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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
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`NDA 20-717/S-020
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`Cephalon, Inc.
`Attention: James M. Ciciriello, RPh
` Director, Regulatory Affairs
`41 Moores Road
`P.O. Box 4011
`Frazer, PA 19355
`
`
`Dear Mr. Ciciriello:
`
`Please refer to your supplemental new drug application dated May 4, 2005, received May 6, 2005,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Provigil® (modafinil)
`Tablets, 100 mg and 200 mg.
`
`We acknowledge receipt of your additional submissions dated May 25, 2005, August 6, 2007 and
`August 15, 2007.
`
`This supplemental new drug application originally provided for revisions to the CLINICAL
`PHARMACOLOGY and PRECAUTIONS sections.
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`We also refer to our action letter dated September 21, 2006 for ---------- ---------------------------- This
`letter requested that revisions to the Provigil product labeling be made to include information regarding
`serious skin rash, psychiatric symptoms, multi-organ hypersensitivity, and pediatric use.
`
`Furthermore, our March 28, 2007 action letter for NDA 21-875, Nuvigil™ (armodafinil) Tablets,
`requested that you adopt a bolded statement in the Warnings section of the labeling describing the risk
`of developing serious skin and other hypersensitivity reactions associated with the use of modafinil.
`Subsequent to this letter, it was agreed that the Warnings sections of both the Nuvigil and Provigil
`labeling would contain a bolded statement describing these risks. Your August 6, 2007 submission in
`conjunction with a telephone conversation on August 16, 2007, reflected these agreements.
`Specifically, in the August 16, 2007 telephone conversation, it was agreed that the following statement
`would be included as a bolded statement in the Warnings section of the Provigil labeling:
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`“Modafinil is not approved for use in pediatric patients for any indication.”
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`This supplemental new drug application, S-020, fulfills the label change requested in our September
`21, 2006 letter and reflects the agreement that the aforementioned bolded statement would be adopted
`into the Provigil product labeling.
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`

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`NDA 20-717/S-020
`Page 2
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`We have completed our review of this supplemental application, S-020, as amended. This application
`is approved, effective on the date of this letter, for use as recommended in the agreed-upon enclosed
`labeling text.
`
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`CONTENT OF LABELING
`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 and text for the patient package insert) and/or submitted labeling (package insert and
`patient package insert submitted on August 6, 2007). 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 20-717.”
`
`
`SUPERCEDE
`We have reviewed the content of the following labeling supplements, and we note that these changes
`have been incorporated into the enclosed labeling text. Therefore, the supplemental applications listed
`below have been superceded and will be retained in our files with no further action.
`
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`Supplement Number:
`-------------- ----------
`-------------- ----------
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`Date Submitted:
`----------------------
`-------- ------ -------
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`
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`POSTMARKETING COMMITMENTS
`We remind you of your postmarketing study commitments in your submissions dated August 6, 2007
`and August 15, 2007 to NDA 20-717 and June 11, 2007 to NDA 21-875. Your June 11, 2007
`submission noted your agreement to provide a Risk Minimization Action Plan (RiskMAP) and
`Pregnancy Registry protocol for both Provigil and Nuvigil. These commitments are described in
`greater detail and are listed below.
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`
`
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`1. Description of Commitment – Provide a RiskMAP for Provigil to address the risk of serious
`rash and other hypersensitivity reactions (See RiskMAP below for additional comments).
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` Submission of Draft RiskMAP:
` Implementation:
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` Eight weeks after approval of S-020
` Eight weeks after concurrence with the Agency
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`2. Description of Commitment – Provide a Pregnancy Registry protocol for Provigil to obtain
`systematically collected data on the effects of exposures during pregnancy, labor, and delivery
`in women of child-bearing age.
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` by 07/16/07
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` Submission of Protocol:
` Implementation: Upon concurrence with the Agency
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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
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`NDA 20-717/S-020
`Page 3
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`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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`RISK MINIMIZATION ACTION PLAN (RiskMAP)
`You have agreed to submit a comprehensive RiskMAP to address the risk of serious skin and other
`hypersensitivity reactions. Your RiskMAP should include the following components:
`
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`•
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`•
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`•
`•
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`Implementation of a program and distribution of materials to educate prescribers, other
`healthcare providers and patients about the risks and benefits of Provigil.
`Implementation of a plan to promote Provigil only to prescribers for the approved indications in
`adult patients, and to limit prescribing in pediatric patients.
`Implementation of a reporting and data collection system for safety surveillance.
`Implementation of a plan to monitor and evaluate the effectiveness of the RiskMAP in
`communicating and minimizing the risk of serious skin and other hypersensitivity reactions and
`limiting the use of Provigil in pediatric patients.
`
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`The following documents should be submitted:
`• A draft version of the RiskMAP document that includes the components listed above. We refer
`you to the RiskMAP guidance available at http://www.fda.gov/cder/guidance/6358fnl.htm.
`• A copy of all healthcare provider and patient educational materials to be provided as part of the
`RiskMAP program.
`• A plan for ongoing assessment (including monitoring for prescribing in pediatric patients) and
`periodic reporting to FDA of the operation of the RiskMAP and any needed revisions.
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`
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`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(s) 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
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`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.
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`NDA 20-717/S-020
`Page 4
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`“DEAR HEALTHCARE PROFESSIONAL” LETTERS
`Although a Dear Healthcare Professional letter is a planned part of the Provigil RiskMAP, we note
`your agreement to mail the Dear Healthcare Professional letter within 4 weeks of the approval of this
`supplement. When that letter is mailed, we request that you submit a final copy of the Dear Healthcare
`Professional letter to the NDA and to the following address:
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`MEDWATCH
`Food and Drug Administration
`5515 Security Lane
`HFD-001, Suite 5100
`Rockville, MD 20852
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`OTHER
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81). In addition to the postmarketing reporting requirements under CFR 314.80, you
`have agreed to submit the following reports received from any source (ie, clinical studies or
`spontaneous reports), and subsequent follow-up information, within 15 days of receipt as 15 day
`expedited reports using a MedWatch form (FDA Form 3500A):
`• Any reports of serious skin and other hypersensitivity adverse events
`
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`If you have any questions, please call Tamy Kim, PharmD, Regulatory Project Manager, at (301) 796-
`2250.
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`
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`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD
`Director
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`
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`Enclosure: Package Insert, Patient Package Insert
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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.
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` /s/
`---------------------
`Russell Katz
`8/17/2007 11:37:54 AM
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