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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 203341
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`Wyeth Pharmaceuticals, Inc.
`Attention: Carl M. DeJuliis, Pharm.D.
` Director, Global Regulatory Affairs
`500 Arcola Road
`Collegeville, PA 19426-3982
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`Dear Dr. DeJuliis:
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`
`Please refer to your New Drug Application (NDA) dated November 17, 2011, received
`November 17, 2011, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for BOSULIF® (bosutinib) Tablets, 100 mg and 500 mg.
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`We acknowledge receipt of your amendments dated December 20, 2011; December 22, 2011 (3);
`December 23, 2011; January 4, 2012; February 22, 2012; March 6, 2012; March 8, 2012;
`March12, 2012; March 19, 2012; April 5, 2012 (2); April 17, 2012; April 25, 2012; May 3, 2012;
`May 16, 2012; May 30, 2012; May 31, 2012; June 13, 2012; July 10, 2012; July 19, 2012;
`August 15, 2012; and August 31, 2012 (via secure e-mail).
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`This new drug application provides for the use of BOSULIF® (bosutinib) Tablets, 100 mg and
`500 mg for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic
`myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.
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`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.
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`An expiration dating period of 24 months is granted for the drug product, when stored at 25°C
`(77°F) excursions permitted between 15°C to 30°C (59°F to 86°F).
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`Reference ID: 3184097
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`

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`NDA 203341
`Page 2
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` CONTENT OF LABELING
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`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
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`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.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the: enclosed immediate
`container labels submitted on August 31, 2012 (via secure e-mail), 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 203341.” Approval of this submission by FDA is not required before the
`labeling is used.
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`Marketing the product 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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`MARKET PACKAGE
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`Please submit one market package of the drug product when it is available to the following
`address:
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`If sending via USPS, please send to:
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`CDR Diane Hanner
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`White Oak Building 22, Room: 2119
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`10903 New Hampshire Avenue
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`Silver Spring, Maryland 20903
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`If sending via any carrier other than USPS (e.g., UPS, DHL, FedEx), please send to:
`CDR Diane Hanner
`Food and Drug Administration
`Center for Drug Evaluation and Research
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`Reference ID: 3184097
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`

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`NDA 203341
`Page 3
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`White Oak Building 22, Room: 2119
`10903 New Hampshire Avenue
`Silver Spring, Maryland 20993
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`ADVISORY COMMITTEE MEETING
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`Your application for BOSULIF® (bosutinib) Tablets, 100 mg and 500 mg was not referred to an
`FDA advisory committee because outside expertise was not necessary; there were no
`controversial issues that would benefit from advisory committee discussion.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`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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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`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 assess a signal of increased
`bosutinib exposure, when bosutinib is co-administered with a moderate CYP3A inhibitor, that
`would likely result in increases in bosutinib toxicities.
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`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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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of increased bosutinib exposure, when co-administered
`with a moderate CYP3A inhibitor, that would likely result in increases in bosutinib toxicities.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`Reference ID: 3184097
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`

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`NDA 203341
`Page 4
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`PMR 1912-1 Conduct a drug-drug interaction trial to evaluate the effect of a moderate CYP3A4
`inhibitor (e.g. erythromycin) on the pharmacokinetics of bosutinib. The proposed
`protocol must be submitted for review and concurrence prior to trial initiation.
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`The timetable you submitted on August 15, 2012, states that you will conduct this trial according
`to the following schedule:
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`Final Protocol Submission: March 2013
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`Trial Completion:
`September 2014
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`Final Report Submission: March 2015
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`Submit the protocols to your IND 068268, 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)”.
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`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
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`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
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`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.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
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`UNDER SECTION 506B
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`We remind you of your postmarketing commitment:
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`The timetable you submitted on August 15, 2012, states that you will conduct this study
`according to the following schedule:
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`Reference ID: 3184097
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`1912-2
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`Continue follow-up of patients (on treatment and in protocol defined post­
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`treatment follow-up) enrolled in Study 200-WW at least an additional 2 years past
`the March 28, 2011 cut-off date. Submit the Final Report, which will consist of an
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`updated report containing, at a minimum, data through March 28, 2013.
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`NDA 203341
`Page 5
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`Final Protocol Submission: N/A
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`Trial Completion:
`N/A
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`Final Report Submission: December 2015
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`Submit clinical protocols to your IND 068268 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)(viii) you should include a status
`summary of each commitment in your annual report to this NDA. The status summary should
`include expected summary completion and final report submission dates, any changes in plans
`since the last annual report, and, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
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`PROMOTIONAL MATERIALS
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`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:
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion
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`5901-B Ammendale Road
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`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
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`information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`Reference ID: 3184097
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`

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`NDA 203341
`Page 6
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` MEDWATCH-TO-MANUFACTURER PROGRAM
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`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
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`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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` POST-ACTION FEEDBACK MEETING
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`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
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` 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.
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`If you have any questions, call CDR Diane Hanner, Regulatory Project Manager, at
`(301) 796-4058.
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`Sincerely,
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` {See appended electronic signature page}
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`Richard Pazdur, M.D.
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` Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
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`Reference ID: 3184097
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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/
`----------------------------------------------------
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`RICHARD PAZDUR
`09/04/2012
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`Reference ID: 3184097
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