ALKERMES EXHIBIT 2007
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Page 1 of 43
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`DEPARTMENT OF HEALTH AND
`HUMANSERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`
`
`From:
`
`Srikanth C. Nallani, Ph.D.
`
`DATE: 4/7/2006
`
`IND No.:
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`NAMEOF DRUG
`[ Vivitrol
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`NDANo. 21-897
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`DATE OF DOCUMENT
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`PRIORITY CONSIDERATION
`Standard
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`Date of informal/Formal
`Consult:
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`2/13/2006
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`|
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`2/13/2006
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`NAMEOF THE SPONSOR:[ Alkermes, 88 Sidney St, Cambridge, MA 02139 |
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`[_] PRE-IND
`[]ANIMAL to HUMAN SCALING
`[_] IN-VITRO METABOLISM
`[_] PROTOCOL
`[_] PHASE II PROTOCOL
`[_] PHASE Il] PROTOCOL
`[|] DOSING REGIMEN CONSULT
`[_] PK/PD- POPPK ISSUES
`L_] PHASE IV RELATED
`
`TYPE OF SUBMISSION
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATEDISSUE
`
`:
`
`[_] DISSOLUTION/IN-VITRO RELEASE
`|] BIOAVAILABILITY STUDIES
`[_] IN-VIVO WAIVER REQUEST
`[_] SUPAC RELATED
`[-] CMC RELATED
`[_] PROGRESS REPORT
`[_] SCIENTIFIC INVESTIGATIONS
`[-] MEETING PACKAGE(EOP2/Pre-
`NDA/CMC/Pharmacometrics/Others)
`:
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`.
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`[_] FINAL PRINTED LABELING
`[_] LABELING REVISION
`[_] CORRESPONDENCE
`[_] DRUG ADVERTISING
`[|] ADVERSE REACTION REPORT
`[_] ANNUAL REPORTS
`[_] FAX SUBMISSION
`XX] OTHER (SPECIFYBELOW):
`[ Complete Response for Action
`(12/28/2005) to Original NDA submitted on
`3/31/2005
`
`And Cycle
`
`
`Clinical Pharmacology & Biopharmaceutics
`
`(HFD 870)
`
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`Tracking/Action Sheet for Formal/Informal Consults
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` To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`Please log-in this consult and review action for the specified IND/NDA submission
`
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`REVIEW ACTION
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`[_] NAI (Noaction indicated)
`["] E-mail commentsto:
`[_]Medical[_]Chemist{”]Pharm-Tox
`[_IMicro[_|Pharmacometrics{_]Others
`(Check as appropriate and attach e-mail)
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`(_] Oral communication with
`Name:
`[
`]
`_] Comments communicated in
`meeting/Telecon. see meeting minutes
`dated:
`[
`]
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`[_] Formal Review/Memo(attached)
`[X]0See comments below
`[_]flSee submission coverletter
`[-] OTHER (SPECIFYBELOW):
`[
`]
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`REVIEW COMMENT(S)
`|_] NEED TO BE COMMUNICATED TO THE SPONSOR
`[_] HAVE BEEN COMMUNICATED TO THE SPONSOR
`COMMENTS/SPECIAL INSTRUCTIONS:
`{ 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 approvableletter, the sponsor agreesto
`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 drugrelease information.
`Thetimeline for this PMC will be addressed by the Office ofNew 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 sponsoralso submitted labeling changes, however, none were
`pertinent to Clinical Pharmcaology and Biopharmaceutics aspects and hence were not reviewed.
`]
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`SIGNATURE OF REVIEWER: Srikanth C. Nallani Ph.D.
`’ SIGNATURE OF TEAM LEADER: Suresh Doddapaneni, Ph.D.
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`Date 4/7/2006
`Date 4/7/2006
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`Project Manager: Lisa Basham-Cruz
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`[
`J; TL:
`Cc. BED#[
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`Date
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`4.4 Consent of Supervisor for the proposed Phase IV commitments
`
`Nallani; Srikanth
`
`From:
`Sent:
`To:
`Subject:
`
`Srikanth
`
`.
