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` DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`Food and Drug Administration
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`Rockville, MD 20857
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`NDA 22-249/S-001
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`Cephalon, Inc.
`Attention: Carol S. Marchione
`Senior Director and Group Leader
`41 Moores Road
`Frazer, PA 19355
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`Dear Ms. Marchione:
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`Please refer to your supplemental new drug application dated August 27, 2008, received
`August 28, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`for Treanda® (bendamustine hydrochloride) for Injection, 100 mg.
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`We acknowledge receipt of your submissions dated August 27, 2008 and November 19, 2008.
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`This supplemental new drug application provides for the addition of a 25 mg vial for the use of
`Treanda® (bendamustine hydrochloride) for Injection for the treatment of patients with Chronic
`Lymphocytic Leukemia and for the treatment of patients with indolent B-cell non-Hodgkin’s
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`lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab­
`containing regimen.
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`We completed our review of this application, as amended. This application is approved, effective on
`the date of this letter, for use as recommended in the agreed-upon labeling text.
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`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
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` 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/S-001.”
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`We remind you of your outstanding postmarketing study commitments listed in the March 20, 2008,
`approval letter. These commitments are listed below.
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`1.
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`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) BCLL
`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.
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`NDA 22-249/S-001
`Page 2
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`Protocol Submission: N/A
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`Study Start: N/A
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`Final Report Submission: February 28, 2009
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`2.
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`3.
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`4.
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`5.
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`6.
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`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.
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`Protocol Submission: May 31, 2008
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`Study Start: December 31, 2008
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`Final Report Submission: March 31, 2010
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`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.
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`Protocol Submission: July 31, 2008
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`Study Start: December 31, 2008
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`Final Report Submission: June 30, 2010
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`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.
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`Protocol Submission: March 31, 2010
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`Study Start: September 30, 2010
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`Final Report Submission: July 31, 2012
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`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.
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`Protocol Submission: March 31, 2010
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`Study Start: September 30, 2010
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`Final Report Submission: December 31, 2012
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`Cephalon commits to conducting in vitro screens to determine if bendamustine is a
`p-glycoprotein substrate or inhibitor.
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`Protocol Submission: March 31, 2008
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`Study Start: September 30, 2007
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`Final Report Submission: June 30, 2008
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`NDA 22-249/S-001
`Page 3
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`Cephalon commits to assess the physico-chemical compatibility of Treanda with the following
`diluents as admixtures to reconstituted TREANDA: D5W, lactated Ringers and half normal
`saline (0.45% sodium chloride).
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`7.
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`Protocol submission: April 1, 2008
`Study start: May 15, 2008
`Final Report: September 1, 2008
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`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 must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
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`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division/ the Division of Drug Oncology Products and two copies of both the promotional
`materials and the package insert directly to:
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`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
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`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
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`MEDWATCH
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`Food and Drug Administration
`Suite 12B05
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`5600 Fishers Lane
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`Rockville, MD 20857
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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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`NDA 22-249/S-001
`Page 4
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`If you have any questions, call Milinda Vialpando, Regulatory Project Manager, at
`(301) 796-1444.
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`Enclosure: Labeling
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`Sincerely,
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` {See appended electronic signature page}
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`Robert L. Justice, M.D., M.S.
`Director
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`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
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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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`---------------------
`Amna Ibrahim
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`5/1/2009 01:01:36 PM
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`For Dr Robert Justice
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