior to initiation of treatment with VIVITROL.” However, having elected this option,
`Alkermes will also be asked to agree to conduct a post—marketing study to determine
`whether Vivitrol is effective in patients who are abstinent by virtue of hospitalization or
`other mechanism to limit access to alcohol, rather than patients who are abstinentin spite
`of access to alcohol As these populations are likely to differ with respect to level of
`motivation and/or alcoholism severity, thisis a relevant question important to clinicians
`deciding whether or not patients being discharged from alcohol-free settings would
`benefit from treatment with Vivitrol upon discharge.
`
`Consultation with the Division of Medication Errors and Technical Support (DMETS) in
`the Office of Drug Safety led to certain other modifications in the directions for use and
`other aspects of the labeling. However, some recommendations from DMETS were not
`implemented. DMETS questioned the need for multiple needles in the dosing kit. These
`are deemed necessary because, per the chemistry reviewer, Dr. Jila Boal, a short needle is
`needed for preparation to prevent aspiration of air into the syringe as the vial containing
`diluent has a small volume of liquidin it. The longer needles are needed for
`intramuscular injection. Although clogging of the needle was not a major problem in
`trials, it seems prudent to provide an extra needle for drug administration to ensure that a
`needle tested with the product (with the necessary lumen size to allow passage of the
`product) will be used. DMETS also recommended the inclusion of the final mg/ml
`concentration of the suspension; however, as the dosing for this product1s essentially unit
`of use, this does not seem necessary and could cause confusion. Furthermore, the vial
`label for the microspheres and the carton label for the kit contain text reading, “upon
`reconstitution with 3.4 ml diluent, each ml will contain 95 mg of naltrexone.” Therefore,
`the information is already included in the packaging.
`
`In addition, as recommended by Dr. Lee of the Division of Pulmonary and Allergy
`Products who provided consultation during the initial review cycle, Alkermes will be
`asked to develop tests to detect allergy to the components of their product, with an eye
`towards identifying patients at risk for the serious, possibly allergy—mediated events noted
`during clinical trials, such as eosinophilic pneumonia and serious injection site reactions.
`
`Since the completion of Dr. Kashoki’s review, Alkermes also submitted additional
`information concerning study participants with CPK abnormalities; these abnormalities
`'were generally isolated and transient and were not associated with symptoms or with
`concomitant creatinine elevations, no subject with extreme CPK values had an SAE
`reported1n association with these findings.
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Celia Winchell
`
`4/11/2006 05:13:39 PM
`MEDICAL OFFICER
`
`

`

`A
`
`(724% 63,0th ,
`
`CLINICAL REVIEW
`
`Application Type N 21—897
`Submission Number
`000
`
`Letter Date February 14, 2006
`, Stamp Date February 14, 2006
`PDUFA Goal Date April 14, 2006
`
`Reviewer Name Mwango Kashoki, MD, MPH
`Review Completion Date April 4, 2006
`'
`
`Established Name: Naltrexone for extended—release
`
`injectable suspension
`Trade Name ViVitrol
`
`Therapeutic ClaSs Opioid antagonist
`Applicant Alkermes
`
`'
`
`Priority Designation
`
`P
`
`F ormulation:'Naltrexone long—acting (depot) injection
`Dosing Regimen
`380 mg IM q month
`Indication Alcohol dependence
`Intended Population Alcohol dependent adults
`
`

`

`Table of contents
`
`Executive Summary .................................................................................. '.................. 3
`1
`2 Background ....................................................... 3
`3 NDAHistory ....................... 4
`3 .1
`Review of non—clinical data .....................................................................7........... 4
`3.2
`Review of clinical efficacy ................................................................................. 4
`3.3
`Review of clinical safety..............- ....................................................................... 5
`3.4
`Regulatory action ................................................................................................ 6
`Applicant’s Response to Approvable Action Letter .............................................. 7
`Safety Update .............................................................................................................. 9
`5.1
`Exposure ............................................................................................................. 9
`5 .2
`Adverse events .................................................................................................. 12
`5.2.1
`Deaths ........................................................_....... . ........................................ 12
`5.2.2
`Serious adverse events ............................................................... 12
`
`4
`5
`
`5.2.3
`5.2.4
`5.3
`
`Significant adverse events ......................................................................... 12
`CommOn adverse events ........................................................................... 12
`Discontinuations due to adverse events ............................................................ 14
`
`6
`
`Review ofthe Proposed Product Label....................‘ ................................................. 14
`6.1
`Review of clinically-related sections ................................................................ 15
`6.1.1
`“Clinical Studies” section ......................................................................... 15
`6.1.2
`“Indications and Usage” section ........................................'....................... 17
`6.1.3
`“Warnings” section ................................................................................... 18
`6.1.4
`“Information for Patients” section ..................._......................................... 19
`6.1.5
`“Adverse Reactions”'section ..................................................................... 20
`
`“Dosage and AdminiStration” section ....................................................... 22
`6.1.6 .
`6.2
`Review of nonclinical-related sections ................. _. .................................. 26
`Review of the Proposed Patient Package Insert ........................................................ 26
`Conclusions ................................................................................................................ 29
`
`7
`8
`
`.................. 29
`Recommended Regulatory Action .......................................................
`9
`Appendix ............................................................................................................... 30
`10 _
`10.1 Appendix 1: Number (%)' SAEs after 6 months ............. '. ................................. 30
`10.2 Appendix 2: Most common AEs after 6 months .............................................. 36
`10.3 Appendix 3-: Discontinuations due to AEs ....................................................
`42
`- 10.4 - Appendix 4: Subjects who shifted from normal CPK at baseline tovhigh ........ 46
`
`

