CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICA TION NUMBER:
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`2 1 -8 9 7
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`CLINICAL PHARMACOLOGY AND
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`BIOPHARMACEUTICS REVIEW! S 2
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`DEPARTMENT OF HEALTH AND
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`HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
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`7;) ad (I ,GI/I/
`-\
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`
`
`From:
`
`Srikanth C. Nallani, PhD.
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`DATE: 4/7/2006
`
`IND No.:
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`NAME OF DRUG
`[ Vivitrol
`
`NDA NO. 21-897
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`DATE OF DOCUMENT
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`2/13/2006
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`PRIORITY CONSIDERATION
`Standard
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`Date Ofinformal/Formal
`Consult:
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`I
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`2/13/2006
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`A
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`NAME OF THE SPONSOR: [ Alkermes, 88 Sidne St, Cambrid_e, MA 02139 ]
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`TYPE OF SUBMISSION
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
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`'
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`Clinical Pharmacology & Biopharmaceutics
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`(HFD 870)
`Tracking/Action Sheet for Formal/Informal Consults
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`To: DOCUMENT ROOM (LOG—1N and LOG—OUT)
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`Please log-in this consult and review action for the specified IND/NDA submission
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`I] PRE—IND
`[:IANIMAL to HUMAN SCALING
`[:1 IN-VITRO METABOLISM
`D PROTOCOL
`[1 PHASE II PROTOCOL
`E] PHASE III PROTOCOL
`[1 DOSING REGIMEN CONSULT
`El PK/PD- POPPK ISSUES
`I:I PHASE IV RELATED
`
`[:1 DISSOLUTION/IN-VITRO RELEASE
`|:| BIOAVAILABILITY STUDIES
`El IN—VIVO WAIVER REQUEST
`1:] SUPAC RELATED
`El CMC RELATED
`I] PROGRESS REPORT
`[I SCIENTIFIC INVESTIGATIONS
`E] MEETING PACKAGE (EOPZ/Pre-
`NDA/CMC/Pharmacometrics/Others)
`'
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`'
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`1:! FINAL PRINTED LABELING
`|:| LABELING REVISION
`E] CORRESPONDENCE
`[I DRUG ADVERTISING
`[j ADVERSE REACTION REPORT
`I] ANNUAL REPORTS
`[I FAX SUBMISSION
`E] OTHER (SPECIFYBELOW):
`[ Complete Response for Action
`(12/28/2005) to Original NDA submitted on
`3/31/2005
`
`REVIEW ACTION
`
`I: NAI (No action indicated)
`E] E—mail comments to:
`DMedicalDChemistDPharm-Tex
`DMicroDPhannacometricsDOthers
`(Check as appropriate and attach e—mail)
`
`El Oral communication with
`Name:
`[
`]
`El Comments communicated in
`meeting/Telecon. see meeting minutes
`dated:
`I
`I
`
`El Formal Review/Memo (attached)
`XUSee comments below
`DUSee submission cover letter
`[:I OTHER (SPECIFY BELOW):
`[
`]
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`COMMENTS/SPECIAL INSTRUCTIONS:
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`
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`REVIEW COMMENT(S)
`D NEED TO BE COM MUNICATED TO THE SPONSOR
`U HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`
`-
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`[ Current submission consists of Alkermes' response to approvable letter issued on 12/28/2005 for NDA 21-897 submitted on 3/31/2005.
