CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 —8 97
`
`PHARMACOLOGY REVIEW
`
`

`

`NDA No. 21—897
`Reviewer: R. Daniel Mellon Ph.D.
`
`find 614/ EAL,-
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PUBLIC HEALTH SERVICE
`
`1
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`21-897
`
`000
`
`DATE RECEIVED BY CENTER:
`
`14—Feb-2006
`
`PRODUCT:
`
`VivitrolTM (naltrexone for extended—
`
`release injectable suspension)
`
`INTENDED CLINICAL POPULATION:
`
`Patients seeking treatment for alcohol
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`dependence
`
`Alkermes® Inc.
`
`Complete response to AE Letter
`Division of Anesthesia, Analgesia, and
`
`Rheumatology Products (HFD—170)
`
`Mamata De, Ph.D.
`
`R. Daniel Mellon, Ph.D.
`
`Bob A. Rappaport, M.D.
`
`Lisa Basham—Cruz, M.S.
`
`Date of review submission to Division File System (DFS): 12—Apr—2006
`
`

`

`
`
`Reviewer: R. Daniel Mellon PhD. NDA No. 21—897
`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability
`
`From the pharmacology toxicology perspective, NDA 21-897 may be
`APPROVED, pending agreement on the labeling and Phase 4 commitments
`outlined below.
`
`In the original action letter dated December 23, 2005, the Sponsor was
`requested to address the following nonclinical deficiency:
`
`Provide pharmacokinetic/toxicokinetic exposure data in the appropriate
`species necessaryfor 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] reproductive and developmental toxicology study
`including toxicokinetic data in a single species with thefinal drug
`productformulation;
`
`b. Segment 1] reproductive and developmental toxicology studies in
`two species including toxicokinetic data with the final drug
`productformulation;
`
`c.
`
`a Segment [1] reproductive and developmental toxicology study
`including toxicokinetic data with thefinal drug product
`formulation; and
`
`d.
`
`carcinogenicity assessment in two species using the final drug
`productformulation.
`
`Following discussions with the Sponsor during a post—action teleconference
`on January 3, 2006, the Division informed the sponsor of the following (e-
`mail dated February 7, 2006):
`
`The review team has considered your proposal to submit a response to the
`December 23, 2005 action letter that employs human comparative PK
`data as an interim bridging strategy and proposes definitive bridging in
`animals as a Phase 4 study. We are willing to acceptfor review a
`response to our action letter that uses your proposed approach to
`deficiency #2 ofour December 23, 2005, action letter, although the review
`team is not in exact agreement with some aspects of the proposed labeling.
`
`

`

`
`
`
`
`'Reviewer: R. Daniel Mellon Ph.D. NDA No. 21—897
`
`The Sponsor has not provided adequate nonclinical bridging data, nor have
`they completed the requested toxicology studies. From the nonclinical
`perspective, the potential for reproductive toxicity and carcinogenicity of oral
`naltrexone was adequately assessed to support the approval of the referenced
`drug product, ReVia®. The exposure to naltrexone via the VivitrolTM drug
`product could theoretically alter the potential for naltrexone—related tumor
`development compared to that of ReVia®. Therefore, with respect to the
`
`
`VivitrolTM label,
`/ - /
`/ / / / / / 7
`
`,
`
`Currently, ReVia® is a Pregnancy Category C drug due to embryocidal and
`fetotoxic effects noted in rats and rabbits treated orally with naltrexone as
`described in the ReVia® labeling. Although the exposure to naltrexone may
`be greater following VivitrolTM administration, a Pregnancy Category of C is
`currently the most restrictive category a drug can receive in the absence of
`well-controlled clinical trial data documenting teratogenic effects in humans.
`
`/
`
`/
`
`/
`
`/ ‘ /
`
`The results of the carcinogenicity studies conducted for ReVia® and
`described in the ReVia® package insert are relevant to the VivitrolTM drug
`product and should be included in the labeling; i
`
`a
`
`f
`
`/
`
`/
`
`l/
`
`[I
`
`_
`
`The
`
`-
`w
`__,_,
`potential for VivitrolTM to alter the incidence of the reported testicular
`mesotheliomas in males and tumors of vascular origin in males and females
`should be included in the product labeling. However, it is important to note
`nonclinical carcinogenicity studies are designed to assess the potential for
`lifelong exposure of a drug to alter tumor formation, and the tumors described
`in the ReVia® labeling were observed following lifelong exposure of the
`animals to naltrexone hydrochloride. However, there is no evidence that
`altering the naltrexone pharmacokinetic profile via VivitrolTM will
`significantly change the riskzbenefit analysis with respect to this patient
`population.
`
`Following extensive discussions, the review team has agreed to allow the
`nonclinical studies requested in the original Approvable letter to be completed
`during Phase 4. As outlined in Dr. Rappaport’s Division Director’s
`Memorandum for this action, from the clinical perspective, specific
`
`