`

`1 Executive Summary
`NDA 21—897 for Vivitrol (naltrexone for extended-release injectable suspension) was re-
`submitted by Alkermes on Febraury 14, 2006. Vivitrol is a new depot formulation of
`naltrexone that is intended to treat alcohol dependence in adults. The application was
`initially submitted on March 31, 2.005, and was issued an “approvable” action based 0n
`limited demonstration Of efficacy and inadequate non-clinical data regarding
`carcinogenicity and reproductive toXicOlogy. The current submission is deemed a
`complete response to the “approvable” letter.
`
`Alkermes has adequately addressed the clinical deficiency by proposing labeling to
`restrict the use of Vivitrol to alcohol-dependent patients who are not actively drinking at
`the time of treatment initiation. Therefore, this review was primarily an assessment of
`the updated safety data, as well as the revised product label and patient package insert.
`
`The updated safety database did not identify any new adverse effects of Vivitrol that were
`not previously identified. However, the update showed an increase in creatinine
`phosphokinase (CPK) with prolonged dosing.
`I recommend inclusion of these data in the
`product label.
`
`Overall, Alkermes agreed with the Division’s revisions to the proposed product label.
`The most notable counter-proposal to the revisions was regarding the “indications and
`usage” section. Alkermes sought to alter language describing the intended treatment
`population, remOving references to
`g N and a ' W
`E _,
`. The Applicant’s rationale was deemed acceptable.
`
`The patient package insert was completely rewritten M , and to
`reflect the warnings and precautions identified during the NDA review.
`
`Overall, therefore, the data and the submission are adequate and the application can be
`approved.
`
`2 Background
`
`Naltrexone for extended release injectable suspension (Vivitrol®) is a. new intramuscular
`depot formulation of naltrexone. Naltrexone is a non——selective opioid antagonist with no
`agonist activity, and an oral formulation of the drug13 currently approved for use in
`opiate dependence and alcohol dependence.
`
`'
`
`The Vivitrol formulation is comprised of extended-release microspheres of naltrexone
`. "base encapsulated in polylactide-co-glycolide (PLG), mixed in a 75:25 ratio. The
`' naltrexone is the active ingredient. PLG is a biodegradable medical polymer which is
`used in several FDA¥approved products. The microspheres are suspended in a diluent
`and the mixture is injected intramuscularly (IM).
`
`

`

`0 Drug established name: Naltrexone for extended release injectable suspension
`0 Chemical name: Morphinan-6--,one 17--(cyclopropylmethyl)-4 5——epoxy--3, 14-
`dihydroxy- (501)
`0 Proposed trade name: Vivitrol
`0 Drug class: non--se1ective opioid antagonist
`0 Proposed indication: Treatment of alcohol dependence, as part on an appropriate
`program fo1 alcohol dependence
`0 Dose: 380—mg M q month
`'
`o Injections are to be administered by a health care professional. Injections are
`to be to the lateral aspect of the gluteal muscle, alternating buttocks with each
`administration.
`
`0 Age groups: Adults
`0 Studies in children waived
`
`0 Studies in adolescents deferred
`
`3 NDA History
`The initial NDA for Vivitrol was submitted on March 31, 2005. The indication sought
`was treatment of alcohol dependence, as part of an appropriate program for alcohol
`dependence, in adults who were —— abstinent from drinking M
`at treatment initiation.
`.
`
`3.1 Review of non-clinical data
`
`Alkermes submitted the NDA under Section. 505(b)(2) of the Food, Drug, and Cosmetic
`Act, citing as basis for the safety of Vivitrol theAgency’s previous finding of safety of
`oral naltrexone, animal studies conducted using Vivitrol, and information from published
`literature of the safety of naltrexone. Review of the NDA found that Alkermes further
`referenced information from other approved'products and the published literature
`regarding carcinogenicity, reproductive toxicology and genetic toxicology data on
`naltrexone and the PLG microspheres. However, no suCh studies were conducted using
`the final Vivitrol formulation. Therefore the referenced data were inadequate to fulfill
`the nonclinical requirements of the Vivitrol NDA, and additional data regarding the
`carcinogenicity and reproductive toxicology of Vivitrol were necessary.
`
`3.2 Review of clinicalifefficacy
`A single Phase 3 trial was submitted in support of efficacy of Vivitrol. The trial enrolled
`627 patients, and 624 of whom took at least one dose of study drug. Patients were -
`randomized to one of three groups: Vivitrol 380--mg (n= 205), Vivitrol 190-mg (n =210),
`and placebo (n= 214). All patients participated1n a psychosocial management program.
`Treatment duration was 6 months.
`
`.
`
`