`With regard to Clinical Pharmacology and Biopharmaceutics comments (# 4, 5 and 6) in the approvable letter, the sponsor agrees to
`address them in an appropriate post—approval submission. The following is the proposed timeline for the completion of post—marketing
`commitments (PMC) agreed to by the Sponsor:
`1. Revise the drug release specifications to include Day 14 and Day 28 drug release information.
`The timeline for this PMC will be addressed by the Office of New Drug Quality Assurance.
`2. Conduct in vitro CYP inhibition studies using conventional CYP substrates and validated analytical methodology.
`Protocol Submission:
`July/2006
`Study Start:
`August/2006
`Final Report Submission:
`May/2007
`3. Conduct in vitro studies in human hepatocytes to evaluate the potential of naltrexone to induce CYP3A4 and CYP1A2.
`Protocol Submission:
`July/2006
`.
`Study Start:
`August/2006
`Final Report Submission:
`May/2007
`Please find the cover letter from sponsor attached to this review. The sponsor also submitted labeling changes, however, none were
`pertinent to Clinical Phaimcaolo and Bio harmaceutics as-ects andhence were not reviewed.
`]
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`SIGNATURE OF REVIEWER: Srikanth C. Nallani PhLD.
`. SIGNATURE OF TEAM LEADER: Suresh Doddallanet Ph.D.
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`CC~= HFD # l
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`Project Manager: Lisa Basham-Cruz
`Date
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`Date 4/7/2006
`Date 4/7/2006
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`4.4 Consent of Supervisor for the proposed Phase IV commitments
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`Nailani, Srikanth
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`
`.
`
`Fro‘m:
`Sent:
`To:
`Subject:
`
`Srikanth
`
`Doddapaneni Suresh
`Friday, November 18 2005 8.34 AM
`Nallani Srikanth
`FW‘. Srlkanth‘s NDA-Naltrexone depot formulationl
`
`Printout this e-mail and attach it to the review as DivisionDirector‘s concurrence. Thisisin line with OCPB'S procedure.
`
`Thanks. Suresh
`-----Original Message-----
`From:
`Malinowski, Henry J
`Sent:
`Friday, November 18, '2005 8:28. AM
`To:
`Doddapan’er‘ii, surie‘sh
`Subject:
`RE: Sn'kanth‘s'NDA-threxonevdepot formulation]
`
`Suresh.
`Looks fine...Hank
`
`, -----Original Message-m—
`From:
`Doddapanerii,5uresh
`Sent:
`Thursday, November 17, 2005 12:44 PM
`To:
`‘Malinowski, Henry’s.)
`Subject:
`Srikanth's NDA-Nallrexone depot formulationl
`
`Hank
`
`I have extracted from the
`The review for depotnaltrexo'n‘e product is being finalized. We hadthe-briefing on this on Tuesday.
`review, the recommendation/phase lV commitment related language'that Srikanth and l drafted. Please provide your
`feedback.
`
`Thanks, Suresh
`
`1.1 Recommendation
`From a Clinical Pharmacology and Biopharmaceutics perspective, NDA21-897IS acceptable provided that a
`mutually satisfactory agreement canbe reached betWeen the Agency and Alke'rmes regarding the (a) languagein
`
`b)
`
`p
`.
`inforrnation
`Conduct in vi‘z‘ro. CYP inhibition studies using conventional substrates as the submitted data used
`florescent substrate‘(si)"w.hich tends to introduce nZOn-sp'eciifieity in detection.
`
`0) Conduct in vitro-.'studies in human hepatocytes to evaluatepotential of naltrexone to induce CYP3A4vand
`CYP 1A2.
`'
`
`1.2 PhaseIV Commihnents
`
`a) Conductin. vitr'oeC-ZYP-inhibition. studies-Wing; conventional CYP substrates and validated analytical
`methodology.
`-
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`b)
`
`Conduct .1' n-Vitrastudies in. human. hepat'ocytes to evaluate potential of naltrexone 'to induce CYP3A4
`and CYR’IAZ.
`
`89
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Srikanth Nallani
`
`11/21/2005 11:09:54 AM
`BIOPHARMACEUTICS
`
`Suresh Doddapaneni
`11/21/2005 01:47:33 PM
`BIOPHARMACEUTICS
`
`

