`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`Viibryd, 10 mg, 20mg, and 40 mg mg Tablets
`
`Vilazodone hydrochloride
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Trovis Pharmaceuticals, LLC
`
`January 21, 2011
`
` Treatment of Major Depressive Disorder
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`X
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`APPROVAL LETTER
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`NDA 022567
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Trovis Pharmaceuticals LLC
`Attention: Kimberly Fabrizio
`Vice President, Regulatory Affairs
`Five Science Park
`New Haven, CT 06511
`
`Dear Ms. Fabrizio:
`
`Please refer to your New Drug Application (NDA) dated March 22, 2010, received March 22,
`2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Viibryd (vilazodone hydrochloride) 10 mg, 20 mg, and 40 mg tablets.
`
`We acknowledge receipt of your amendments dated May 4, 2010, May 7, 2010, May 18, 2010,
`May 19, 2010, May 25, 2010, June 3, 2010, June 8, 2010, June 30, 2010, August 4, 2010, August
`19, 2010, August 23, 2010, August 31, 2010, September 27, 2010, November 4, 2010, November
`18, 2010, November 30, 2010, December 3, 2010, December 13, 2010, December 15, 2010,
`December 23, 2010, December 29, 2010, January 4, 2011, January 6, 2011, January 7, 2011,
`January 11, 2011, and January 13, 2011.
`
`This new drug application provides for the use of Viibryd (vilazodone hydrochloride) for the
`treatment of Major Depressive Disorder.
`
`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.
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling. Information on submitting SPL files using eLIST may be
`found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs
`and As” at
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 2
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels as agreed upon in our January 14, 2011 communication 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 (June 2008).” Alternatively, you may submit 12 paper copies,
`with 6 of the copies individually mounted on heavy-weight paper or similar material. For
`administrative purposes, designate this submission “Final Printed Carton and Container
`Labels for approved NDA 22567.” 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.
`
`ADVISORY COMMITTEE
`
`Your application for vilazodone was not referred to an FDA advisory committee because this
`drug is not the first in its class, and the safety profile is similar to that of other drugs approved for
`this indication.
`
`PROPRIETARY NAME
`
`The Division of Medication Error and Prevention and Analysis (DMEPA) and the Division of
`Psychiatry Products do not object to the use of the proprietary name, Viibryd, for this product.
`
`REQUIRED 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 6 years old in the treatment of
`major depressive disorder, because studies are highly impractical due to the low prevalence of
`this disorder in this age range.
`
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 3
`
`
`We are deferring submission of your pediatric studies for ages 7 to 17 years old in the treatment
`of major depressive disorder, because this product is ready for approval for use in adults and the
`pediatric studies have not been completed.
`
`Your deferred pediatric studies required under 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 FDCA. These
`required studies are listed below.
`
`
`1723-1
`
`Deferred pediatric study under PREA for the treatment of major depressive
`disorder in pediatric patients aged 7 to 17. Conduct a study to obtain
`pharmacokinetic, safety, and tolerability data and provide information pertinent to
`dosing of vilazodone in the relevant pediatric population.
`
`
`
`
`
`1723-2
`
`
`
`
`1723-3
`
`
`
`
`
`
`1723-4
`
`
`
`Final Protocol Submission Date:
`Study Completion Date:
`
`Final Report Submission:
`
`
`January 31, 2012
`February 28, 2013
`January 31, 2016
`
`Deferred pediatric study under PREA for the treatment of major depressive
`disorder in pediatric patients aged 7 to 17. Conduct a study to obtain data on the
`efficacy and safety of vilazodone in the relevant pediatric population. This must
`be a placebo-controlled and active-controlled (fluoxetine) study. This study must
`be a fixed-dose study.
`
`Final Protocol Submission Date: May 31, 2013
`Study Completion Date:
`
`July 31, 2015
`Final Report Submission:
`
`January 31, 2016
`
`Deferred pediatric study under PREA for the treatment of major depressive
`disorder in pediatric patients aged 7 to 17. Conduct a second study to obtain data
`on the efficacy and safety of vilazodone in the relevant pediatric population. This
`must be a placebo-controlled and active-controlled (fluoxetine) study. This study
`may be a fixed-dose study.
`
`Final Protocol Submission Date: May 31, 2013
`Study Completion Date:
`
`July 31, 2015
`Final Report Submission:
`
`January 31, 2016
`
`To support the use of vilazodone in children less than 13 years of age, you must
`conduct a study to assess the safety of vilazodone in juvenile rats. This study must
`include evaluation of neurological/behavioral development and reproductive
`development. You should submit the protocol for our comments prior to initiating
`the study.
`
`Final Protocol Submission Date:
`
`January 30, 2012
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 4
`
`
`
`Study Completion Date:
`Final Report Submission:
`
`
`
`
`January 30, 2014
`January 30, 2015
`
`
`Submit final reports to this NDA. For administrative purposes, all submissions related to this
`required pediatric postmarketing study must be clearly designated “Required Pediatric
`Assessment(s).”