`

`The Applicant’s primary efficacy endpoint was the “event rate of heavy drinking”, and
`was analyzed using a multiple event time analytic approach. This novel endpoint was
`intended to evaluate both the number and the timing of drinking events, and Alkermes
`demonstrated efficacy based on this endpoint. However, the Division deemed the
`endpoint inadequate for several reasons. First, the endpoint is not clinically intuitive —
`the clinical meaning of a reduction1n the “event rate” of heavy drinking13 not clear.
`Also, the magnitude of a reduction1n the event rate of heavy drinking that13 assOciated
`with clinical improvement is not known Finally, the endpointIS a result of a group mean
`analysis, and does not provide information on the effects of treatment on an individual
`patient level
`
`Based on recent (unpublished) data from the National Institute of Alcohol Abuse and
`Alcoholism which found that sustained absence of heavy drinking over the treatment
`period was associated with few drinking consequences, the Division considered ‘absence
`of heavy drinking’ as the optimal definition for treatment success in alcoholism trials.
`‘Heavy’ drinking is Z 4 drinks/day (women), and 25 drinks/day (men).
`
`Actual number of
`
`heavy drinking
`days" per month
`
`Placebo
`
`190 mg
`
`380 mg
`
`The Division’s re—anal-ysis of the efficacy data found that overall there were no numerical
`or statistical differences between either dose of Vivitrol and placebo with respect to the
`proportion of patients who were able to refrain from heavy drinking during the treatment
`period. However, when treatment response was evaluated based on drinking status at
`study initiation (i. e. actively drinking vs. abstinent from any drinking), the proportion of
`patients meeting the definition of treatment success greatly increased, and a difference
`between the Vivitrol and placebo groups was suggested for patients abstinent at baseline.
`The efficacy results are summarized in the table below:
`
`
`
`N (%)
`P value ‘
`
`190mg vs
`380-mg
`
`
`'
`vs.
`placebo
`lacebo
`
`
`
`
`All patients (abstinent and non-abstinent at baseline)
`
`0
`l
`0.5107 1
`11 (5%)
`15(7%)
`[
`140%)
`0.4325
`
`
`
`
`l
`Patients abstinent at baseline
`_
`A
`
`0.1212
`6(35%)
`l
`6(35%)
`0
`l
`2(11%)
`012in
`* “Heavy drinking day” is defined as 2 4 drinks/day (women), and 25 drinks/day (men).
`
`
`
`
`
`
`In addition, when the “event rate” analysis was repeated using these subgroups, it was
`apparent that the efficacy shown in the primary analysis was driven almost exclusively by
`the subgroup of patients that was abstinent at baseline. Thus, evenusing the protocol—
`specified analytic approach, efficacy was not demonstrated for those patients who were
`actively drinking at baseline.
`
`3.3 Review of clinical safety
`
`Alkermes partly relied on the Agency’s previous finding of safety of oral naltrexone to
`support its NDA for Vivitrol. Additional safety information on naltrexone was based on
`
`