`

`/ ST 09612/
`
`CLINICAL PHARMACOLOGY AND BIOPHARMACE‘UTICS REVIEW
`
`NDA: 21—897
`
`Brand Name
`
`Generic Name
`
`Reviewer
`
`Team Leader
`
`OCPB Division
`
`ORM Division
`
`Submission Date(s): 03/31/05
`
`Vivitrol® (Naltrexone Long-Acting Injection)
`
`Naltrexone
`
`Srikanth C. Nallani, Ph.D.
`
`Suresh Doddapaneni, Ph.D.
`
`Division of Pharmaceutical Evaluation II
`
`Division of Anesthesia, Analgesia, , and
`Rheumatology Products
`
`Sponsor
`
`Alkermes, 88 Sidney St, Cambridge, MA
`
`Relevant IND(s)
`
`61,138
`
`Submission Type; Code
`
`Original NDA; 3P
`
`Formulation; Strength(s)
`
`Extended release microsphere formulation of
`naltrexone for suspension to be administered by IM
`injection; 380 mg in 5 mL vials
`
`Indication
`
`Treatment of alcohol dependence
`
`Dosing Regimen
`380 mg IM every 4 weeks or once a month
`
`
`Table of Contents
`
`1
`
`Executive Summary ..................................................................................................... 2
`1.1
`Recommendation..............................................; ................................................................... 2
`1.2
`Phase IV Commitments ......................................................................................................... 2
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ......................................... 2
`1.3
`2 QBR .......................................................................................-....................................... 6
`2.1
`General Attributes ................................................................................................................. 6
`2.2 General Clinical Pharmacology .............................................................................................. 8
`2.3
`Intrinsic Factors .................................................................................................................. 20
`2.4
`Extrinsic Factors ...................,.............................................................................................. 26
`
`General ’Biopharmaceutics ........................................................... _........................................ 27
`2.5
`2.6 Analytical Section ............................................................................................................... 32
`
`Detailed Labeling Recommendations ................................................................... 34
`3.
`4 Appendix...........................- ......................._ .................................................................. 3 6
`4. 1
`Proposed Package Insert ...................................................................................................... 36
`4.2
`Study Synopses ................................................................................................................... 57
`4.3
`CPB filing/review form ....................................................................................................... 87
`4.4
`Consent of Supervisor for the proposed Phase IV commitments .............................................. 89
`
`

`

`1
`
`Executive Summary
`
`1.1 Recommendation
`
`From a Clinical Pharmacology and Biopharmaceutics perspective, NDA 21-897 is
`acceptable provided that a mutually satisfactory agreement can be reached between the
`Agency and Alkermes regarding the (a) language in the package insert (b) in vitro drug
`release method, and (0) post marketing commitment to further investigate potential of this
`product to inhibit or induce CYP enzymes. Specifically,
`
`a) The drug release specifications should be revised with addition of Day 14 and
`Day 28 drug release information.
`b) Conduct in vitro CYP inhibition studies using conventional substrates as the
`submitted data used florescent substrate(s) which tends to introduce non-
`specificity in detection.
`.
`0) Conduct in vitro studies in human hepatocytes to evaluate potential of naltrexone
`to induce CYP3A4 and CYP1A2.
`'
`
`1.2
`
`Phase IV Commitments
`
`a)
`
`b)
`
`Conduct in vitro CYP inhibition studies using conventional CYP substrates
`and validated analytical methodology.
`
`Conduct in vitro studies in human hepatocytes to evaluate potential of
`naltrexone to induce CYP3A4 and CYP1A2.
`
`1.3
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`Naltrexone is a pure opioid antagonist with highest affinity for the u-opioid receptor.
`The mechanism of action of naltrexone in alcoholism is not clearly understood.
`However, it is believed that naltrexone decreases alcohol consumption through the
`blockade of endogenous opioids at u-opioid receptors, resulting in inhibition of the
`reward pathways and thus reducing the subjective euphoric and reinforcing properties of
`alcohol. In 1994, oral naltrexone (ReviaTM) was approved for the treatment of
`alcoholism. Current NDA is a 505(b)(2) submission by Alkermes Inc. for a once a month
`extended release microsphere formulation of naltrexone for intramuscular injection for
`the same indication (referred to as Vivitrol in this document). Based on the sponsor’s
`argument that this product will improve compliance compared to once a day
`administration of oral naltrexone, the NDA was awarded priority review status.
`
`Data from five completed Clinical Pharmacology and Biopharmaceutics studies (ALK21-
`001, -002, -004, -005 & -009), one Phase III Clinical efficacy (ALK21~003) and safety
`study (ALK21-006), and one long-term safety study (ALK21-003extension) was
`submitted. The Clinical Pharmacology studies investigated the relative bioavailability,
`single dose (ALk21—001, -002) and multiple dose pharmacokinetics (ALK21-005),
`pharmacokinetics in mild and moderate hepatic impairment (Study # ALK21-009), effect
`of covariates (such as age, sex, body weight, race, and polysubstance dependency and
`markers of renal and hepatic function)_using population pharmacokinetic analysis
`
`