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the 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.
`
`The major human metabolite of vilazodone, M17, was not demonstrated to be present in plasma
`of either rats or rabbits. Therefore the embryo-fetal reproductive toxicity studies with vilazodone
`did not adequately assess the potential reproductive toxicity of M17.
`
`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 the reproductive toxicity
`of the major human metabolite M17.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA is not yet sufficient to assess this serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`1723-5
`
`Assess the reproductive toxicity of metabolite M17 by conducting an embryo-
`fetal study in either rats or rabbits in which M17 is administered by a route that
`will produce systemic exposure equal to or greater than the exposure in humans at
`the maximum recommended human dose (MRHD).
`
`
`The timetable, as agreed upon on a January 19, 2011 communication, states that you will conduct
`this study according to the following schedule:
`
`
`Final Protocol Submission Date:
`Study Completion Date:
`
`Final Report Submission:
`
`
`Not applicable
`November 30, 2012
`January 31, 2013
`
`
`1723-6
`
`Assess the reproductive toxicity of metabolite M17 by demonstrating that the
`original rabbit study was adequate to assess the embryo-fetal toxicity of M17.
`This will require data demonstrating that the systemic exposure to M17 in rabbits
`in that study was equal to or greater than that in humans at the MRHD.
`
`
`
`The timetable, as agreed upon on a January 19, 2011 communication, states that you will conduct
`this study according to the following schedule:
`
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 5
`
`
`
`Not applicable
`November 30, 2012
`January 31, 2013
`
`Final Protocol Submission Date:
`Study Completion Date:
`
`Final Report Submission:
`
`
`
`If you are able to address postmarketing study 1723-6 adequately through analyses of existing
`data, FDA may release you from postmarketing study 1723-5.
`
`Submit the protocol to your IND 54613, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission 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(o),” “Required Postmarketing Final Report Under
`505(o),” “Required Postmarketing Correspondence Under 505(o).”
`
`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.
`
`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
`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 trials 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.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments agreed upon in your communications dated
`January 19, 2011:
`
`1723-7
`
`A controlled trial to evaluate the longer-term (i.e., maintenance) efficacy of
`vilazodone in the treatment of adults with major depressive disorder. This trial
`must be placebo-controlled, utilize a randomized withdrawal design, and include
`an adequate period of stabilization with open-label treatment of vilazodone prior
`to double-blind randomization.
`
`Final Protocol Submission:
`Trial Completion Date:
`
`Final Report Submission:
`
`
`September 30, 2011
`January 31, 2015
`January 31, 2016
`
`
`
`
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 6
`
`
`1723-8
`
`
`
`
`1723-9
`
`
`
`
`1723-10
`
`
`
`
`1723-11
`
`
`
`
`
`Submit clinical protocols to your IND 54613 for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under
`
`Reference ID: 2894777
`
`It is not apparent from the trials you have conducted in major depressive disorder
`that the lowest effective dose of vilazodone has been identified, because only one
`dose (40 mg/day) was studied. However, there are suggestions that 20 mg/day
`may be effective at least in some subjects. In one of the trials, those who did not
`tolerate 40 mg/day could continue in the trial on a dose of 20 mg/day, and some
`may have had a significant treatment effect. In addition, data from the phase 2
`fixed-dose trials suggest that there may have been a signal of efficacy with the 20
`mg/day dose, as measured by the secondary efficacy measure (MADRS).
`Moreover, some important adverse reactions are dose-related. Thus, we request
`that you further characterize the efficacy and safety of vilazodone in the treatment
`of adults with MDD using fixed doses of vilazodone (20 mg and 40 mg), an active
`control (for assay sensitivity), and placebo in an adequate and well controlled
`trial.
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`October 31, 2011
`January 31, 2013
`January 31, 2014
`
`Vilazodone is metabolized primarily by CYP3A4. You have not submitted
`information on the potential effect of CYP3A4 induction on vilazodone exposure.
`We request that you conduct a drug-drug interaction trial of vilazodone using a
`CYP3A4 inducer (carbamazepine) in healthy subjects.
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`July 31, 2011
`July 31, 2012
`January 31, 2013
`
`Vilazodone is extensively metabolized; however, the pharmacokinetics of
`vilazodone in patients with severe hepatic impairment has not been assessed. We
`request that you conduct a Phase 1 trial to evaluate the pharmacokinetics of
`vilazodone in patients with severe hepatic impairment.
`
`Final Protocol Submission:
`Trial Completion:
`
`
`Final Report Submission:
`
`
`July 31, 2011
`July 31, 2012
`February 28, 2013
`
`Information on the effect of PgP on the pharmacokinetics of vilazodone and the
`effect of vilazodone on PgP was not submitted. We request that you conduct an in
`vitro study to evaluate whether vilazodone is a substrate or inhibitor of PgP.
`
`Final Protocol Submission:
`Study Completion:
`
`
`Final Report Submission:
`
`
`July 31, 2011
`September 30, 2011
`December 31, 2011
`
`