`
`Deddapaneni, Suresh
`Friday, November 18, 2005 8'34 AM
`Nallani, Srikanth
`FW: Srikanth's NDA-Naltrexone depot formulation|
`
`Print out this:e-mail and attachit to:the reviewas Division:Director's.concurrence. This:is.in line with OCPB's procedure.
`
`Thanks, Suresh
`soneOriginal’ Message-----
`From:
`Malinowski, Henry:J
`Sent:
`Friday, November 18, :2005°8:28 AM
`To:
`Doddapaneni, Suresty
`Subject:
`RE: Srikanth's: NDA-Naltrexone depot formulation!
`
`Suresh,
`Looks fine... Hank
`
`ccOriginal Message-----
`From:
`Doddapaneni, Suresh
`Sent:
`Thursday, November 17, 2005 12:44 PM
`To:
`Malinowski, Henty.J
`Subject:
`Srikanth's NDA-Naltrexone: depotformulation!
`
`Hank
`
`| have extracted from the
`The review for depot naltrexerie product is being finalized. Wehadthe-briefing.on this on Tuesday.
`review, the recommendation/phase |V commitment related languagethat Srikanth and I drafted. Please provide-your
`feedback.
`
`Thanks, Suresh
`
`1.1 Recommendation
`From a Clinical Pharmacology and Biopharmaceutics perspective,NDA.21-897 is acceptable provided that a
`
`mutually satisfactoryagreement¢canbe reachedbetweentheAgency and Alkermes regarditig the (a) languageiin
`
`b)
`
`a
`information,
`Conductin vitro'CYPinhibition studies using conventional substrates as the submitted data used
`florescent suibstrate(s)whichtends to introduce rion-specificity in détection.
`c)} Conduct in vitro:studies in human hepatocytes to evaluate:potential of naltrexone to induce CYP3A4-and
`CYPIA2.
`
`1.2
`
`Phase IV Commitments
`
`a) Conduct in vitro'CYPinhibitionstudies-using:conventional CYP substrates and validated analytical
`methodology.
`
`b)
`
`Conduct in vitro: studies ii human hepatocytes to evaluate. potential of naltrexone to induce CYP3A4
`and CYP1A2.
`
`Page 3 of 43
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`89
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`Page 3 of 43
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`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
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`Page 4 of 43
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`Page 4 of 43
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`/s(ele
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`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA: 21-897
`
`Brand Name
`
`Generic Name
`
`Reviewer
`
`Team Leader
`
`OCPBDivision
`
`ORM Division
`
`Sponsor
`
`Relevant IND(s)
`
`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
`
`Alkermes, 88 Sidney St, Cambridge, MA
`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 mLvials
`
`Indication
`
`Treatment of alcohol dependence
`
`Dosing Regimen
`380 mg IM every 4 weeksor once a month
`
`
`Table of Contents
`
`1
`
`Executive Summary oc. cecccccseseescesessecssseesecescsscaesecscessesussessrsescssssecsessssesecsessevaseass 2
`L.2
`Recommendation 2.0.0.0... cee eeeceeceeceeceesecesseseseaeenenssensaecesseccececcassssaesesssaseserssesesteaessreeessas 2
`1.2
`Phase FV Commitments ..0....0..ccccccccecsscccesscccessescsecessescesancevscecersrecseseesesseseessesesausesssaecessacecses 2
`1.3.