`

`a synopsis of the post—marketing experience with oral naltrexone, as well as summaries of
`and datasets from trials using both oral naltrexone and Vivitrol.
`
`A key focus of the safety review was the effect of Vivitrol on the liver. The current
`product label for oral naltrexone contains a boxed warning regarding the potential for
`hepatotoxicity with naltrexone treatment. The warning stems from the observation of
`elevated transaminases following treatment of obese patients with high doses (300-
`mg/day) of oral naltrexone. Alkermes was of the opinion that because (1) intramuscular
`administration of Vivitrol avoided first-pass metabolism, (2) the total monthly dose at
`which hepatoxicity was observed with’oral naltrexone was 22-fold higher than the total
`monthly Vivitrol dose, Vivtrol would not be hepatotoxic.
`' _‘_fv_\ 0.. . -,
`u
`
`The Division’s review of the safety data found that there was no clear safety advantage of
`Vivitrol over oral naltrexone with respect to effects on the liver. The risk of adverse
`laboratory changes (e. g. increased liver function tests) or of hepatic-related adverse
`
`outcome was not sufficiently different for the Vivitrol group
`v
`
`The NDA'review showed that there was a higher frequency of injection site reactions
`(ISRs) in the Vivitrol patients compared to placebo patients. The types of ISRs reported
`included pain, induration, pruritus, and redness. Events of injection site pain were dose-
`related. “Nodules” and “lumps” were also described, with associated swelling,
`discoloration, and rash. One patient experienced a serious ISR, with tissue necrosis at the
`injection site which required surgical excision. The pathological report of the excised
`tissue described a ‘hypersensitivity’ reaction.
`
`A number of findings, when taken together, suggested that patients may experience an
`allergic response to Vivitrol. Mean eosinophil counts rose in all treatment groups over
`the course of treatment, with a higher mean increase in the Vivitrol patients than in the
`placebo patients. In addition, there were cases of urticaria and angioedema, albeit
`infrequently reported._ Finally, there were two cases of eosinophilic pneumonia, and the
`serious ISR with hypersensitivity reaction. The Division concluded that the data were
`insufficient to definitively ascribe an allergic basis for the observed reactions, and that
`perhaps the reactions were due to a non-IgE-mediated mast cell degranulation response.
`Nevertheless, assessment of whether Vivitrol elicits an immune response, via testing for
`drug-specific antibodies, was not unreasonable.
`
`3.4 Regulatory action
`
`An approvable action was taken on the NDA. The action letter described two main
`deficiencies:
`'
`
`1. “You have not provided evidence of efficacy of Vivitrol in alcohol-dependent
`.
`.
`.
`.
`.
`.
`.
`.
`. /
`patients who are actively drinking at the time of treatment Initiation.m- 1" n 1
`
`r
`
`u
`
`
`
`
`
`
`
`

`

`propose labeling to restrict the use ofthe product to alcohol-dependent patients Who
`have refrained from drinking ' _
`prior to treatment-initiation.
`
`Note that if you elect this latter option, we would expect you to conduct a
`postapproval study to determine whether Vivitrol is effective .in patients whose
`pretreatment abstinence is enforced (i.e. via hospitalization) rather than spontaneous
`(as was the case with the population studied in your efficacy trial, ALK21—003).
`
`2. Provide pharmacokinetiC/toxicokinetic exposure data in the appropriate species
`necessary for interpreting the existing carcinogenicity and reproductive toxicology
`data in the product labeling. In the absence of adequate bridging data, the following '
`nonclinical studies would have to be conducted:
`
`a.
`
`a Segment I reproductive and developmental toxicology study including
`toxicokinetic data in a single species with the final drug product formulation;
`b. Segment II reproductive and developmental toxicology studies in two species
`including toxicokinetic data with the final drug product formulation;
`a Segment III reproductive and developmental toxicology study including
`toxicokinetic data'with the final drug product formulation; and
`d. carcinogenicity assessment in two species using the final drug product
`formulation.”
`
`c.
`
`Additional clinical comments that were not approvability issues were:
`
`0
`
`“To further evaluate the allergenic potential of Vivitrol, conduct a trial to ascertain
`whether patients develop naltrexone-speCific, naltrexone-
`g
`carboxymethylcellulosespecific, and carboxymethylcellulose-specific antibodies
`(IgG, IgM, and IgEl) following Vivitrol administration. Evaluate whether
`development ofthese specific antibodies is associated with adverse events of urticaria
`and angioedema.
`0 Conduct in vitro CYP inhibition studies using conventional CYP substrates and
`validated analytical methodology.
`.
`0 Conduct in vitro studies in human hepatocytes to evaluate the potential of naltrexone
`to induce CYP3A4 and CYP1A2.”
`
`4 Applicant’s Response to Approvable ActiOn Letter
`Response to the clinical deficiency
`W
`
`, Alkermes has agreed to the Agency’s alternate recommendation to
`. N— _
`.
`restrict the use of Vivitrol to a subgroup of alcohol-dependent patients: “patients who are
`able to abstain from alcohol prior to treatment initiation.” Alkermes has modified the
`proposed product label to reflect the 69> treatment population.
`
`