`

`NDA 022567
`Page 7
`
`
`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/trials, number of patients entered into each study/trial. All
`submissions, including supplements, relating to these postmarketing commitments should be
`prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment
`Final Report,” or “Postmarketing Commitment Correspondence.”
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA determines that such a strategy is necessary to ensure that
`the benefits of the drug outweigh the risks [section 505-1(a)]. The details of the REMS
`requirement were outlined in our REMS notification letter dated November 1, 2010.
`
`Your proposed REMS, submitted on December 15, 2010, and appended to this letter, is
`approved. The REMS consists of a Medication Guide and a timetable for submission of
`assessments of the REMS.
`
`The REMS assessment plan should include, but is not limited to, the following:
`
`
`a. An evaluation of patients’ understanding of the serious risks of Viibryd (vilazodone
`hydrochloride) Tablets.
`b. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24.
`c. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance.
`
`
`Assessments of an approved REMS must also include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. With respect to any such postapproval
`study, you must include the status of such study, including whether any difficulties completing
`the study have been encountered. With respect to any such postapproval clinical trial, you must
`include the status of such clinical trial, including whether enrollment has begun, the number of
`participants enrolled, the expected completion date, whether any difficulties completing the
`clinical trial have been encountered, and registration information with respect to requirements
`under subsections (i) and (j) of section 402 of the Public Health Service Act. You can satisfy
`these requirements in your REMS assessments by referring to relevant information included in
`the most recent annual report required under section 506B and 21 CFR 314.81(b)(2)(vii) and
`including any material or significant updates to the status information since the annual report was
`prepared. Failure to comply with the REMS assessments provisions in section 505-1(g) could
`result in enforcement action.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 8
`
`
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of the FDCA.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 22567 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 22567
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE) FOR NDA 22567
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`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
`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, 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
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`Please submit one market package of the drug product when it is available.
`
`DISSOLUTION METHOD AND SPECIFICATIONS
`
`The dissolution method test conditions for all tablet strengths (10 mg, 20 mg, and 40 mg) are as
`follows:
`
`Reference ID: 2894777
`
`

`

`NDA 022567
`Page 9
`
`
`
`USP Apparatus: 2 (Paddle) x 60 rpm
`Medium: 0.1% Acetic Acid (pH 3.1), 1000 mL at 37ºC
`Specifications: Q=
` at 30 min
`
`EXPIRY DATE
`
` A
`
` 24 month expiry date is granted based on the available stability data.
`
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you decide to 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, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA to the following
`address:
`
`
`MedWatch Program
`Office of Special Health Issues
`Food and Drug Administration
`10903 New Hampshire Ave
`Building 32, Mail Stop 5353
`Silver Spring, MD 20993
`
`
`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
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`
`
`Reference ID: 2894777
`
`(b) (4)
`
`

`

`NDA 022567
`Page 10
`
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, email CDR Bill Bender, Senior Regulatory Project Manager, at
`william.bender@fda.hhs.gov.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Ellis Unger, M.D.
`Deputy Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`Enclosures:
`Content of Labeling
`REMS
`
`
`
`
`Reference ID: 2894777
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELLIS F UNGER
`01/21/2011
`
`Reference ID: 2894777
`
`