`Summary of Clinical Pharmacology and Biopharmaceutics Findings -......0....00:ccccccceccceesseceseeeees 2
`2 QBR ioe eeccccesceseesseeseesscesecsesseeesseceesuesaecseesssesscseceeesessasesessaseNeve eeaeeeeeeeneteeeeeteeeeteeteeetes 6
`2.1
`General Attributes 20.0... cc ceceecceeeeseeeeeeecesseeesecesseeceneessaesesaesusseecnsaeescseeessssecssseseiaes 6
`2.2 General Clinical Pharmacology ........0...:ccccccceccceceeeectesetesecaescaeesaceaeesaeeaeesseeenseesneeesseeenseesaeeeas 8
`2.3
`Intrinsic Factors ......00...ec cc ceccececeeeeeeceececeeecaeeeeaceesseesuaesesseeeeseceesteccaeeesaeseesaeeesensaeeeeseesensesens 20
`2.4
`Extrinsic Factors ..................:steecaaaeeeeeeeeeeesensenaaaeeeeeeeesaaaaaneeeceesessescueaeeeeeseeeereeeseeecsnssaneneaaees 26
`2.5
`General Biopharmaceutics ..0.........cceeceeeseceeeeceeeceeeescetsetesteceteaeespeviceeeeeeeeesaceeesatseetuneeereeeeess 27
`2.6 Analytical Section ........... cc ceccccecceeescceeeeececceessseeesaeeceseeseneeeesueecsseeeeseecesseeescaseesessaesesseseseaeeees 32
`Detailed Labeling Recommendations ..........cccccsccccssceeesesseseeseeseeserseeeseteeeeeseasenes 34
`3.
`A Appendix oo... cesesccseeedeerceseeseeeeseeeeeeeseeenececeeeneeseeeeaeesseeeeeeeseesaesaceceseeesaseseseesaeenaees 36
`4.1
`Proposed Package Insert «0.2.00... ....ececceeceecesceesenceesceeccacecesaeecenessnaetesseeeceeseeessareeseteeseneeaeeniees 36
`4.2—Studty Symopses 0... cccsececsccesecceseresessseeseeeeesseessaseccassessaeceaeccaseseseecseesessausecaeeeeseaecesaaes 57
`4.3
`CPB filing/review form 0.0.0... ees cscccsssesseeseceeeeseecaceneceeeceaeeaeesseeecaecsaeccasecsaseeseeeeeesenueenaes 87
`4.4
`Consent of Supervisor for the proposed Phase IV commitment...............ccccccccecccssssceeseseseseees 89
`
`Page 5 of 43
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`4
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`1
`
`Executive Summary
`
`1.1 Recommendation
`
`From a Clinical Pharmacology and Biopharmaceutics perspective, NDA 21-897is
`acceptable provided that a mutually satisfactory agreement can be reached between the
`Agency and Alkermesregarding the (a) language in the package insert (b) im vitro drug
`release method, and (c) post marketing commitmentto further investigate potential ofthis
`productto inhibit or induce CYP enzymes. Specifically,
`
`a) The drugrelease specifications should be revised with addition of Day 14 and
`Day 28 drug release information.
`b) Conductin vitro CYPinhibition studies using conventional substrates as the
`submitted data used florescent substrate(s) which tends to introduce non-
`specificity in detection.
`;
`c) Conductin vitro studies in human hepatocytes to evaluate potential of naltrexone
`to induce CYP3A4 and CYPIA2.
`,
`
`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
`
`Naltrexoneis a pure opioid antagonist with highest affinity for the p-opioid receptor.
`The mechanism ofaction of naltrexone in alcoholism is not clearly understood.
`However,it is believed that naltrexone decreases alcohol consumption through the
`blockade of endogenousopioids at p-opioid receptors, resulting in inhibition of the
`reward pathways and thus reducing the subjective euphoric and reinforcing properties of
`alcohol. In 1994, oral naltrexone (Revia™) was approved for the treatment of
`alcoholism. Current NDAis a 505(b)(2) submission by AlkermesInc. 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
`argumentthat this product will improve compliance compared to once a day
`administration of oral naltrexone, the NDA was awardedpriority 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
`markersofrenal and hepatic function)using population pharmacokinetic analysis
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`(Report# ALK21-011), and a dose-finding opiate challenge study in opiate users
`_(ALK21-004).
`
`
`
`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;
`
`
`
`Phase 1
`The Initial Release phase takes place during the first day following exposure
`Initial
`of the microspheres to an aqueous environment. A small quantity of drug at
`
`
`
`Release
`or near the surface is released.