`

`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`quantification of both the potential reproductive toxicity and carcinogenic
`potential following exposure to naltrexone via VivitrolTM product is
`outweighed by the potential clinical benefit that VivitrolTM may have for this
`patient population. The reader is referred to Dr. Rappaport’s memorandum
`regarding the specific details supporting the decision to allow the studies to be
`completed as a phase 4 commitment.
`
`B. Recommendation for nonclinical studies
`
`The following nonclinical studies should be conducted as a Phase 4
`commitment:
`
`1.
`
`a Segment 1 reproductive and developmental toxicology study
`including toxicokinetic data in a single species with the final drug
`product formulation,
`
`Protocol Submission: by October 7, 2006
`Study Start: by January 7, 2007
`Final Report Submission: by January 7, 2008
`
`Segment II reproductive and developmental toxicology studies in
`two species including toxicokinetic data with the final drug
`product formulation,
`
`Protocol Submission: by October 7, 2006
`Study Start: by January 7, 2007
`Final Report Submission: by January 7, 2008
`
`a Segment III reproductive and developmental toxicology study
`including toxicokinetic data with the final drug product
`formulation, and
`
`Protocol Submission: by October 7, 2006
`Study Start: by January 7, 2007
`Final Report Submission: by January 7, 2008
`
`Carcinogenicity assessment in two species using the final drug
`product fomiulation.
`
`Protocol Submission: by April 7, 2007
`Study Start: by August 7, 2007
`Final Report Submission: by August 8, 2010
`
`In lieu of the animal studies listed in commitments 1 through 4
`above, you may be able to obtain adequate
`
`

`

`Reviewer: R. Daniel Mellon, Ph.D.
`
`NDA No. 21-897
`
`pharmacokinetic/toxicokinetic exposure data in the appropriate
`species necessary for interpreting the existing carcinogenicity and
`reproductive toxicology data on oral naltrexone in the product
`labeling. Bridging data will be needed for the mouse, rat, pregnant
`rat and pregnant rabbit. The following timelines should be
`followed for this option:
`
`Protocol Submission: by October 7, 2006
`Study Start: by January 7, 2007
`Final Report Submission: by January 7, 2008
`
`C. Recommendations on labeling
`
`At the time of this action, the following labeling is recommended:
`
`Carcinogenesis, mutagenesis, impairment of fertility
`
`Carcinogenicity studies have not been conducted with VlVlTROL.
`
`Carcinogenicity studies for 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 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/mzlday). There
`was no 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
`VIVlTROL. 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 when given orally to rats at doses 2 30 mg/kg/day (180
`mg/m2/day) and rabbits administered 2 60 mg/kg/day (720 mg/mzlday).
`
`

`

`Reviewer: R. Daniel Mellon, Ph.D.
`
`NDA No. 21-897
`
`There are no adequate and well-controlled studies of oral naltrexone and
`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 6B—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.
`
`R. Daniel Mellon, Ph.D.
`Pharmacology Toxicology Supervisor, DAARP
`
`APPEARS THlS WAY
`ON ommrmt
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`R. Daniel Mellon
`
`4/12/2006 01:34:33 PM
`PHARMACOLOGI ST
`
`Pharmacology Toxicology Supervisor
`
`

