Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
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`
`
`
`NDA 203415
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`
`
`Medivation, Inc.
`525 Market Street, 36th Floor
`San Francisco, CA 94105
`
`Attention:
`
`
`
` Lynn Seely, M.D.
`Chief Medical Officer
`
`
`Dear Dr. Seely:
`
`
`
`
`Please refer to your New Drug Application (NDA) dated May 21, 2012, received May 22, 2012,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Xtandi® (enzalutamide) Capsules, 40 mg.
`
`
`
`We acknowledge receipt of your amendments dated June 7, 15, 20, 21, 27, 28, 29, July 12, 13,
`16, 17, 19, 23, 25, 27, and August 3, 7, 9, 15, 20, 21, 24, and 30, 2012.
`
`This new drug application provides for the use of Xtandi® (enzalutamide) Capsules for the
`treatment of patients with metastatic castration-resistant prostate cancer who have previously
`received docetaxel.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`patient package insert). Information on submitting SPL files using eLIST may be found in the
`
`guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`Reference ID: 3183415
`
`AVENTIS EXHIBIT 2162
`Mylan v. Aventis, IPR2016-00712
`
`1
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`

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`NDA 203415
`Page 2
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`
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`
` CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels, as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`“Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (June 2008).”
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 203415.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`
`
`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.
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`ADVISORY COMMITTEE
`
`
`Your application for Xtandi® (enzalutamide) Capsules was not referred to an FDA advisory
` committee because outside expertise was not necessary; there were no controversial issues that
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`would benefit from advisory committee discussion.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`We are waiving the pediatric study requirement for this application because necessary studies are
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`impossible or highly impracticable as this indication does not occur in children.
`
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious
`risk of drug-drug interactions between the active metabolite N-desmethyl enzalutamide and
`CYP450 inducers or inhibitors.
`
`
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Reference ID: 3183415
`
`2
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`

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`NDA 203415
`Page 3
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`
`1918-1:
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`Perform an in vitro screen to determine if N-desmethyl enzalutamide is metabolized
`by the major human CYP450 isozymes. Based on results from the in vitro screen,
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`clinical drug-drug interaction trials may be needed.
`
`
`The timetable you submitted on August 9, 2012, states that you will conduct this study according
`to the following schedule:
`
`
`12/2012
`
`06/2013
`
`12/2013
`
`
`
`
`
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess the known serious risk of seizure and signals of serious risks of
`impaired metabolism of enzalutamide in patients with severe hepatic impairment and of drug-
`drug interactions with enzalutamide.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`
`1918-2:
`
`
`Convene a panel of experts in oncology and neurology to obtain
`recommendations regarding which patients, if any, who were excluded from the
`randomized clinical trial because of increased risk of seizure should be evaluated
`in a postmarketing safety trial. Following the panel's recommendations, conduct a
`single-arm safety trial to assess the risk of seizure with enzalutamide 160 mg/day
`in at least 350 patients with metastatic castrate-resistant prostate cancer who are at
`increased risk for seizure, e.g., patients with a history of seizure (taking/not taking
`anticonvulsants), loss of consciousness, transient ischemic attack or
`cerebrovascular accident, arteriovenous malformation in the brain, head trauma
`
`with loss of consciousness, treated brain metastases, use of medications which
`may decrease the seizure threshold, or other risk factors for the development of
`seizures. The primary endpoint should be the incidence of seizure. Patients
`should remain on the trial until disease progression, development of a seizure or
`the development of an unacceptable adverse reaction. The protocol should
`contain clear stopping rules for an excessive incidence of seizures.
`
`
`
`
`Reference ID: 3183415
`
`The timetable you submitted on August 9, 2012, states that you will conduct this trial according
`to the following schedule:
`
`12/2012
`
`06/2013
`
`06/2018
`
`03/2019
`
`
`Expert Panel Recommendations:
`
`Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`
`
`
`3
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`

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`NDA 203415
`Page 4
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`
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`1918-3:
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`
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`Conduct a clinical trial in patients with normal hepatic function and patients with pre­
`existing severe hepatic impairment to assess the effect of severe hepatic impairment
`on the pharmacokinetics of enzalutamide and N-desmethyl enzalutamide. The
`proposed protocol must be submitted for review prior to trial initiation.
`
`03/2013
`
`05/2014
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`11/2014
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`
`
`
`
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`Final Protocol Submission:
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`Trial Completion:
`Final Report Submission:
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`Conduct a drug interaction trial to evaluate the effect of rifampin (a strong CYP3A
`inducer and a moderate CYP2C8 inducer) on the pharmacokinetics of enzalutamide
`and N-desmethyl enzalutamide. The proposed protocol must be submitted for review
`prior to trial initiation.
`
`The timetable you submitted on August 9, 2012, states that you will conduct this trial according
`to the following schedule:
`
`The timetable you submitted on August 9, 2012, states that you will conduct this trial according
`to the following schedule:
`
`
`1918-4:
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`
`
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`1918-5:
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`
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`04/2013
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`07/2014
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`04/2015
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`
`
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`
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`Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`
`Conduct a drug interaction trial to evaluate the effect of enzalutamide at steady state
`
`on the pharmacokinetics of CYP2D6 substrates. The proposed trial protocol must be
`submitted for review prior to initiation of the trial.
`
`07/2013
`
`12/2014
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`06/2015
`
`
`
`
`
`
`Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`
`Conduct a drug interaction trial to evaluate the effect of enzalutamide at steady state
`
`on the pharmacokinetics of CYP1A2 substrates. The proposed trial protocol must be
`submitted for review prior to initiation of the trial.
`
`
`1918-6:
`
`
`
`The timetable you submitted on August 9, 2012, states that you will conduct this trial according
`to the following schedule:
`
`07/2013
`
`12/2014
`
`06/2015
`
`
`
`
`
`
`Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`
`
`
`Reference ID: 3183415
`
`The timetable you submitted on August 9, 2012, states that you will conduct this trial according
`to the following schedule:
`
`4
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`NDA 203415
`Page 5
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`
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`Submit the protocols to your IND 074563, with a cross-reference letter to this NDA. Submit all
`final reports to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
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`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`
`information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`METHODS VALIDATION
`
`
`
`
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`Reference ID: 3183415
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`5
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`

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`NDA 203415
`Page 6
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` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
` MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
` POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`
`
`
`
`If you have any questions, call Christy Cottrell, Regulatory Project Manager, at (301) 796-4256.
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Richard Pazdur, M.D.
`
` Director
`Office of Hematology & Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3183415
`
`6
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`

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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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`08/31/2012
`
`Reference ID: 3183415
`
`7