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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 022249/S-019
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Cephalon, Inc. (a wholly owned subsidiary of Teva Pharmaceuticals, Ltd.)
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` Attention: Michael J. McGraw, PharmD, MS
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` Director, Regulatory Affairs
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` 41 Moores Road
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` P.O. Box 4011
` Frazer, PA 19355
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`Dear Dr. McGraw:
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`Please refer to your Supplemental New Drug Application (sNDA) dated March 6, 2015, received
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`March 6, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
` (FDCA) for TREANDA® (bendamustine hydrochloride) Injection (solution) 45mg/0.5mL or
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` 180mg/2mL, and TREANDA® (bendamustine hydrochloride) for Injection (lyophilized powder),
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` 25 mg/vial or 100mg/vial.
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` We acknowledge receipt of your submissions related to this NDA dated February 26, March 2, 3,
` 4, and 6, 2015. We also acknowledge receipt of your amendments to this supplement on March
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` 9 and 10, 2015.
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` This “Changes Being Effected” supplemental new drug application provides for updates to the
` Unites States Prescribing Information (USPI) to include both formulations, Treanda Injection
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` (Solution) and Treanda for Injection (lyophilized powder). In addition, the label provides for
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`additional information on the use of Treanda liquid formulation and incompatibilities with
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` Closed System Transfer Devices (CSTD) that contains polycarbonate or acrylonitrile-butadiene­
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` styrene (ABS).
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`We also have the following comments regarding this sNDA approval:
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`1. Submit quarterly reports until March 2017 of complaints about preparation and use of
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`Treanda injection (solution) and Treanda for injection (lyophilized powder).
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`2. We remind you of your commitment to continue conducting device compatibility studies
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`with Treanda injection (solution) to ensure safe preparation and use of Treanda injection
`(solution).
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`Reference ID: 3713848
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` NDA 022249/S-019
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` Page 2
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` APPROVAL & LABELING
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` We have completed our review of this supplemental application, as amended. It is approved,
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` effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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` text.
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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
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` 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
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` http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert), with the
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`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
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`well as annual reportable changes not included in the enclosed labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
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`“SPL Standard for Content of Labeling Technical Qs and As at
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
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`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that includes labeling changes
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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` Until carton labeling and vial changes are implemented, as an interim measure for the Treanda
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`liquid product that has already been distributed to pharmacies, hospitals, etc., you need to
`provide stickers/labels that can adhere to the carton labeling with the Treanda liquid product.
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`FDA recommends the following statement on the sticker: “Not for use with devices that
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` accompanied with the Dear Healthcare Provider (DHCP) letter. Furthermore, the same sticker
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` should be attached to carton and any other appropriate labeling of already existing and ready for
` shipment product supply at the manufacturers and distributors sites.
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`contain polycarbonate or acrylonitrile‐butadiene‐styrene (ABS)”. The sticker should be
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`Reference ID: 3713848
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` NDA 022249/S-019
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` Page 3
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` Carton Labeling
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` 1. In the proposed statement “Do not use with devices that contain polycarbonate or
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`acrylonitrile butadiene-styrene (ABS)” increase the prominence of negation “NOT,”
`by using all capital letters or bolding as negative sentences containing NOT can be
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`misinterpreted as the opposite since NOT can be overlooked”.
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`2. Increase the prominence of the storage information on the side panel by bolding the
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`entire statement “Store refrigerated at….” As storage for Treanda Injection differs
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`from the storage of Treanda for Injection and this information should be easily
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`identified by healthcare providers.
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` Vial Container
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`1. We recommend addition of a flag to the actual vial containing a statement “Do not
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`use with devices that contain polycarbonate or acrylonitrile butadiene-styrene (ABS)”
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`on the container. Increase the prominence of negation “NOT,” by using all capital
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`letters or bolding as negative sentences containing NOT can be misinterpreted as the
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`opposite since NOT can be overlooked.
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`Submit final printed carton and immediate container labels that are identical to the submitted
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`carton and immediate container labels dated March 6, 2015, except with the revisions listed
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`above, as soon as they are available, but no more than 7 days after they are printed. Please
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`submit these labels electronically according to the guidance for industry Providing Regulatory
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`Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related
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`Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit 12
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`paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar
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`material. For administrative purposes, designate this submission “Final Printed Carton and
`Container Labels for approved NDA 022249/S-019.” Approval of this submission by FDA is
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`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
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`product misbranded and an unapproved new drug.
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`PROPRIETARY NAME
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`To prevent medication errors related to confusion between the two formulations of bendamustine
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`hydrochloride due to different products’ concentrations, we recommend you consider one of the
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`following options regarding proprietary name:
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`1. Propose a modifier to be added to the proprietary name Treanda for the injection
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`dosage form to help differentiate the product from the lyophilized powder
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`formulation and submit to the Agency for evaluation. We continue to recommend
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`Reference ID: 3713848
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` NDA 022249/S-019
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` Page 4
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` against the
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` as stated in proprietary name request unacceptable
`letter sent to you on June 13, 2013 (see attached).
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`2. Alternatively, you can propose a dual proprietary name for the injection dosage form.
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`However, if choosing this option, consider retaining a portion of the original Treanda
`name in the new name (e.g. TreanXXXX) so health care practitioners recognize that
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`this product is associated with, (or an extension of) Treanda.
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`Please submit a request for review of your proposed proprietary name. The content requirements
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`for such a submission can be found in the draft Guidance for Industry entitled, Contents of a
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`Complete Submission for the Evaluation of Proprietary Names
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/.
`UCM075068.pdf). Further information about how FDA evaluates propriety names for drug
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`products is available in the following guidance, Best Practices in Developing Proprietary Names
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`for Drugs
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM398997.pdf.
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`If you intend to have a proprietary name for this product, the name and its use in the labels must
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`conform to the specifications under 21 CFR 201.10 and 201.15. We recommend that you submit
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`a request for a proposed proprietary name review. (See the guidance for industry titled,
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`“Contents of a Complete Submission for the Evaluation of Proprietary Names”, at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
`cm075068.pdf and “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years
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`2008 through 2012”.)
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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
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because none of these criteria apply to your application, you are exempt from this requirement.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
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`(3) the package insert(s) to:
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`Reference ID: 3713848
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`(b) (4)
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` NDA 022249/S-019
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` Page 5
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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 (OPDP)
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` 5901-B Ammendale Road
` Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`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
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, please call Kimberly Scott, Regulatory Project Manager, at
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`(240) 402-4560.
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`Sincerely,
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`{See appended electronic signature page}
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`Ann T. Farrell, MD
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`Director
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`Division of Hematology Products
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`Office of Hematology and Oncology Products
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`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`Content of Labeling
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`Carton and Container Labeling
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`Reference ID: 3713848
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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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`ANN T FARRELL
`03/10/2015
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`Reference ID: 3713848
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