`

`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`21-897
`
`000
`
`31-Mar-2005
`
`Vivitrol®
`
`INTENDED CLINICAL POPULATION:
`SPONSOR:
`
`Alcohol dependence
`Alkermes Inc.
`
`DOCUMENTS REVIEWED:
`
`Pharmacology Toxicology Review by Dr. Mamata
`
`De, with reference to the Sponsor’s electronic
`submissions and the relevant literature
`
`REVIEW DIVISION:
`
`Division of Anesthesia, Analgesia, and
`
`Rheumatology Products (HFD-170)
`
`PHARM/TOX REVIEWER:
`
`Mamata De, Ph.D.
`
`PHARM/TOX SUPERVISOR:
`
`R. Daniel Mellon, Ph.D.
`
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`Bob A. Rappaport, M.D.
`Lisa Basham-Cruz
`
`Date of review submission to Division File System (DFS): 21—Dec-2005
`
`

`

`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`EXECUTIVE SUMMARY
`
`I.
`
`Recommendations
`
`A. Recommendation on approvability
`
`From the pharmacology toxicology perspective, NDA 21-897 is Approvable.
`
`. Recommendation for nonclinical studies
`
`The Sponsor has not provided data necessary to demonstrate the adequacy of
`the existing carcinogenicity or reproductive and developmental toxicology
`data referenced as part of this 505(b)(2) NDA. The Sponsor should either
`complete the following studies to support the NDA:
`
`The Sponsor must 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:
`
`1.
`
`2.
`
`3.
`
`4.
`
`a Segment 1 reproductive and developmental toxicology study
`including toxicokinetic data in a single species with the final drug
`product formulation,
`
`Segment II reproductive and developmental toxicology studies in
`two species including toxicokinetic data with the final drug
`product formulation,
`
`21 Segment III reproductive and developmental toxicology study
`including toxicokinetic data ,with the final drug product
`formulation, and
`
`carcinogenicity assessment in two species using the final drug
`product formulation.
`
`In addition, the proposed label W
`m
`
`

`

`1
`
`-
`
`2
`
`
`
`%_
`
`
`
`Page(s) Withheld
`
`Trade Secret / Confidential
`
`DQliberative Process.
`
`
`
`/Draft Labeling
`
`

`

`
`Reviewer: R. Daniel Mellon Ph.D.
`NDA No. 21—897
`
`i/ /
`
`p
`
`/ /
`
`/
`
`BASIS OF CONCLUSIONS AND RECOMMENDATIONS
`
`Following review of Dr. Mamata De’s primary review of NDA 21—897, the numerous
`discussions that took place between Dr. De and myself during the review process, my
`own reference to the NDA application, and discussion with Dr. Kenneth Hastings, Ph.D.
`(Associate Director for Pharmacology and Toxicology for'ODE 2 and 3), it is my opinion
`that from the pharmacology and toxicology perspective, the NDA is Approvable. There I
`are several deficiencies that could be overcome with additional toxicokinetic studies or
`toxicology studies that, from this discipline’s perspective, could make the NDA
`approvable. This memo was written to outline the key areas of concern and delineate
`how they could be resolved.
`
`Although the Sponsor’s application is deficient from a regulatory perspective in terms of
`failing to provide adequate patent certification for the multiple referenced NDAs, it is my
`opinion that in the absence of the referenced findings from NDAs other than the
`referenced oral naltrexone drug product Revia (NDA 18-932), the deficiencies noted
`above for NDA 21-897 Vivitrol) would be the same. In other words, the other NDAs
`discussed in the Sponsor’s submission were not required for this action.
`
`Sponsor’s Basis for NDA Application:
`
`As stated in the NDA application (Nonclinical overview, page 1—2):
`
`Alkermes Inc., is submitting this NDA under Section 505(b)(2) of the FDC Act.
`The non-clinical safety of Vivitrex (naltrexone long-acting injection) is established
`based upon:
`
`.
`
`o
`
`The Agency’s previous determination of the safety of oral naltrexone
`tablets, 50 mg (Revia NDA 18-932, approved December 30, 1994 for the
`treatment alcohol dependence). A paragraph ll patent certification which
`certifies to the patents listed in the Orange Book is included in Section
`1.3.5.2.
`
`The following specific studies conducted with Vivitrex microspheres in
`accordance with the agreements from the pre-NDA meeting (March 25,
`2004p
`
`

