`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`NDA APPROVAL
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NDA 22-249
`
`
`
`Cephalon, Inc.
`Attention: Carol S. Marchione
`Senior Director and Group Leader
`41 Moores Road
`Frazer, PA 19355
`
`Dear Ms. Marchione:
`
`Please refer to your new drug application (NDA) dated September 19, 2007, received September
`20, 2007, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act
`for TREANDA® (bendamustine hydrochloride) for Injection, for intravenous infusion.
`
`We acknowledge receipt of your submissions dated October 3, 18, 22, 24, 26, November 1, 2, 9,
`15 (2), 27, 28, December 10 and 17, 2007, January 7 (2), 8, 11, 14, 15, 17, 18, 23, 24, 25, 28, 31,
`February 12, 13, 14, 20, 22, 25, 28, March 3, 6, 7, 12, 13 (2), 14, 17 (2), 18 (electronic) and 19 (4
`electronic), 2008.
`
`This new drug application provides for the use of TREANDA® (bendamustine hydrochloride) for
`Injection, for intravenous infusion, for the treatment of patients with chronic lymphocytic
`leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been
`established.
`
`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.
`
`An expiration dating period of 24 months is granted when stored as recommended in the
`approved product labeling. You may extend the expiration dating based on accrual of real-time
`stability data and report this in an annual report for this NDA.
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert). Upon receipt, we will transmit that version to the National Library of
`Medicine for public dissemination. For administrative purposes, please designate this
`submission, “SPL for approved NDA 22-249.”
`
`We acknowledge your March 13, 2008, submission containing final printed carton and container
`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.
`
`
`

`

`NDA 22-249
`Page 2
`
`This application was not referred to the Oncologic Drugs Advisory Committee because the
`improvements in response rate and progression-free survival with bendamustine compared
`to chlorambucil were clinically and statistically robust and the safety profile is comparable
`to other therapies used for the treatment of CLL.
`
`We remind you of your postmarketing study commitments in your submission dated March 19
`(electronic), 2008. These commitments are listed below.
`
`1. Cephalon commits to providing an updated study report of Protocol 02CLLIII titled “Phase
`III, Open-Label, Randomized, Multicenter Efficacy and Safety Study of Bendamustine
`Hydrochloride Versus Chlorambucil in Treatment-Naive Patients with (Binet Stage B/C) B-
`CLL Requiring Therapy” at data cut off date in May 2008. Response rate, progression-free
`survival, overall survival and safety updates will be provided in this study report.
`
`Protocol Submission: N/A
`Study Start: N/A
`Final Report Submission: February, 2009
`
`2. Cephalon commits to submitting the results and data from the ADME Study 1039 titled "An
`Open-Label Study to Investigate the Pharmacokinetics (Distribution, Metabolism, and
`Excretion) of Bendamustine Hydrochloride Following Intravenous Infusion of
`[14C]Bendamustine Hydrochloride in Patients With Relapsed or Refractory Malignancy
`(Hematologic or Nonhematologic)". Results from this study may indicate a need for
`dedicated renal and/or hepatic organ impairment studies.
`
`Protocol Submission: May, 2008
`Study Start: December, 2008
`PK Report Submission: December, 2009
`Final Report Submission: March, 2010
`
`
`3. Cephalon commits to conducting a study to assess the potential for bendamustine to prolong the
`QT interval in patients. The QT plan will be submitted prior to initiation for IRT review and
`concurrence.
`
`
`
`
`
`Protocol Submission: July, 2008
`Study Start: December, 2008
`Final Report Submission: June, 2010
`
`
`4. Since bendamustine is a CYP1A2 substrate in vitro, Cephalon agrees to perform an in vivo
`drug interaction study of the ability of fluvoxamine (CYP1A2 inhibitor) to alter the
`pharmacokinetics of a single dose of bendamustine. The necessity to conduct this study will
`be predicated upon the results from Study 1039.
`
`
`
`Protocol Submission: March, 2010
`Study Start: September, 2010
`PK Report Submission: January, 2012
`Final Report Submission: July, 2012
`
`
`

`

`NDA 22-249
`Page 3
`
`5. Since bendamustine is a CYP1A2 substrate in vitro, Cephalon agrees to perform an in vivo drug
`interaction study of the ability of smoking (CYP1A2 inducer) to alter the pharmacokinetics of a
`single dose of bendamustine. The necessity to conduct this study will be predicated upon the
`results from Study 1039.
`
`Protocol Submission: March, 2010
`Study Start: September, 2010
`PK Report Submission: July, 2012
`Final Report Submission: December, 2012
`
`6. Cephalon commits to conducting in vitro screens to determine if bendamustine is a p-
`glycoprotein substrate or inhibitor.
`
`Protocol Submission: March, 2008
`Study Start: September, 2007
`Final Report Submission: June, 2008
`
`7. Cephalon commits to assess the physico-chemical compatibility of Treanda with the
`following diluents as admixtures to reconstituted TREANDA:
`
`
` sodium chloride).
`
`
`
`
`
`
`Protocol submission: April 1, 2008
`Study start: May 15, 2008
`Final Report: September 1, 2008
`
`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)(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, number of patients entered into each study. All
`submissions, including supplements, relating to these postmarketing study commitments should
`be prominently labeled “Postmarketing Study Commitment Protocol,” “Postmarketing
`Study Commitment Final Report,” or “Postmarketing Study Commitment
`Correspondence.”
`
`We also remind you of your agreement dated February 12, 2008, to initiate change controls for
`all the documents impacted by the revision to the maximum hold time not to exceed
`
` and to submit appropriate post-approval
`
`correspondence reflecting this change in the next annual report.
`
`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(s)
`to:
`
`
`
`
`
`

`

`NDA 22-249
`Page 4
`
`
`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(s), 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 www.fda.gov/cder/ddmac.
`
`If you 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 an electronic copy of
`the letter to both this NDA and to the following address:
`
`
`MedWatch
`Food and Drug Administration
`HFD-001, Suite 5100
`5515 Security Lane
`Rockville, MD 20852
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`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 www.fda.gov/medwatch/report/mmp.htm.
`
`If you have any questions, please call Frank H. Cross, Jr., Regulatory Project Manager, at (301)
`796-0876.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Office Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`Enclosure
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Robert Justice
`3/20/2008 10:23:41 AM
`
`Richard Pazdur
`3/20/2008 10:46:28 AM
`
`