CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`APPROVAL LETTER
`
`

`

`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 22—192
`
`NDA APPROVAL
`
`Vanda Pharmaceuticals
`
`Attention: John Feeney, M.D.
`Acting Chief Medical Officer
`9605 Medical Center Drive
`Suite 300
`
`Rockville, MD 20850
`
`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.
`
`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.
`
`Your submission of November 6, 2008 constituted a complete response to our July 25, 2008
`action letter.
`
`This new drug application provides for the use of Fanapt (iloperidone) for the acute treatment of
`schizophrenia in adults.
`
`We have completed our review of this application. It is approved, effective on the date of this
`letter, for use as recommended in the agreed-upon labeling text.
`
`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.
`
`CONTENI _OF LABELmG
`
`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(1)] in structured product labeling (SPL) format as described
`at hflp://www.fda.gov/oc/datacouncil/splhtml that is identical to the enclosed agreed-upon
`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.”
`
`

`

`NDA 22-192
`
`Page 2
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`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.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`' PROPRIETARY NAME
`
`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.
`
`RE UIRED PEDIATRIC ASSESSMENTS
`
`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.
`
`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.
`
`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
`completed.
`
`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.
`
`1. A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric
`patients ages 13 to 17. A study to obtain pharmacokinetic data and provide information
`pertinent to dosing of iloperidone tablets in the relevant pediatric population.
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`by March 1, 2010
`by September 1, 2013
`by March 1, 2014
`
`2. A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric
`patients ages 13 to 17. A study of the efficacy and safety of iloperidone tablets in the
`relevant pediatric population.
`
`

`

`NDA 22-192
`
`Page 3
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`by March 1, 2010
`by September 1, 2013
`by March 1, 2014
`
`Submit final reports to this NDA. Use the following designator to prominently label all
`submissions:
`
`Required Pediatric Assessment(s)
`
`POSTMARKETING REQUIREMENTS UNDER 50510!
`
`Section 505(0) 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(0)(3)(A)).
`
`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.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following studies:
`
`3. Complete the ongoing P95 carcinogenicity study.
`
`The timetable you submitted on April 24, 2009 states that you will conduct this study according
`to the following timetable:
`
`Study Completion Date:
`Final Report Submission:
`
`by February 28, 2010
`by May 31, 2010
`
`4. Conduct a study investigating the possible in vitro interaction of iloperidone and P—
`Glycoprotein (P-Gp).
`
`The timetable you submitted on April 15, 2009 states that you will conduct this study
`according to the following timetable:
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`
`by August 1, 2009
`by October 1, 2009
`by November 1, 2009
`
`

`

`NDA 22- 192
`
`Page 4
`
`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 dysfimction.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following clinical trial:
`
`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.
`
`The timetable you submitted on April 15, 2009 states that you will conduct this trial
`according to the following timetable:
`
`Final Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`by November 1, 2009
`by November 1, 2010
`by May 1, 2011
`
`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:
`
`REQUIRED POSTMARKETING PROTOCOL under 505(0)
`REQUIRED POSTMARKETING FINAL REPORT under 505(0)
`REQUIRED POSTMARKETING CORRESPONDENCE under 505(0)
`
`Section 505(0)(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 postrnarketing commitments or required studies or clinical
`trials.
`
`‘
`
`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(0)(3)(E)(ii)
`provided that you include the elements listed in 505(0) and 21 CFR 314.81(b)(2)(vii). We
`remind you that to comply with 505(0), 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(0) on the date required
`will be considered a violation of FDCA section 505(0)(3)(E)(ii) and could result in enforcement
`action.
`
`POSTMARKETING COMMITMENTS
`
`We remind you of the following postrnarketing commitment agreed upon in our communication
`dated April 15, 2009:
`
`

`

`NDA 22-192
`
`Page 5
`
`6. Long-Term Efficacy Trial
`
`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.
`
`Protocol Submission:
`Trial Completion Date:
`Final Report Submission:
`
`by November 1, 2009
`by November 1, 2012
`by May 1, 2013
`
`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.”
`
`
`ADVISORY COMMITTEE
`
`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.
`
`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
`
`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.
`
`

`

`NDA 22— 1 92
`
`Page 6
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`DISSOLUTION METHOD AND SPECIFICATIONS
`
`The dissolution method and specification for all strengths of the immediate release tablets should
`be:
`
`
`
`
`
`
`
`
`EXPIRY
`
`
`
`2 rotatin addle
`0.1 N HCl
`
`Dissolution Method and S n ecification
`
`
`
`500 m1
`
`
`
`
` $3 in 30 minutes
`
`
`
`
`A 36 month expiry date is granted based on the available stability data.
`
`LETTERS T0 HEALTH CARE PROFESSIONALS
`
`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
`Suite 12B05
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`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/mmphtm.
`
`

`

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

`

`
`
`v This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Temple
`5/6/2009 04:36:30 PM
`
`