`

`(Report# ALK21-011), and a dose—finding opiate challenge study in opiate users
`. (ALK21-OO4).
`
`Vivitrol is an extended release microsphere—based formulation of naltrexone incorporated
`into a biodegradable matrix of polylactide-co-glycolide for intramuscular use. Based on
`in vitro studies, the drug release from the microsphere formulation is hypothesized to
`
`occur in three phases as described below;
`'
`
`The Initial Release phase takes place during the first day following exposure
`of the microspheres to an aqueous environment. A small quantity of drug at
`
`or near the surface is released.
`
`
`The Hydration phase occurs during the first week. Physical erosion of the
`Phase 2
`
`Hydration microspheres begins and some subsurface drug is released.
`
`Phase 1
`Initial
`Release
`
`
`
`
`
`
`
`
`
`Phase 3
`
`
`
`Sustained
`
`
`Release
`
`
`
`The Sustained Release phase takes place from Week 2 until drug release is
`complete and is governed by polymer erosion. The Sustained Release phase
`constitutes the majority of the release profile both in terms of overall
`
`duration and quantity of drug released.
`
`
`
`A real time release method was used to determine the in vitro profile [initial phase, secondary (hydration)
`phase and sustained release phase] of Vivitrol microspheres in the presence of buffered aqueous media
`(phosphate buffered saline with Tween 20 and sodium azide) at physiological pH (7.4) and temperature
`(37°C)
`
`Based on the pharrnacokinetic, pharrnacodynamic, safety and efficacy profile of Vivitrol,
`the sponsor is proposing the use of 380 mg dose of Vivitrol for the treatment of
`alcoholism.
`
`PK characteristics of Vivitrol
`
`After 1M administration of Vivitrol, peak plasma levels of naltrexone are observed in
`about 5 hours to 2 days. The increase in AUC of naltrexone was approximately dose-
`proportional in the range of 141 — 784 mg Vivitrol (study # ALK21-001, -002).
`Naltrexone elimination appears release rate-dependent as the elimination half life for the
`product is approximately 8 days; while oral naltrexone has a 5 hour half life (study #
`ALK21-005) (Figure 1).
`
`Semilogaiishmic Seal-
`160.!)
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`
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`56
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`

`

`Following IM administration of 380 mg IM Vivitrol, the plasma levels of 6B-naltrexol are
`~ two—fold higher than naltrexone and the PK profile appears to be in parallel to
`naltrexone. This would indicate that 6B-naltrexol disposition is formation rate-dependent.
`Repeated administration of Vivitrol, once a month for four months, did not result in
`significant accumulation of naltrexone.
`
`Semilogmitluuic Scaie
`
`Figure 2: 50 mg
`Oral naltrexone PK
`
`- = Naltrexone
`_ Gfi-unnrmi
`
`is}
`
`
`
`
`
`Ei‘iztsniziI’Znnmiu‘miun(lig'lil
`
`0.0
`
`0.5.
`
`1.0
`
`1.5
`
`2.0
`
`Time from Dose- (Days)
`
`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 (AUC0_23) 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. The Cmax of naltrexone is highly variable following Revia and Vivitrol
`administration. Compared to oral naltrexone, 6B-naltrexol formation is only 36%
`following IM administration of Medisorb 380 mg Naltrexone dose. As shown in Figure
`2, following oral administration, 6B-na1trexol plasma levels are ~ 15-fold higher and a tug
`of~ 13 hours.
`
`Plasma protein binding (21%) is not expected to change with this route of administration
`compared to oral route of naltrexone administration.
`
`Dose-finding 0r PK-PD results
`
`Evidence to support the dose, duration of action/dosing interval of Vivitrol suspension
`was derived from a pilot opioid blockade study (ALK21-004), where 75, 150 and 300 mg
`doses were studied. The presumed mechanism of action of naltrexone in the treatment of
`alcohol dependence is the blockade of endogenous rather than exogenous opioids.
`Nevertheless, results suggested that doses of Vivitrol 2150 mg demonstrated blockade of
`opioid effects of hydromorphone challenge test over 28 days.
`
`Pharmacokinetics in special populations
`
`Population pharmacokinetic analysis (Study report # ALK21-011) was conducted to
`determine if demographic variables (such as age, sex, body weight, race, and
`polysubstance dependency) and laboratory markers of renal and hepatic function
`
`