`
`
`Phase 2
`The Hydration phase occurs during the first week. Physical erosion of the
`
`Hydration|microspheres begins and some subsurface drugis released.
`
`
`The Sustained Release phase takes place from Week 2 until drug release is
`
`
`Phase 3
`
`complete and is governed by polymererosion. The Sustained Release phase
`
`
`Sustained
`constitutes the majority of the release profile both in terms of overall
`
`Release
`duration and quantity of drug released.
`
`
`A real time release method wasused 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 pharmacokinetic, pharmacodynamic, safety and efficacy profile of Vivitrol,
`the sponsoris proposing the use of 380 mg dose of Vivitrol for the treatment of
`alcoholism.
`
`PK characteristics of Vivitrol
`
`After IM administration of Vivitrol, peak plasma levels of naltrexone are observed in
`about 5 hours to 2 days. The increase in AUC ofnaltrexone was approximately dose-
`proportionalin the range of 141 — 784 mg Vivitrol (study # ALK21-001, -002).
`Naltrexone elimination appears release rate-dependentas the elimination half life for the
`product is approximately 8 days; while oral naltrexone has a 5 hourhalflife (study #
`ALK21-005) (Figure 1).
`
`Semilogarithmie Seal
`100.0
`
`04 oT
`
`(0 TB Un BH 2 56
`a TimefiomDae (Days).
`
`
`
`
`
`PlasmasConcentration{ng/mL}
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`Page 7 of 43
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`Following IM administration of 380 mg IM Vivitrol, the plasmalevels of 6B-naltrexol are
`~ two-fold higher than naltrexone and the PK profile appears to bein 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.
`
`Semilogarithmie Scaie
`100.0
`
`Figure 2: 50 mg
`Oral naltrexone PK
`
`68 Naltrexone
`#8.
`6G:unltrexo!
`
`Gl
`
`
`
`PiaainConcentration(ea
`
`6.0
`
`a3
`
`io
`
`13
`
`2.0
`
`Timéfrom Dose (Days)
`The proposed 380 mg doseof IM Vivitrol is approximately 13" comparedtooral
`naltrexone (50 mg QD for 28 days = 1400 mg over 28 days). However, the exposure to
`naltrexone (AUCo.28) over 28 days is approximately four-fold higher than that observed
`with oral naltrexone. This appearsto be a result of bypassing offirst pass metabolism by
`the IM route. The Cmax of naltrexone is highly variable following Revia and Vivitrol
`administration. Comparedto oral naltrexone, 6B-naltrexol formation is only 36%
`following IM administration of Medisorb 380 mg Naltrexone dose. As shownin Figure
`2, following oral administration, 6B-naltrexol plasma levels are ~ 15-fold higher and a ti/2
`of ~ 13 hours.
`
`Plasmaprotein binding (21%) is not expected to change with this route of administration
`compared to oral route of naltrexone administration.
`
`Dose-finding or 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 ofaction of naltrexone in the treatment of
`alcohol dependenceis the blockade of endogenousrather than exogenousopioids.
`Nevertheless, results suggested that doses of Vivitrol 2150 mg demonstrated blockade of
`opioid effects of hydromorphonechallengetest 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 markersofrenal and hepatic function
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`contributed to differences in PK parameter estimates among individuals. The data from
`studies ALK21-004 (PK/PDstudy), -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
`impairmentdid not affect pharmacokinetics of naltrexone following Vivitrol
`administration. Data was not acquired in severe hepatic impairment and the productis not
`recommendedto be used dueto the risk of coagulation.
`
`Extra-hepatic sites play a majorrole in the clearance ofnaltrexone to 6B-naltrexol. Aldo-
`keto-reductases, the enzymesresponsible for conversion ofnaltrexone to 6f-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 substratesis
`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 AUCo.23 were
`similar between females and males following a single dose of 380 mg Vivitrol. Dosage
`adjustment is not necessary based on genderof 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-naltrexolis
`likely to accumulate in renal impairment. However, the levels are substantially lower for
`Vivitro] comparedto oral naltrexone and any accumulation in renal impairmentis not
`likely to haveclinically 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 acquiredin pediatric patients
`less than 18 years of age.