`

`Alkermes has also committed to conducting a post—approval study to determine whether
`Vivitrol is efficacious in patients whose pretreatment abstinence is enforced (e. g. via
`hospitalization) or maintained despite access to alcohol in the outpatient setting.
`
`Response to the non-clinical deficiency
`Refer to the Pharmacology/Toxicology review for details.
`
`Believing itself to have adequately addressed the identified NDA deficiencies, the
`Applicant has submitted a revised product label and patient package insert for review,
`and is seeking additional Agency action on the NDA.
`
`Safety Update
`As requested in the Action Letter, Alkermes has provided an update of the safety data
`from all clinical studies, and an evaluation of how the data compare to those1n the
`original NDA.
`
`Revisions to the product label
`The major clinical changes to the initially that the Division proposed for product label are
`' listed below. (Refer to the Pharmacology/Toxicology review for details regarding the
`changes proposed for the non-clinical sections of the label)
`
`0 The clinical studies section was rewritten to describe the alternate endpoint used to
`describe efficacy, as well as the magnitude of efficacy observed. The characteristics
`of the population studied (e.g. individuals abstinent at baseline) was emphasized. The
`
`Applicant’s
`»N were deleted,
`
`“ 4-,
`Also deleted were w
`
`[
`
`/
`
`/
`
`o The indications section was rewritten to describe the specific populatiOn in which
`efficacy was shown. The requirement for concurrent participation in an appropriate
`psychosocial management program was included.
`
`0 The contraindications section was modified as follows: statements statingthat
`Vivitrol is contraindicated in the following individuals
`_
`0 Persons who have failed the naloxone challenge test or who has a positive
`urine screen for opioids; and
`0 Persons with acute hepatitis or liver failure
`
`0 Warnings describing the following risks were added:
`0 HepatototoXicity
`o Eosinophilic pneumonia
`0 Unintended precipitation of opioid withdrawal with Vivitrol
`0 Potential overdose with attempts to overcome naltrexone blockade
`
`- The precautions section was expanded to describe
`
`

`

`o I The risk of injection site reactions
`0 The need for monitoring for emergence of depressive symptoms, and suicidal
`ideation/attempt following treatment with Vivitrol
`
`Alkermes accepted the majority of the Division’s revisions to the product label, with
`minor editorial corrections. The most significant counter proposals to the label language
`were with respect to the:
`'
`
`a) Clinical studies section — The Applicant proposed inclusion of _ A
`
`b)
`
`Indications and usage section — Alkermes removed references to ‘
`
`abstinence from alcohol, as well as the
`(f
`
`'
`
`,
`
`j 7 7
`
`c)_ Dosage and administration section — Alkermes modified theinstructions regarding
`drug preparation using the kit components
`
`A ,
`
`Alkermes did not propose any major revisions to the patient package insert.
`
`5- Safety Update
`The Safety Update Report (SUR) in this NDA resubmission contains new information
`from two ongoing long-term extension studies. There is no new information from
`clinical pharmacology studies or blinded, short-term trials.
`
`The resubmission incorporates data from the ongoing studies ALK21-006-EXT and
`ALK21-010, through August 31, 2005. Study ALK21-006-EXT is an extension of
`ALK21-006, therefore subjects in the —EXT study are a subset of the ALK21—006
`(previously described in the original submission). Similarly, subjects in ALK21-010 are
`a subset of the ALK21—003 population (also described in the original submission).
`
`Alkermesreported safety data using three categories:
`0 Application data — These are the data as originally reported in the NDA
`o
`SUR data — Reflect data obtained-during the SUR period (i.e. 9/1/04 through
`8/3 1/05)
`0 Combined > 6 month data — Represent the most updated Vivitrol safety profile
`for subjects with > 6 months’ exposure (i.e. incorporates the SUR data)
`
`5. 1 Expos ure
`A totalof 1,232 subjects have participated in 7 primary clinical trials and 3 extension
`studies of Vivitrol suspension. No new subjects were enrolled during the SUR period.
`
`As of 31 August 2005, 1065 subjects have been treated with Vivitrol: 84 healthy subjects,
`12 with hepatic impairment but who were not substance dependent, 838 with alcohol
`
`

`

`dependence, 27 non—dependent opioid users, and 104 who were either opiate dependent
`or mixed alcohol~opiate dependent.
`
`Table 1 (following page) shows the cumulative exposure to Vivitrol. Altogether, 942
`alcohol and/or opiate dependent patients have received at least one dose of Vivitrol. A
`total of 408 subjects have received at least 6 doses '(i.e. 6 months of exposure) of Vivit