`

`contributed to differences in PK parameter estimates among individuals. The data from
`studies ALK21-004 (PK/PD study), -005 (PK study), -006 (Safety & efficacy study), -
`009 (PK study) were utilized in the population PK analysis. None of the covariate — '
`parameter relationships determined by either the population PK analysis or the ANCOVA
`suggests that adjustments to the dosing regimen of Vivitrol are necessary.
`
`The hepatic impairment study # ALK21-009 revealed that mild and moderate hepatic
`impairment did not affect pharmacokinetics of naltrexone following Vivitrol
`administration. Data was not acquired in severe hepatic impairment and the product is not
`recommended to be used due to the risk of coagulation.
`
`Extra-hepatic sites play a major role in the clearance of naltrexone to 6B-naltrexol. Aldo—
`keto-reductases, the enzymes responsible for conversion of naltrexone to 6B-naltrexol, is
`expressed primarily in liver but also in brain, heart, kidney, lung, prostate, skeletal
`muscle, small intestine, spleen and testis. As such, it is unlikely that the CYP inhibitors
`affect the pharmacokinetics of Vivitrol.
`
`In vitro CYP inhibition by naltrexone was evaluated by employing a high throughput
`fluorogenic substrate assay. While the results suggest remote possibility of CYP
`inhibition mediated drug—drug interactions by naltrexone; use of fluorogenic substrates is
`not acceptable per current Agency practices. These data would need to be required using
`conventional substrates.
`
`Naltrexone and 6B-naltrexol Cmax were about 30 to 40% lower while AUC0_2g were
`similar between females and males following a single dose of 380 mg Vivitrol. Dosage
`adjustment is not necessary based on gender of the subject as the pharmacokinetics were
`not significantly altered.
`
`Based on naltrexone PK following Vivitrol microsphere administration, dose adjustment
`. may not be necessary for subjects with renal impairment. If anything, 6B—naltrexol is
`likely to accumulate in renal impairment. However, the levels are substantially lower for
`Vivitrol compared to oral naltrexone and any accumulation in renal impairment is not
`likely to have clinically significant effect.
`
`Data summarized from available sources did not show reports of QT prolongation or
`cardiac safety events.
`
`Safety, effectiveness, and pharmacokinetics data was not acquired in pediatric patients
`less than 18 years of age.
`
`The sponsor proposed the following in vitro drug release method and specifications for
`real time drug release testing:
`
`Proposed drug release method and Specifications
`
`A real time drug release method was used to determine the in vitro profile [initial phase,
`secondary (hydration) phase and sustained release phase] of Vivitrol microspheres in the
`presence of buffered aqueous media (release media) at physiological pH (7.4) and
`temperature (37°C).
`
`

`

`, specifications are acceptable; the
`’__,
`=— _ and Day 7
`While the Day 1 :
`specifications should be tightened based on CMC reviewers assessment of the stability
`data for the pertinent lots. In addition, the sponsor’s assumption that the Day 7 to Day 14
`sampling will be representative of the remaining 14 days of drug release is not
`acceptable. About 26 — 75 % of drug from various lots of Vivitrol was released by day
`14 from real time release method; hence additional sampling up to 30 days may be
`necessary depending on the stability of the drug in solution. Consistent product
`performance over 28 days is pivotal for the safety and efficacy of this drug. Hence,
`tentative specifications for Day 14 and Day 28 are proposed as
`=44
`J and —--
`respectively. The specifications may be revised following CMC reviewers’ assessment
`of the stability data provided for the pertinent lots.
`
`Bridging of clinical trial and to-be-marketed formulation
`
`The clinical studies were conducted employing lots from a — batch of Vivitrol. The to-
`be—marketed formulation lots are from a
`“-1 oatch of Vivitrol. The Agency indicated
`that bioequivalence study will not be necessary if the Sponsor provides stability data as
`well as comparative multi—point dissolution testing data using an acceptable dissolution
`testing method. Accordingly, employing a real time drug release method, drug release
`was evaluated from three lots of A batch and three lots of
`-— oatch. Comparison
`was done by means of the standard and a modified f2 test which takes into consideration
`the multiphasic release characteristics of Vivitrol. Release of naltrexone on Day 1, Day
`2-7 and Day 7-14 of the test and reference batches was in general comparable with the
`standard and modified f2 test.
`'
`
`2 QBR
`
`2.1 General Attributes
`
`2.1.1. What is the rationale for the development of naltrexone long-acting
`injection?
`
`Naltrexone long-acting injection is to be administered once a month and is supposed
`to improve compliance over the oral naltrexone.
`
`Oral naltrexone (Revia Tablet, NDA# 18-932) was first approved in 1984 for the
`treatment of opioid addiction. In 1994, Revia was approved for alcohol addiction
`treatment. The recommended dose of oral naltrexone is 50 mg QD for up to 12 weeks.
`Since Naltrexone long acting injection is to be used once a month, compliance may be
`V better by minimizing disruptions in therapy caused by missed medication due to
`impairment and fluctuation of motivation for treatment.
`
`Alkermes, Inc., submitted this NDA under section 505(b)(2) of the Food Drug and
`Cosmetic Act for the treatment of alcohol dependence, using Revia as a Reference Listed
`Drug.
`
`This product has not been approved anywhere else in the world at this time.
`
`

