`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`201023s000
`
`
`Jevtana
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`
`
`cabazitaxel
`
`Sanofi-aventis U.S., Inc.
`
`June 17, 2010
`
`In combination with prednisone for the treatment of
`patients with hormone-refractory metastatic prostate
`cancer previously treated with a docetaxel-containing
`treatment regimen.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`201023s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`20-1023
`20-1023
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 201023
`
`sanofi-aventis U.S., LLC
`c/o sanofi-aventis U.S., Inc.
`200 Crossing Boulevard, Mailstop: BX2-712B
`Bridgewater, NJ 08807
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`Attention:
`
`Linda M. Gustavson
`Director, U.S., Associate Therapeutics Head, Oncology
`
`Dear Ms. Gustavson:
`
`Please refer to your New Drug Application (NDA) dated March 31, 2010, received
`March 31, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Jevtana® (cabazitaxel) Injection, 60 mg/1.5 mL.
`
`We acknowledge receipt of your submissions dated April 16 (2), May 5, 7, 10, 18, 21, 24,
`25 (2), 28, June 1, 4 (2), 8, 14, 16, and 17, 2010.
`
`This new drug application provides for the use of Jevtana® (cabazitaxel) Injection in
`combination with prednisone for the treatment of patients with hormone-refractory metastatic
`prostate cancer previously treated with a docetaxel-containing treatment regimen.
`
`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, via the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`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/
`UCM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`

`

`NDA 201023
`Page 2
`
`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 (October
`2005)”. 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 201023.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`ADVISORY COMMITTEE
`
`Your application for Jevtana® (cabazitaxel) Injection was not referred to an FDA advisory
`committee because taking this NDA to an advisory committee would result in a several month
`delay in making this advance in prostate cancer therapy available to patients for whom there is
`currently no available therapy.
`
`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.
`
`We are waiving the pediatric study requirement for this application because necessary studies
`are impossible or highly impracticable since prostate cancer does not occur in children.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) 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 (section 505(o)(3)(A)).
`
`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 intravenous infusion of particulate matter into the blood stream.
`
`

`

`NDA 201023
`Page 3
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under
`section 505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these
`serious risk(s).
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`PMR 1649-1:
`To evaluate the potential for a serious risk of intravenous infusion of particulate matter into the
`blood stream, it is necessary to better understand and characterize the supersaturated pre-mix.
`Conduct a study to provide data which address particulate nucleation and kinetic factors of
`precipitation in the pre-mix. Conduct this study using multiple samples drawn from multiple
`batches so as to more fully support an in-use life of the pre-mix.
`Study considerations include (but are not necessarily limited to); interior surface properties of
`the container closure (e.g., treatments, roughness, scratches, etc.), initial mixing agitation force
`(vigorous shaking), physical shock on standing (e.g., vigorous shaking during in-use storage),
`needle sticks, syringe use, temperature (and temperature changes during in-use storage), and
`additional time point sampling beyond the proposed duration of in-use storage of the pre-mix
`solution (e.g., 1 to 4 hours).
`
`Collect and provide photographs of the precipitate as it appears in the container and isolated
`photomicrographs of the particles, as feasible, in the final report.
`Provide by mass balance, the mass of precipitated drug as precipitated mass and as mass
`percent of the total cabazitaxel content, in the final report.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this study
`according to the following schedule:
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`September 2010
`March 2011
`June 2011
`
`PMR 1649-2:
`To evaluate the potential for a serious risk of intravenous infusion of particulate matter into the
`blood stream, it is necessary to better understand and characterize the supersaturated infusion
`solution. Conduct a study which addresses particulate nucleation and kinetic factors of
`precipitation from the infusion solution. Conduct this study using multiple samples drawn for
`at least three additional batches in the containers (bags and sets) which you propose to label for
`this use so as to more fully support an in-use life of the infusion solution.
`Study factors include (but are not necessarily limited to); interior surface properties of the
`container (e.g., treatments, roughness, plasticizers, etc.), initial mixing agitation force (vigorous
`shaking), physical shock on standing (e.g., vigorous shaking during in-use storage), needle
`sticks, temperature (and temperature changes during in-use storage), and additional time point
`sampling beyond the proposed duration of in-use storage of the infusion solution.
`
`

`

`NDA 201023
`Page 4
`
`Collect and provide photographs of the precipitate as it appears in the container and isolated
`photomicrographs of the particles, as feasible, for each observed precipitation or evidence of
`precipitation (e.g., clogged filters, impeded infusion flow, etc.), in the final report.
`Provide by mass balance, the mass of precipitated drug as precipitated mass and as mass
`percent of the total cabazitaxel content in the final report.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this study
`according to the following schedule:
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`September 2010
`March 2011
`June 2011
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess the known serious risks of the unusually high incidence and
`severity of the entire toxicity spectrum observed in your Phase 3 Jevtana® (cabazitaxel)
`Injection trial in metastatic hormone refractory prostate cancer, with special concern for
`neutropenia, febrile neutropenia, infection, diarrhea, renal and cardiac toxicities and the
`increased incidence of drug-related death. A lower Jevtana® (cabazitaxel) Injection dose may
`be equally effective with less toxicity. We have also determined that only a clinical trial
`(rather than a nonclinical or observational study) will be sufficient to assess the signals of the
`serious risks of hepatic impairment, Q-T prolongation and drug-drug interaction with Jevtana®
`(cabazitaxel) Injection.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`PMR 1649-3:
`Conduct a Phase 3 randomized controlled trial in patients with hormone-refractory metastatic
`prostate cancer comparing 75 mg/m2 docetaxel with prednisone with cabazitaxel 25 mg/m2
`with prednisone and cabazitaxel 20 mg/m2 with prednisone as first-line therapy. The primary
`endpoint should be overall survival to evaluate the incidence of drug-related death as well as
`efficacy. The trial should be powered to detect a 25% difference in overall survival. The trial
`will include interim analyses for evaluation of efficacy based on overall survival and safety of
`the 25 mg/m2 with prednisone arm versus the 20 mg/m2 with prednisone arm to potentially
`drop one of the cabazitaxel arms. Submit the protocol for agency review prior to commencing
`the trial.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`November 2010
`December 2017
`June 2018
`
`

