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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 APPROVAL
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`NDA 22-192
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`Vanda Pharmaceuticals
`Attention: John Feeney, M.D.
`Acting Chief Medical Officer
`9605 Medical Center Drive
`Suite 300
`Rockville, MD 20850
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`Dear Dr. Feeney:
`
`
`Please refer to your new drug application (NDA) dated and received September 27, 2007,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Fanapt
`(iloperidone) 1, 2, 4, 6, 8, 10, and 12 mg tablets.
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`We acknowledge receipt of your submissions and communications dated November 6, 2008,
`November 19, 2008, January 9, 2009, March 10, 2009, March 17, 2009, April 15, 2009, and
`April 24, 2009.
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`Your submission of November 6, 2008 constituted a complete response to our July 25, 2008
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` action letter.
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`This new drug application provides for the use of Fanapt (iloperidone) for the acute treatment of
`schizophrenia in adults.
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`We have completed our review of this application. It is approved, effective on the date of this
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`letter, for use as recommended in the agreed-upon labeling text.
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
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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, 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 agreed-upon
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`labeling text. 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 22-192.”
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`
`
`

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`NDA 22-192
`Page 2
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` CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels 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
`(October 2005). For administrative purposes, designate this submission “Final Printed Carton
`and Container Labels for approved NDA 22-192” 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
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`product misbranded and an unapproved new drug.
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`PROPRIETARY NAME
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`The Division of Medication Error Prevention and Analysis (DMEPA) and the Division of
`Psychiatry Products do not object to the use of the proprietary name, Fanapt, for this product.
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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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`We are waiving the pediatric study requirement for ages 0 to 12 years because necessary studies
`are highly impractical due to the very low incidence of schizophrenia diagnosed prior to age 13.
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`We are deferring submission of your pediatric studies for ages 13 to 17 years for this application
`because the drug is ready for approval in adults and the pediatric studies have not been
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`completed.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the Federal Food,
`Drug, and Cosmetic Act. These required studies are listed below.
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`1. A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric
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`patients ages 13 to 17. A study to obtain pharmacokinetic data and provide information
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`pertinent to dosing of iloperidone tablets in the relevant pediatric population.
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`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
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`2. A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric
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`patients ages 13 to 17. A study of the efficacy and safety of iloperidone tablets in the
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`relevant pediatric population.
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`by March 1, 2010
`by September 1, 2013
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`by March 1, 2014
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`

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`NDA 22-192
`Page 3
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`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
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`by March 1, 2010
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` by September 1, 2013
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`by March 1, 2014
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`Submit final reports to this NDA. Use the following designator to prominently label all
`submissions:
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`Required Pediatric Assessment(s)
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o) of the Federal Food Drug and Cosmetic Act (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
`(section 505(o)(3)(A)).
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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 a serious risk
`of carcinogenicity and to identify an unexpected serious risk of drug interactions.
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` Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following studies:
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`3. Complete the ongoing P95 carcinogenicity study.
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`The timetable you submitted on April 24, 2009 states that you will conduct this study according
`to the following timetable:
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`Study Completion Date:
`Final Report Submission:
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`by February 28, 2010
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`by May 31, 2010
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`4. Conduct a study investigating the possible in vitro interaction of iloperidone and P-
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`Glycoprotein (P-Gp).
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`Final Protocol Submission: by August 1, 2009
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`Study Completion Date:
`by October 1, 2009
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`Final Report Submission:
`by November 1, 2009
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`The timetable you submitted on April 15, 2009 states that you will conduct this study
`according to the following timetable:
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`

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`NDA 22-192
`Page 4
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify an unexpected serious risk of Fanapt (iloperidone) to patients
`with hepatic dysfunction.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following clinical trial:
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`5. A repeat of your clinical trial CIL0522A0103, conducted with a group of subjects with
`mildly and moderately impaired hepatic function, comparing them to normals in the same trial.
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`The timetable you submitted on April 15, 2009 states that you will conduct this trial
`according to the following timetable:
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`Final Protocol Submission: by November 1, 2009
`Trial Completion Date:
`by November 1, 2010
`Final Report Submission:
`by May 1, 2011
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`Submit clinical protocols to your IND for this product, with a cross-reference letter to this NDA.
`Submit all final reports to your NDA. Prominently identify the submissions with the following
`wording in bold capital letters at the top of the first page of the submission, as appropriate:
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`REQUIRED POSTMARKETING PROTOCOL under 505(o)
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`REQUIRED POSTMARKETING FINAL REPORT under 505(o)
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`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
`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
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`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 trial 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
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`We remind you of the following postmarketing commitment agreed upon in our communication
`dated April 15, 2009:
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`

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`NDA 22-192
`Page 5
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`6. Long-Term Efficacy Trial
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`You have agreed to conduct and submit the results of a randomized withdrawal clinical trial
`to address longer-term efficacy for your drug at appropriate doses.
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`Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
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`by November 1, 2009
`by November 1, 2012
`by May 1, 2013
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`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all 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 trials, number of patients entered into each study. 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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`ADVISORY COMMITTEE
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`Your application was not referred to an advisory committee for review because this drug is not
`the first in its class, the clinical study design was acceptable, evaluation of the safety data did not
`reveal particular safety issues that were unexpected for this class and the efficacy trials did not
`pose particular concerns.
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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(s)
`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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`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
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`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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`

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`NDA 22-192
`Page 6
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`DISSOLUTION METHOD AND SPECIFICATIONS
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`The dissolution method and specification for all strengths of the immediate release tablets should
`be:
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`Parameter
`Apparatus Type
`Media
`Volume
`Frequency
`Acceptance Criteria
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`EXPIRY
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`A 36 month expiry date is granted based on the available stability data.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`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:
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`Dissolution Method and Specification
`2 (rotating paddle)
`0.1 N HCl
`500 ml
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`50 rpm
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`% in 30 minutes
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`MedWatch
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`Food and Drug Administration
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`Suite 12B05
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`5600 Fishers Lane
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`Rockville, MD 20857
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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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`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
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` instructions and program description details at www.fda.gov/medwatch/report/mmp.htm.
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`(b)
`(4)
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`

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`NDA 22-192
`Page 7
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`If you have any questions, call Kimberly Updegraff, M.S., Regulatory Project Manager,
`at (301) 796-2201.
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`Sincerely,
`
` {See appended electronic signature page}
`
`Robert Temple, M.D.
`Director
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`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Enclosure
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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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`---------------------
`Robert Temple
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`5/6/2009 04:36:30 PM
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