`

`2.1.2. What are the highlights of the formulation of naltrexone long—acting
`injection?
`
`Vivitrol is an extended release microsphere-basedformulation of naltrexone
`incorporated into a biodegradable matrix ofpolylactide-co-glycolide for intramuscular
`use.
`
`Polylactide-co-glycolide is a common, biodegradable medical polymer with a history of
`safe human use in several medical products and is listed in the FDA Inactive Ingredient
`Guide (poly-
`~lactide-co—glycolide, Polyglactin, CAS # 026780507). The microspheres
`are comprised of approximately 34% (w/w) naltrexone within the polymer matrix.
`Following a single intramuscular (IM) injection, Vivitrol microspheres release naltrexone
`for greater than 1 month. The formulation and composition are described below:
`
`Injection components: Vivitrol is provided as a kit containing a vial each of
`microspheres, diluent, one 5 mL syringe, one 1/2 inch 20 gauge preparation
`needle, two 11/2 inch 20 gauge administration needles with safety device.
`
`.Active & Inactive Ingredients: Naltrexone is micro—encapsulated in 75:25
`poly'lactide—co-glycolide (PLG) at a concentration of 337 mg of naltrexone per
`gram of microspheres.
`Inactive ingredients used and their function in the
`manufacture of the PLG microspheres are listed below:
`I
`COMPONENTS W,
`l
`FUNCTION
`
`I
`
`
`
`
`Diluent: The diluent for parenteral use is a sterile, clear, colorless solution. The
`composition of the diluent
`includes carboxymethylcellulose sodium salt,
`polysorbate 20, sodium chloride, and water for injection. The microspheres are
`suspended in the diluent prior to injection.
`
`2.1.3. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Naltrexone is a pure opioid u-receptor antagonist that reversibly blocks the effects of
`opiates by binding competitively at opioid receptors. It is believed that naltrexone
`decreases alcohol consumption through the blockade of endogenous opioids at u-opioid
`receptors, resulting in inhibition of the reward pathways and thus reducing the subjective
`euphoric and reinforcing properties of alcohol. In patients with alcohol dependence,
`blockade of the endogenous opioid peptides leads to decreased craving for alcohol,
`decreased urge to drink, and reduction in the consumption of alcohol.
`
`