`

`NDA 201023
`Page 5
`
`PMR 1649-4:
`Conduct a Phase 3 randomized controlled trial in 1222 patients with hormone-refractory
`metastatic prostate cancer previously treated with docetaxel comparing cabazitaxel 20 mg/m2
`with prednisone versus cabazitaxel 25 mg/m2 with prednisone and powered to preserve 50% of
`the treatment effect of cabazitaxel 25 mg/m2. The study will include interim analyses for
`evaluation of drug-related deaths and safety as well as overall survival of the cabazitaxel 25
`mg/m2 with prednisone arm versus the cabazitaxel 20 mg/m2 with prednisone arm to potentially
`discontinue the trial. Submit the protocol for agency review prior to commencing the trial.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`November 2010
`September 2017
`June 2018
`
`PMR 1649-5:
`Complete and submit the final report of trial TES10884, along with a thorough review of
`cardiac safety data, for the potential of cabazitaxel to cause QTc interval prolongation in
`patients.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`January 2010
`December 2011
`June 2012
`
`PMR 1649-6:
`Conduct the trial POP6972 to determine the pharmacokinetics and safety of cabazitaxel in
`patients with hepatic impairment.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`March 2010
`May 2012
`November 2012
`
`

`

`NDA 201023
`Page 6
`
`PMR 1649-7:
`Conduct a drug interaction trial to evaluate the effect of a strong CYP3A4 inhibitor
`(e.g., ketoconazole) on the pharmacokinetics of cabazitaxel in cancer patients.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`October 2010
`April 2012
`December 2012
`
`PMR 1649-8:
`Conduct a drug interaction trial to evaluate the effect of a strong CYP3A inducer
`(e.g., rifampin) on the pharmacokinetics of cabazitaxel in cancer patients.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`October 2010
`April 2012
`December 2012
`
`PMR 1649-9:
`Organize a group of renal experts to review and analyze renal toxicity from all currently
`available cabazitaxel clinical trials to identify etiologies and to provide recommendations for
`toxicity mitigation by patient selection or other measures and for trials needed to delineate the
`mechanism of toxicity. This group’s findings and recommendations should be submitted
`within 9 months of the cabazitaxel approval date.
`
`Final Report Submission Date:
`
`March 2011
`
`PMR 1649-10:
`Submit integrated analyses of renal toxicity from two randomized trials in patients with
`metastatic hormone refractory prostate cancer every 6 months for 3 years from the initiation of
`the clinical trial. These trials have been described in PMR 1649-3 and PMR 1649-4.
`
`The timetable you submitted on June 16, 2010, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Interim Report Submission:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Final Report Submission:
`
`
`
`
`
`
`November 2010
`May 2011
`November 2011
`May 2012
`November 2012
`May 2013
`November 2013
`
`
`
`
`
`
`
`
`
`

`

`NDA 201023
`Page 7
`
`Submit the protocols to your IND, with a cross-reference letter to this NDA. Submit all final
`report(s) 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:
`
`x REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
`x REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
`x 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.
`
`CHEMISTRY, MANUFACTURING, AND CONTROLS
`
`(b) (4)
`Based on the available primary and supportive drug substance stability data, an
`retest date for the drug substance is granted when stored under the long term storage conditions
`of 5º C.
`
`Based on the provided stability data, an 18-month expiration dating period for the drug product
`is granted when stored under the following long term storage conditions:
`x Store at 25º C (77º F); excursion permitted between 15º C – 30º C (59º F – 86º F)
`x Do not refrigerate
`
`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.
`
`

`

`NDA 201023
`Page 8
`
`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
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`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 Division of Drug
`Marketing, Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`Please submit one market package of the drug product when it is available.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at
`least 24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
`
`MedWatch
`Food and Drug Administration
`Suite 12B-05
`5600 Fishers Lane
`Rockville, MD 20857
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`

`

`NDA 201023
`Page 9
`
`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}
`
`
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`
`
`Richard Pazdur, M.D.
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`
`

`

`Application
`Type/Number
`--------------------
`NDA-201023
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Product Name
`Submitter Name
`------------------------------------------
`--------------------
`SANOFI AVENTIS CABAZITAXEL (XRP6258)
`SPA
`
`---------------------------------------------------------------------------------------------------------
`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
`06/17/2010
`
`