`
`The sponsor proposed the following in vitro drug release method and specifications for
`real time drugreleasetesting:
`
`Proposed drug release method and Specifications
`
`A real time drug release method wasused 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).
`
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`, specifications are acceptable; the
`-——~ and Day7* “_4
`While the Day 1:
`specifications should be tightened based on CMCreviewers assessmentof the stability
`data forthe 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 variouslots of Vivitrol was released by day
`14 from real time release method; hence additional sampling up to 30 days may be
`necessary depending onthe stability of the drug in solution. Consistent product
`performance over 28 daysis pivotal for the safety and efficacy of this drug. Hence,
`tentative specifications for Day 14 and Day 28 are proposedas —~
`sand —
`respectively. The specifications may be revised following CMCreviewers’ assessment
`of the stability data provided for the pertinentlots.
`Bridging ofclinical trial and to-be-marketed formulation
`
`Theclinical studies were conducted employing lots from a — batch of Vivitrol. The to-
`be-marketed formulation lots are froma —_ vatch 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 —+ oatch and three lots of
`-— oatch. Comparison
`was done by meansofthe standard and a modified f; test which takes into consideration
`the multiphasic release characteristics of Vivitrol. Release of naltrexone on Day 1, Day
`2-7 and Day 7-14 ofthe test and reference batches was in general comparable with the
`standard and modified f, test.
`,
`
`2 QBR
`
`2.1 General Attributes
`
`2.1.1. Whatis 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 overthe oral naltrexone.
`
`Oral naltrexone (Revia Tablet, NDA# 18-932) wasfirst approved in 1984 for the
`treatmentof opioid addiction. In 1994, Revia was approvedfor alcohol addiction
`treatment. The recommendeddoseoforal 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
`better by minimizing disruptionsin therapy caused by missed medication dueto
`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 anywhereelse in the worldat this time.
`
`Page 10 of 43
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`2.1.2. Whatare the highlights of the formulation of naltrexone long-acting
`injection?
`
`Vivitrol is an extended release microsphere-basedformulation ofnaltrexone
`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 1% inch 20 gauge administration needles with safety device.
`
`Active & Inactive Ingredients: Naltrexone is micro-encapsulated in 75:25
`polylactide-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 microspheresare listed below:
`COMPONENTS —__
`|
`FUNCTION
`
`|
`
`
`
`Diluent: The diluent for parenteral useis 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
`suspendedin the diluentpriorto injection.
`
`2.1.3. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Naltrexone is a pure opioid p-receptor antagonist that reversibly blocksthe effects of
`opiates by binding competitively at opioid receptors. It is believed that naltrexone
`decreases alcohol consumption through the blockade of endogenousopioids at p-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 endogenousopioid peptides leads to decreased craving for alcohol,
`decreased urge to drink, and reduction in the consumption of alcohol.
`
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`2.1.4. What are the proposed dosage(s) and route(s) of administration?
`The recommendeddose 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 doseof 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.
`.
`a
`
` e
`
`
`
`2.2. General Clinical Pharmacology
`
`ClinicalPharmacology oforal naltrexone knownfrom the approved oralproduct
`
`(Revia)
`
`Following oral administration, naltrexone undergoesrapid and nearly complete
`absorption with approximately 96% of the dose absorbed from the gastrointestinal tract.