`

`Reviewer: R. Daniel Mellon, Ph.D.
`
`NDA No. 21—897
`
`STUDY
`NUMBER
`
`AT-21-01
`
`"“5
`
`A Local Tolerance Study of Medisorb Naltrexone in Rabbits Following
`a Single Subcutaneous Injection
`
`AT-21-02
`
`One-Month Toxicokinetic Study of Medisorb Naltrexone in Rhesus
`Monkeys with One-Month Recovery
`
`
`
`AT-21 03
`
`AT-21-O4
`
`AT—21-05
`
`AT-21 06
`
`AT-21-07
`
`A 3-month Repeated-Dose Toxicokinetic Study of Medisorb Naltrexone
`Administered by Subcutaneous Injection to Rhesus Monkeys, With a
`3-Month Recovery Period.
`
`Chronic Local Tolerance Study of Medisorb Naltrexone in Rabbits
`following a Single Subcutaneous and Intramuscular Injection
`
`Chronic Local Tolerance and Pharmacokinetic Evaluation of Medisorb
`.
`.
`.
`.
`Naltrexone in Dogs followmg Repeated Intramuscular Injections
`
`Investigative Acute Local Tolerance Evaluation of Medisorb Naltrexone
`.
`.
`.
`.
`.
`in Dogs followmg Intramuscular Administration
`
`Investigative Local Tolerance Study of Medisorb Naltrexone in Rabbits
`.
`-
`-
`-
`followmg Intramuscular Administration
`_
`
`-
`
`Information from published literature on the safety of naltrexone available
`in the public domain
`
`Upon review of the NDA application and the submitted labeling, it is clear that
`the Sponsor refers to the Agency’s previous findings for more than just the Revia
`NDA. Specifically, the table below outlines the nonclinical data the Sponsor
`references in the NDA application in support Vivitrol formulation. The Sponsor
`did not submit nonclinical studies with Vivitrol formulation for any of the
`nonclinical requirements listed in the table. The table therefore breaks down the
`references to naltrexone alone and references to data on polylactide-co—glycolide
`microspheres that were either published or submitted in support of other NDA
`applications.
`
`.
`Naltrexone
`‘ Referenced Data
`
`PLG microspheres‘
`
`Referenced Data
`
`
`
`
`
`NDA 18-932 (Revia)
`
`
`NDA 18-932 (Revia)
`
`
`NDA 18-932 (Revia)
`
`
`
`NDA 18-932 (Revia)
`
`

`

`
`Reviewer: R. Daniel Mellon Ph.D.
`NDA No. 21-897
`
`Tabte 2.6: Comparison of NOAELS from Ora! Maltrexone Studies and Dose
`Maitiples Reiative to Vivitrex suspension
`
`
`NOAEL"
`ORAL
`(mglkgklay)
`DOSE
`
`
`
`MULTfPLE
`
`SPECIES
`
`TYPE OF
`STUD-Y
`
`DOSE MULTIPLE RELATIVE TO VIVITREX
`380 mg‘
`
`mglkg BASIS
`
`
` BSA BASE?
`
`
`
`
`
`
`
`Monkey
`f
`
`EU
`
`
`
`Subchrnms.
`
`Dag
`
`a
`
`2Q
`
`7!]
`
`40
`
`.
`
`_.
`
`a:m
`
`
`
`
`.,
`
`~-
`
`‘ 7 -
`
`R31.
`
`R ,
`
`
` Mouse
`
`
`66
`
`@813
`
`
`
`f‘ NGAEL: No Observed Advelse Effect Lave?
`'7 Ciatctéated using a therapeutic human dose of '1 mg naltrexonefitgfday (derived fer the stand-am? daié’y
`_ orai naltrexone dese- crf 50 mg, and an assumed body weight of 59 kg}.
`" Catcuéated by comparésm of the ALICE?“ for Vwittex to the aggregate AUG“ "28 days fer orat
`
`ficrnmlatioa MUCH“ $1.2 ngrday'z’mi for oral and $55 t 24 ng-day'fml. for a 330 mg dose of ‘v
`.. resulting in a conversion factor of 3.9)
`
`mg g :0 BSA conversion factors adapted from Freireich 1913i. {20} and Gasarett and Doull’s
`Toxicotogy {2'1}.
`
`The Sponsor’s exposure margin assessments as noted in the table above are not adequate
`for the following reasons:
`
`1. Due to the differences between routes of administration and PK profile, a
`direct comparison of doses on a mg/kg basis is not informative. Therefore,
`the dose multiples in the second column from the right above cannot be taken
`into consideration for interpretation and labeling.
`
`2. The determination of the multiples of exposure based on body surface area is
`not appropriate for this formulation either due to the differences in PK
`between the daily oral route and that produced by monthly Vivitrol injections.
`Specifically,
`
`a. The toxicology studies supporting the Revia NDA utilized the oral route
`of administration whereas Vivitrol is administered via IM inj ection and
`did not provide toxicokinetic data.
`
`b. Oral naltrexone is subjected to significant first pass metabolism by the
`liver. The IM route of administration provides greater exposure, in part
`due to reducing drug lost to first pass metabolism in the liver.
`
`