`

`2.1.4. What are the proposed d0sage(s) and route(s) of administration?
`
`The recommended dose of Vivitrol is 380 mg by intramuscular injection every 4 weeks or
`once a month.
`
`The proposed dosage and route of administration are as follows:
`
`The recommended dose of Vivitrol is 380 mg by intramuscular injection every 4
`weeks or once a month. The injection should be administered by a health care
`professional as an IM gluteal
`injection, alternating buttocks using the kit
`components provided. Vivitrol should not be administered intravenously.
`
`If a patient misses a dose, he/she should be instructed to receive the next dose as
`
`soon as possible. Pretreatment with oral naltrexone is not required before using
`Vivitrol.
`,
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`
`
`
`2.2 General Clinical Pharmacology
`
`Clinical Pharmacology of oral naltrexone known from the approved oral product
`(Revia)
`'
`
`Following oral administration, naltrexone undergoes rapid and nearly complete
`absorption with approximately 96% of the dose absorbed from the gastrointestinal tract.
`Naltrexone undergoes extensive first pass metabolism to 6B-naltrexol and the peak
`plasma levels of both occur within one hour of dosing. The volume of distribution for
`naltrexone following intravenous administration is estimated to be 1350 liters. In vitro
`tests with human plasma Show naltrexone to be 21% bound to plasma proteins over the
`therapeutic dose range. The renal clearance for naltrexone ranges from 30 — 127 mL/min
`and suggests that renal elimination is primarily by glomerular filtration. In comparison,
`
`the renal clearance for 6B-naltrexol ranges from 230-369 mL/min, suggesting an
`additional renal tubular secretory mechanism. The urinary excretion of unchanged
`naltrexone accounts for less than 2% of an oral dose; urinary excretion of unchanged and
`conjugated 6-B-naltrexol accounts for 43% of an oral dose. The pharmacokinetic profile
`of naltrexone suggests that naltrexone and its metabolites may undergo enterohepatic
`recycling. Naltrexone appears to have extra-hepatic sites of drug metabolism and its
`major metabolite undergoes active tubular secretion. Caution should be exercised when
`naltrexone hydrochloride is administered to patients with liver disease. In subject with
`compensated or decompensated hepatic impairment, there is an increase in naltrexone
`AUC of approximately 5- and 10—fold, respectively; while, 6B-naltrexol formation was
`delayed (longer Tmax) .
`'
`
`Clinical Pharmacology of Vivitrol
`
`In this NDA, Sponsor Icharacterized the pharmacokinetic characteristics of the long acting
`formulation and obtained bridging information as applicable to this product while relying
`on the previously known Clinical Pharmacology aspects of naltrexone. As such, data
`
`

`

`from five completed Clinical Pharmacology and Biopharmaceutics studies, one Phase III
`clinical efficacy and safety study, and one long-term safety study was submitted. The
`Clinical Pharmacology studies investigated the relative bioavailability, single dose and
`multiple dose pharmacokinetics, pharmacokinetics in mild and moderate hepatic
`impairment, effect of covariates (such as age, sex, body weight, race, and polysubstance
`dependency and markers of renal and hepatic function) using population pharmacokinetic
`analysis, and an opiate challenge study in opiate users. The Pivotal clinical study
`(ALK21-003) investigated the efficacy and safety of the product against placebo in 624
`enrolled subjects. The ongoing clinical safety study (ALK-006) evaluated the safety
`aspects when Vivitrol was administered over a period of 24 weeks (6 doses, interim
`cutoff date 8/31/2004) in 436 subjects. The subjects participating in ALK21-003 and
`ALK21-006 could continue on extension studies for upto 5 years’ total treatment with
`Vivitrol suspension.
`
`2.2.1 What is the rationale for the proposed dose of naltrexone long acting
`injection?
`
`The proposed dosing regimen is based on the pharmacokinetic, pharmacodynamic and
`efficacy evidence.
`
`Pharmacokinetic basis: Based on initial PK study (# ALK21-001) with various doses of
`Vivitrol (141, 269, 530 and 784 mg) the sponsor estimated that the 190 mg dose would
`provide similar exposure compared to 50 mg oral naltrexone administeredfor 28 days.
`Based on PK study# ALK2'I-005, however, it appears that 190 mg and 380 mg doses of
`Vivitrol suspension may provide 2- and 4-fold higher AUC, respectively, compared to
`oral dosing of 5 0 mg per day for 28 days.
`
`Pharmacodynamic basis: Evidence to support the dose, duration ofaction/dosing
`interval of Vivitrol suspension was derivedfrom pilot opioid blockade study # ALK21-
`004; where 75, 150 and 300 mg doses were studied. The presumed mechanism ofaction
`ofnaltrexone in the treatment ofalcohol dependence is the blockade ofendogenous
`rather than exogenous opioids. Nevertheless, results suggested that doses of Vivitrol
`2150 mg demonstrated blockade ofopioid eflects ofhydromorphone challenge test over
`28 days.
`
`Efficacy analysis: The sponsor evaluated the safety and efficacy 0f190 and 380 mg of
`Vivitrol suspension in Phase III study # ALK21—003. The 380 mg dose of Vivitrol showed
`significant diflerence compared to subjects receiving placebo treatment employing the
`primary efficacy endpoint of ”event rate ofheavy drinking ”. The 190 mg dose showed
`evidence ofa trend toward significance with this endpoint. Please refer to the Medical
`Ofiicer ’s review for safety and eficacy assessments.
`
`The single and multiple dose pharmacokinetics of Vivitrol suspension are discussed-
`separately in the sections below (QBR question 3).
`
`Study ALK21-004 is a randomized, single dose opiate challenge study of Vivitrol
`suspension in opioid using adult subjects. Subjects were randomized in a 1:1:1 ratio to
`receive a single gluteal IM injection of Vivitrol suspension 75, 150, or 300 mg. Subjects
`were administered hydromorphone challenge, naloxone challenge and oral naltrexone
`
`