`Naltrexone undergoesextensivefirst pass metabolism to 6B-naltrexol and the peak
`plasmalevels of both occur within one hour of dosing. The volumeofdistribution for
`naltrexone following intravenous administration is estimated to be 1350 liters. In vitro
`tests with human plasma show naltrexone to be 21% bound to plasmaproteins over the
`therapeutic dose range. The renal clearance for naltrexone ranges from 30 — 127 mL/min
`and suggests that renal elimination is primarily by glomerularfiltration. 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 andits
`major metabolite undergoesactive 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 increasein naltrexone
`AUCofapproximately 5- and 10-fold, respectively; while, 6B--naltrexol formation was
`delayed (longer Timax) -
`
`Clinical Pharmacology of Vivitrol
`In this NDA, Sponsor characterized the pharmacokinetic characteristics of the long acting
`formulation and obtained bridging informationas applicable to this product while relying
`on the previously known Clinical Pharmacologyaspectsof naltrexone. As such, data
`
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`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 Whatis 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# ALK21-005, however, it appears that 190 mg and 380 mg doses of
`Vivitrol suspension may provide 2- and 4-fold higher AUC, respectively, comparedto
`oral dosing of50 mg per dayfor 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 dependenceis the blockade ofendogenous
`rather than exogenous opioids. Nevertheless, results suggested that doses of Vivitrol
`2150 mg demonstrated blockade ofopioid effects ofhydromorphonechallenge test over
`28 days.
`
`Efficacy analysis: The sponsor evaluatedthe safety and efficacy of190 and 380 mg of
`Vivitrol suspension in Phase III study # ALK21-003. The 380 mg dose of Vivitrol showed
`significant difference comparedto 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
`Officer’s reviewfor safety and efficacy 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 randomizedin a 1:1:1 ratio to
`receive a single gluteal IM injection of Vivitrol suspension 75, 150, or 300 mg. Subjects
`were administered hydromorphonechallenge, naloxone challenge and oral naltrexone
`
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`

`tolerability assessment before study drug treatment. At Day0, eligible subjects were
`administered the first dose of study drug. Experimental hydromorphonechallenge
`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 measurementofnaltrexone and 6B-naltrexol were obtainedat
`screening and before hydromorphone/placebo administration on Days 7, 14, 21, 28, 42,
`and 56.
`
`Hydromorphone Challenge: IM hydromorphoneinjections were administered at 1-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-hourintervals.
`
`A variety of pharmacodynamic assessments were recorded upto 15 minutes before the
`first hydromorphonedose or placebo for hydromorphonedose 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 wereutilized in
`the statistical analysis. Please see the attached study synopsis for information on details
`of the statistical plan other pharmacodynamic measuresand their outcomes.
`
`-
`
`The sponsorindicated that they had difficulty in enrolling desired numberof subjects for
`the complete study and hence, they amendedthe protocolto 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.
`
`1
`
`Vivitrex 75 mg
`
`9 718 21 78 8 47 #2? _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 whiskersof the
`box plot include the data, the
`top of the box indicates 75"
`percentile, bottom of the box
`indicates 25" percentile, solid
`circles indicate median, solid
`squares indicate outliers.
`
`
`
`
`
`
`
`(ng/mL) n ————————L
`PlasmaNaltrexoneConcentration
`
`
`
`a
`
`»
`
`o
`
`The abovefigure is depicts the
`plasmalevels of naltrexonein
`blood samples collected on
`Days 7, 12, 21, 28, 42 and 56.
`pay
`PK parameters, particularly Cmax and complete AUC, may not be derived from this
`profile as plasmalevels from a significant segment following dosing (Day 1-7) was not
`obtained. Nevertheless, the figure demonstrates that more numberof subjects had plasma
`levels above 1 ng/mL at day following the 300 mg dose than any other dose group. The
`relevance of Ing/mL plasmalevel is explained below.
`
`0
`
`7
`
`14 21 28 35 42 49 56
`
`0
`
`7 14 21 28 35 42 4956
`
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`10
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`

`Drug Effect During Hydromorphone Challenge In Subjects Receiving Vivitrex 75 mg
`
`
`
`
`
`
`
`
`DrugEffect(VASScore)
`
`-15 90 175-15 90 175-15 90 175-15 90 175-15 90 175-15 90 175-15 90 175
`Time (minutes) During Hy