`

`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`Dr. Srikanth Nallani, the clinical pharmacology and biopharmaceutics reviewer for NDA
`21-897 stated the following in his review:
`
`The proposed 380 mg dose of IM Vivitrol is approximately 1/3rd compared
`to oral naltrexone (50 mg QD for 28 days = 1400 mg over 28 days).
`However, the exposure to naltrexone (AUCo—zs) over 28 days is
`approximately four-fold higher than that observed with oral naltrexone.
`This appears to be a result of bypassing of first pass metabolism by the IM
`route.
`
`As outlined in Dr. Nallani’s Clinical Pharmacology and Biopharmacetics review,
`differences between these two formulations include: 1) differences in Cmax and AUC
`such that Vivitrol has on average a 4-fold greater AUC, and 2) differences in the effects
`of first pass metabolism due to the different routes of administration (Vivitrol resulted in
`significantly lower levels of 6B-naltrexol). However, even using a mean value over the
`course of the month is an oversimplification of the exposure margin, which can be
`illustrated by the Sponsor’s Clinical data. Specifically, the figure below (Figure 6, page
`43 of 66 of Study Report ALK2l-005) illustrates the plasma concentration of naltrexone
`(open circles) after 4 injections of 380 mg once every 28 days. It is clear from the time
`course that the AUC over the interval from Day 0 to Day 7 is far greater than the AUC
`over the interval from Day 21 to Day 28.
`
`SmagM-‘w": 342214
`203.9
`
`{minis}
`
`amfilfimfi‘nn
`
`figure. 5 Mean 2 ialtii‘exone and éfi—Naitrexoi Plasma Concentration versus Time
`Profile (9-56 Days) following Dose :1 of 4 of a‘s-‘Iediserh Naitz‘emne 3813 mg
`(Coherf B, 2 "=12;
`
`A further limitation of the data referenced in the Revia NDA is that the studies that were
`
`completed for the Revia NDA do not contain toxicokinetic values that could be as the
`basis for comparison. Without toxicokinetic exposure data for the conditions tested in the
`nonclinical studies submitted for Revia, the results cannot be put into perspective to the
`clinical exposure to the Vivitrol product.
`
`:MOOEMISSQ‘d1838
`
`

`

`Reviewer: R. Daniel Mellon, Ph.D.
`
`NDA No. 21-897
`
`Regulatory Status of the Polylactide—co—glycolide Polymer
`
`-- poly mactideico-glycolide polymer '
`The NDA submission states that the 75:25 '
`(also referred to as 7525 V "‘
`polymer by the Sponsor) is listed in the FDA Inactive
`'
`Ingredient Database under Polyglactin (CAS # 026780-50-7), and there is considered to
`be safe. Specifically, Section 3.2.P.2.1.2.1 7525
`"‘" POLYMER of the NDA
`describes the drug product component as follows:
`
`The biod/aradable polymer excipient used for Vivitrex microspheres'Is
`7525
`a 5 ® polymer comprised of lactide
`and glycolide monomers in a mole ratio of 75. 25.7525 —.
`polymer'IS a
`member of the poly
`.lactide——co-glycolide) (PLG) class of biodegradable
`copolymers.
`
`'
`
`PLG is a common, biodegradable medical polymer having a history of safe
`human usage in sutures, orthopedics, bone plates and extended release
`pharmaceuticals.
`It is also listed in the FDA Inactive Ingredients Database
`(polyglactin CAS # 026780507) and is usedIn a similar dosage form, the same
`route of administration andIn essentially the same concentration'In Vivitrex
`microspheres.
`
`The Inactive Ingredients Database does report that polyglactin 370 (CAS 26780-50—7) is
`an inactive ingredient in approved implanted and injected drug products.) "fi
`
`//
`
`-_
`
`.//-. /_ .
`
`//
`
`The Vivitrol drug productIS a member of the class of polymers that has a specific
`lactide:glycolide mole ratio of 75:25. Changing the lactide:glycolide mole ratio alters the
`rate of biodegradation. In general, the greater glycolide content, the faster the rate of
`biodegradation. This characteristic of the class of copolymers is illustrated by the figure .
`below which depicts the amount of radioactivity that is recovered from the rat when the
`radiolabel is attached to the lactide component of the polymer [reproduced from
`(Anderson and Shive, 1997)].
`
`