`

`tolerability assessment before study drug treatment. At Day 0, eligible subjects were
`administered the first dose of study drug. Experimental hydromorphone challenge
`sessions (to assess the level of opiate blockade) were conducted at Days 7, 14, 21, 28, 42,
`and 56, with 1 placebo hydromorphone challenge administered at a randomly selected
`visit. Blood samples for measurement of naltrexone and 6B-naltrexol were obtained at
`screening and before hydromorphone/placebo administration on Days 7, 14, 21, 28, 42,
`and 56.
`
`Hydromorphone Challenge: IM hydromorphone injections were administered at l—hour
`intervals at doses of 0 (placebo), 3, 4.5, and 6 mg. At a randomly selected evaluation
`visit, subjects received four 0 mg (placebo) doses at 1-hour intervals.
`
`A variety of pharmacodynamic assessments were recorded upto 15 minutes before the
`first hydromorphone dose or placebo for hydromorphone dose and at 15, 30, 45 and 60
`' minutes after each dose. For the primary measure of pharmacodynamic effect, response
`to VAS question “Do you feel any drug effect?” and pupil measurements were utilized in
`the statistical analysis. Please see the attached study synopsis for information on details
`of the statistical plan other pharmacodynamic measures and their outcomes.
`
`‘
`
`The sponsor indicated that they had difficulty in enrolling desired number of Subjects for
`the complete study and hence, they amended the protocol to delete the placebo treatment
`arm. Accordingly, statistical comparisons were between different dose treatment groups
`and results are inconclusive based on the absolute analysis plan proposed. However,
`from an exploration stand point this study served the purpose of deriving qualitative
`information on duration of opiate blockade by Vivitrol.
`
`Vivitrex 75 mg
`
`0
`
`l 1fj1iai41239,56 Vivitrex 300 mg
`Vivitrex 150 mg
`
`Figure Legend: Box-plot
`indicating plasma naltrexone
`concentrations at different
`
`days (0-56) in subjects
`receiving 75, 150 and 300 mg
`Vivitrol. The whiskers of the
`
`box plot include the data, the
`top of the box indicates 75th
`percentile, bottom of the box
`indicates 25th percentile, solid
`circles indicate median, solid
`
`squares indicate outliers.
`
`
`
`0')
`
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`
`.._|—:.
`
`I
`
`0
`
`7
`
`14 21 28 35 42 49 56
`
`The above figure is depicts the
`plasma levels of naltrexone in
`blood samples collected on
`Days 7, 12, 21, 28, 42 and 56.
`‘
`DAY
`PK parameters, particularly Cmax and complete AUC, may not be derived from this
`profile as plasma levels from a significant segment following dosing (Day 1-7) was not
`obtained. Nevertheless, the figure demonstrates that more number of subjects had plasma
`1eVels above 1 ng/mL at day following the 300 mg dose than any other dose group. The
`relevance of lng/mL plasma level is explained below.
`
`0
`
`7
`
`14 21 28 35 42 49 56
`
`10
`
`
`
`PlasmaNallrexoneConcentration(nglmL)
`
`
`
`
`
`

`

`Drug Effect During Hydromorphone Challenge In Subjects Receiving Vivitrex 75 mg
`
`
`
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`
`
`
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`DrugEffec