ALKERMES EXHIBIT 2001
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 8
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`og SERVIC,awh
`
`otWALT,ost—-ap:Ya0& DEPARTMENTOFHEALTH&HUMANSERVICES
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-897
`
`Alkermes, Inc.
`88 Sydney Street
`Cambridge, MA 02139-4136
`
`Attention: Priya Jambhekar
`Global Vice President, Regulatory and GovernmentAffairs
`
`Dear Ms. Jambhekar:
`
`Please refer to your new drug application (NDA) dated March 31, 2005, received March 31, 2005,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Vivitrol
`(naltrexone for extended-release injectable suspension).
`
`Weacknowledgereceipt of your submissions dated May6, 9, 12, 16, and 19, June 17, 24, 27, and 29,
`July 6, 13, and 29, August 8, 12, 15, 16, 22, and 31, September6, 7, 12, 14, 23, and 30, October 3, 5,
`12, 14, and 27, November3, 4, and 14, December 14, and 28, 2005, January 10, and 31, February 7,
`and 14, March 10, and 13, and April 10, 2006.
`
`The February 14, 2006, submission constituted a complete response to our December 23, 2005, action
`letter.
`
`This new drug application provides for the use of Vivitrol (naltrexone for extended-release injectable
`suspension) for the treatment of alcohol dependencein patients whoare able to abstain from alcoholin
`an outpatient setting prior to initiation of treatment with Vivitrol.
`
`Wehave completed our review ofthis application, as amended,andit is approved, effective on the
`date ofthis letter, for use as recommendedin the agreed-upon labeling text and with the minoreditorial
`revisionslisted below.
`
`1. Tray Lid
`-a. Removethe term “kit” from thetray lid.
`b. Revise “380 mg/vial dose kit” to “380 mg/vial” and movethis statement underneath the
`established name.
`c. Reorient the trade name and established name, marketing information, company logos, and
`bar codeto theleft side ofthetray lid.
`d. Reorient the carton contents to the right side ofthe tray lid and revise the language as
`follows:
`
`'
`
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`NDA21-897
`Page 2
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`Each Carton Contains:
`1) Onevial of 380 mg of Vivitrol (naltrexone for extended-release injectable
`suspension)*
`2) One vial containing 4 mL of diluent
`3) One 5-mL prepackaged syringe
`4) One 20-guage 2-inch needle
`5) Two 20-guage 14-inch safety needles
`
`2. Carton Label
`a. Removethe term “kit” from the carton labels.
`b. Revise “380 mg/vial dose kit” to 380 mg/vial” and movethis statement underneath the
`established name.
`c. Revise the carton contents as above.
`
`3. Removeall references to the term “kit” in any other labeling and replace with “carton.”
`
`The final printed labeling (FPL) mustbe identical to, except for including the agreed-uponrevisions
`listed, the enclosed labeling (text for the package insert, text for the patient package insert, directions
`for use, and immediate container and carton labels). Marketing the product(s) with FPL that is not
`identical to the approved labeling text may render the product misbranded and an unapproved new
`drug.
`
`Please submit an electronic version of the FPL according to the guidancefor industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soonasit is available but no more than 30 daysafter it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission(s) “FPL for approved NDA 21-873.” Approval of this submission by FDAis not
`required
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimensare required to contain an assessmentof the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`waiving the pediatric study requirement for ages 0 through 11 years and deferring pediatric studies for
`ages 12 through 16 years for this application.
`
`Yourdeferred pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA)
`are considered required postmarketing study commitments. The statues ofthese postmarketing studies
`shall be reported annually according to 21 CFR 314.81. This commitmentis listed below.
`
`1. Conduct a pediatric study under PREAforthe treatmentofalcohol dependencein patients ages
`12 through 16 whoare able to abstain from alcohol in an outpatient setting prior to initiation of
`treatment with Vivitrol.
`
`Protocol Submission: April, 2007
`Study Start: October, 2007
`Final Report Submission: April, 2011
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`NDA21-897
`Page 3
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`Submitfinal study reports to this NDA. For administrative purposes,all submissionsrelated to
`this/these pediatric postmarketing study commitment(s) mustbe clearly designated “Required
`Pediatric Study Commitments.”
`
`Weremind you of your postmarketing study commitments in your email dated April 11, 2006. These
`commitmentsare listed below.
`.