`

`mooMissedrm
`
`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`g
`7;
`g 30
`=5
`
`amidesalyeolide Mala Ratio
`II 100:0
`92:3
`37113
`74:25
`50:50
`
`E. so
`
`58
`
`a:
`
` mo
`
`40
`
`.
`
`2,; 20
`IL
`
`:2. .V’IOD
`
`.7 “he fav;
`
`.
`\
`
`
`Time, weeks
`
`As illustrated above the biodegradation of a copolymer with a lactide:glycolide mole ratio
`of 50:50 is relatively rapid, with the polymer being virtually eliminated from the rat by
`~10 weeks after IM injection. In contrast, decreasing the glycolide content to make a
`copolymer with a lactide:glycolide mole ratio of 74:26 has a significant effect on the
`biodegradation rate. As illustrated above, approximately 20% of the injected 74:26
`polylactide-co-glycolide polymer was still present in the rat over 35 weeks after IM
`injection. All of the copolymers described in the figure above are poly:
`-1actide-co-
`glycolide) compounds with the same CAS number.
`
`In addition to the lactide:glycolide ratio, the characteristics of the drug incorporated into
`the polylactide-co-glycolide polymers alters the release rate and biodegradation of the
`drug product. The effect of
`l
`,_ “"~
`on the biodegradation rate of the
`polymer was noted in the NDA submission. Specifically, the Drug Product Overview
`states the following:
`
`"In vitro release data show drug content strongly affects naltrexone microsphere
`drug release behavior.”
`
`“Because ..W it
`a
`
`Collectively, the Sponsor’s references to data reported in NDAs drug products
`
`-.,—--
`
`'
`”
`product.
`
`' "
`
`.10 not provide adequate support for the safety of the Vivitrol drug
`
`Based upon these clear differences in PK and inability to provide a meaningful
`assessment of the potential exposure margins extrapolated from the referenced Revia
`
`10
`
`

`

`Reviewer: R. Daniel Mellon, Ph.D.
`
`NDA No. 21-897
`
`data, I must conclude that the NDA should be supported by either adequate toxicokinetic
`exposure data necessary to interpret the referenced reproductive and developmental
`toxicology and carcinogenicity data and to complete these portions of the label for
`Vivitrol.
`’
`
`Unresolved toxicologyy issues (if any}:
`
`Reproduction and Developmental Toxicology:
`
`The Sponsor elected to reference the NDA for Revia to support the requirement for
`reproduction and developmental toxicology assessment of their drug product.
`I agree
`with Dr. De’s conclusion that the existing data on naltrexone alone is inadequate to
`support the Vivitrol NDA. The basis for this conclusion, as outlined above, is that
`inadequate data were provided to determine meaningful exposure margins for Vivitrol
`based on the studies submitted for Revia. The Sponsor’s proposed use of body surface
`area comparisons to establish the exposure margins for the carcinogenicity data are do
`not provide meaningfill assessment of the study findings due to differences in PK.
`
`Carcinogenicity:
`
`The Sponsor elected to reference the NDA for Revia to support the requirement for
`carcinogenicity assessment of their drug product.
`I agree with Dr. De’s conclusion that
`the existing data on naltrexone alone is inadequate to support the Vivitrol NDA. The
`basis for this conclusion, as outlined above, is that inadequate data were provided to
`determine meaningfiil exposure margins for Vivitrol based on the studies submitted for
`Revia. The Sponsor’s proposed use of body surface area comparisons to establish the
`exposure margins for the carcinogenicity data are do not provide'meaningful assessment
`of the study findings due to differences in PK.
`
`Recommendations:
`
`The Sponsor has not provided data necessary to demonstrate the adequacy of
`the existing carcinogenicity or reproductive and developmental toxicology
`data referenced as part of this 505(b)(2) NDA. The Sponsor should either
`complete the following studies to support the NDA:
`
`The Sponsor must 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:
`
`1.
`
`a Segment I reproductive and developmental toxicology study
`including toxicokinetic data in a single species with the final drug
`product formulation,
`
`11
`
`

`

`
`
`Reviewer: R. Daniel Mellon Ph.D. NDA No. 21-897
`
`2.
`
`3.
`
`4.
`
`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
`
`carcinogenicity assessment in two species using the final drug
`product formulation.
`
`Reference List
`
`Anderson JM and Shive MS (1997) Biodegradation and biocompatibility of PLA and
`PLGA microspheres. Advanced Drug Delivery Reviews 28:5-24.
`
`12
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electrOnic signature.
`
`R. Daniel Mellon
`
`12/21/2005 06:16:24 PM
`PHARMACOLOGIST
`.
`
`Pharmacology Toxicology Supervisor
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`21—897
`
`000
`
`03/30/05
`
`Vivitrol®
`
`INTENDED CLINICAL POPULATION:
`
`Treatment of alcohol dependence
`
`SPONSOR:
`
`DOCUMENTS REVIEWED:
`
`Alkermes, Inc.
`
`eCTD Module 2 and 4
`
`REVIEW DIVISION:
`
`Division
`
`of
`
`Anesthesia,
`
`Analgesia,
`
`and
`
`Rheumatology Products (HFD-170)
`
`PI—IARM/TOX REVIEWER:
`
`Mamata De, Ph.D.
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`R. Daniel Mellon, Ph.D.
`
`Bob A. Rapapport, M.D.
`
`Lisa Basham Cruz, M.S.
`
`Date ofreview submission to Division File System (DFS): December 16, 2005
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................. 19
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY ................................................................. 19
`
`2.6.2 PHARMACOLOGY ................. 22
`2.6.2.1
`Brief summary ...................................................................................................................... 23
`2.6.2.2
`Primary pharmacodynamics ................................................................................................. 23
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................. 36
`2.6.2.4
`Safety pharmacology ............................................................................................................ 37
`2.6.2.5
`Pharmacodynamic drug interactions ..................................................................................... 38
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY ....................................................... 38
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 38
`2.6.4.1
`Brief summary ...................................................................................................................... 38
`2.6.4.2
`Methods of Analysis ............................................................................................................. 39
`2.6.4.3
`Absorption ............................................................................................................................ 39
`2.6.4.4
`Distribution ........................................................................................................................... 41
`2.6.4.5
`Metabolism ........................................................................................................................... 49
`2.6.4.6
`Excretion ............................................................................................................................... 53
`2.6.4.7
`Pharmacokinetic drug interactions ........................................................................................ 59
`2.6.4.8
`Other Pharmacokinetic Studies ............................................................................................. 60
`2.6.4.9
`Discussion and Conclusions ................................................................................................. 6O
`2.6.4.10
`Tables and figures to include comparative TK summary ...................................-.............. 6 1
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY ............................................... 62
`
`2.6.6 TOXICOLOGY .............................................................................................................. 62
`2.6.6.1
`Overall toxicology summary ................................................................................................ 62
`2.6.6.2
`Single-dose toxicity .............................................................................................................. 77
`2.6.6.3
`Repeat-dose tox1crty ......................................... 78
`2.6.6.4
`Genetic toxicology .............................................................................................................. 1 13
`2.6.6.5
`Carcinogenicity ................................................................................................................... 114
`2.6.6.6
`Reproductive and developmental toxicology ...................................................................... 1 15
`2.6.6.7
`Local tolerance ................................................................................................................... 117
`2.6.6.8
`Special toxicology studies .................................................................................................. 125
`2