`
`2. Conducta clinical study to determine whether Vivitrol is effective in patients who are abstinent
`by virtue of hospitalization or other mechanism to limit access to alcohol, rather than patients
`whoare abstinent in spite of access to alcohol. As these populationsare likely to differ with
`respect to level of motivation and/or alcoholism severity, this is a relevant question important
`to clinicians deciding whetheror not patients being discharged from alcohol-free settings would
`benefit from treatment with Vivitrol upon discharge.
`
`‘Protocol Submission October 2006
`Study Start: April 2007
`Study Report Submission October 2009
`
`3. Perform a SegmentI reproductive and developmental toxicology study including toxicokinetic
`data in a single species with the final drug product formulation,
`
`Protocol Submission: October 2006
`Study Start: January 2007
`Final Report Submission: January 2008
`
`4. Conduct SegmentII reproductive and developmental toxicology studies in two species
`including toxicokinetic data with the final drug product formulation,
`
`Protocol Submission: October 2006
`Study Start: January 2007
`Final Report Submission: January 2008
`
`5. Conduct a Segment III reproductive and developmental toxicology study including
`toxicokinetic data with the final drug product formulation, and
`
`Protocol Submission: October 2006
`Study Start: January 2007
`Final Report Submission: January 2008
`
`6. Conduct carcinogenicity assessment in two species using the final drug product formulation.
`
`Protocol Submission: April 2007
`Study Start: August 2007
`‘Final Report Submission: August 2010
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`NDA 21-897
`Page 4
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`7.
`
`Jn lieu of the animal studies listed in commitments 3 through 6 above, you may beable to
`obtain adequate 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: October 2006
`Study Start: January 2007
`Final Report Submission: January 2008
`
`8. 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
`
`9. Conductin vitro studies in human hepatocytes to evaluate thepotential ofnaltrexone to induce
`
`CYP3A4 and CYPIA2.
`
`Protocol Submission: July 2006
`Study Start: August 2006
`Final Report Submission: May 2007
`
`10. Develop an immediate hypersensitivity skin test to Vivitrol drug product, naltrexone drug
`substance, and carboxymethylcellulose (CMC). Perform a study with this test to detect
`. immediate hypersensitivity in patients who have been exposed to Vivitrol. Include appropriate .
`controls to assess whetherthere is a direct, non-immune,histamine releasing effect of Vivitrol.
`drug product, naltrexone drug substance, and CMC.
`
`Protocol Submission: October 2006
`Study Start: March 2007
`Final Study Report Submission: October 2007
`
`11. Develop in vitro tests for drug-specific IgE, IgG, and IgM to Vivitrol drug product, naltrexone
`drug substance, and CMC. Perform a study using these tests to detect drug specific IgE, IgG,
`and IgM to Vivitrol drug product, naltrexone drug substance, and CMC.
`
`Protocol Submission: October 2006
`Study Start: March 2007
`Final Study Report Submission: October 2007
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`NDA 21-897
`Page 5
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`12. Develop an in-vivo test for delayed hypersensitivity testing or patch testing to detect Type IV
`or delayed hypersensitivity reactions to Vivitrol and its components (naltrexone, CMC).
`
`Protocol Submission: October 2006
`Study Start: March 2007
`Final Study Report Submission: October 2007
`
`In addition, we remind youofthe following agreements.
`
`1. Revise the drug release specifications to include Day 14 and Day 28 drug release information.
`
`2. Tighten the in-vitro drug release acceptancecriteria to an acceptable range and assess the need
`to establish a specification to control percent crystallinity of naltrexone in the microspheres
`based on the manufacturing experience with five consecutive commercial scale batches or on
`one-year manufacturing experience from the date of approval of the NDA, whichever comes
`first, and submitthe results of this evaluation in a CBE-30 supplement.
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(vii1), you should include a status summary of each
`commitment in your annualreport to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changesin planssince the last annual
`report, and, for clinical studies, numberofpatients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol’, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form,notfinal print. Send one copy to
`this division and twocopiesofboth the promotional materials and the packageinsert directly to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Please submit one market package ofthe drug product whenitis available.
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`cooperation to resolve any problems that may beidentified.
`
`This product is approved with an expiration dating period of 18 months.
`
`Weremind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
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`NDA21-897
`Page 6
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`If you have any questions, call Lisa Basham-Cruz, Regulatory Project Manager, at (301) 796-1175.
`
`Smeerely,
`
`{See appended electronic signature paze}
`
`Bob Rappaport, MD
`Director
`Division of Anesthesia, Analgesia, and
`Rheumatology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`Enclosure
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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.
`
`Bob Rappaport
`4/13/2006 03:38:09 PM
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