CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`CLINICAL REVIEW
`
`
`
`Application Type NDA
`Application Number(s) 022567
`Related IND 054613
`Priority or Standard Standard
`
`Submit Date(s) March 22, 2010
` Received Date(s) March 22, 2010
`PDUFA Goal Date January 22, 2011
`Division / Office DPP/ODE1
`
`
`
`Reviewer Name(s) Cheri Lindberg, MD
`Review Completion Date January 19, 2011
`
`Established Name Vilazodone HCl
`(Proposed) Trade Name Viibryd
`Therapeutic Class Antidepressant
`Applicant PGxHealth, LLC
`
`Formulation(s) 10, 20, 40 mg tablet
`Dosing Regimen Once daily – oral
`Indication(s) Major Depressive Disorder
`Intended Population(s) Adult
`
`
`
`Reference ID: 2893768
`
`

`

`Template Version: March 6, 2009
`
`Reference ID: 2893768
`
`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 5
`1.1 Recommendation on Regulatory Action ............................................................. 5
`1.2 Risk Benefit Assessment.................................................................................... 5
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 6
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7
`2.1 Product Information ............................................................................................ 7
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 8
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 8
`2.4
`Important Safety Issues with Consideration to Related Drugs............................ 8
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 9
`2.6 Other Relevant Background Information .......................................................... 10
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 11
`3.1 Submission Quality and Integrity ...................................................................... 11
`3.2 Compliance with Good Clinical Practices ......................................................... 11
`3.3 Financial Disclosures........................................................................................ 12
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 12
`4.1 Chemistry Manufacturing and Controls ............................................................ 12
`4.2 Clinical Microbiology......................................................................................... 13
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 13
`4.4 Clinical Pharmacology...................................................................................... 13
`4.4.1 Mechanism of Action.................................................................................. 13
`4.4.2 Pharmacodynamics.................................................................................... 14
`4.4.3 Pharmacokinetics....................................................................................... 14
`5 SOURCES OF CLINICAL DATA............................................................................ 15
`5.1 Tables of Studies/Clinical Trials ....................................................................... 15
`5.2 Review Strategy ............................................................................................... 20
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 20
`6 REVIEW OF EFFICACY......................................................................................... 39
`Efficacy Summary...................................................................................................... 39
`6.1
`Indication – Major Depressive Disorder............................................................ 39
`6.1.1 Methods ..................................................................................................... 39
`6.1.2 Subject Disposition..................................................................................... 43
`6.1.2 Demographics............................................................................................ 45
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 48
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 49
`6.2.0 Efficacy Conclusions......................................................................................... 64
`
`Reference ID: 2893768
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`3
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`7 REVIEW OF SAFETY............................................................................................. 64
`Safety Summary ........................................................................................................ 64
`7.1 Methods............................................................................................................ 65
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 65
`7.1.2 Categorization of Adverse Events.............................................................. 66
`7.1.3 Pooling of Data across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 66
`7.2 Adequacy of Safety Assessments .................................................................... 67
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 67
`7.2.2 Explorations for Dose Response................................................................ 69
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 70
`7.2.4 Routine Clinical Testing ............................................................................. 70
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 71
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 71
`7.3 Major Safety Results ........................................................................................ 73
`7.3.1 Deaths........................................................................................................ 73
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 73
`7.3.3 Dropouts and/or Discontinuations .............................................................. 87
`7.4
` Supportive Safety Results ............................................................................ 93
`7.4.1 Common Adverse Events .......................................................................... 93
`7.4.2 Laboratory Findings ................................................................................... 97
`7.4.3 Vital Signs ................................................................................................ 103
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 106
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 111
`7.5 Other Safety Explorations............................................................................... 116
`7.5.3 Drug-Demographic Interactions ............................................................... 118
`7.5.4 Drug-Disease Interactions........................................................................ 119
`7.5.5 Drug-Drug Interactions............................................................................. 119
`7.6 Additional Safety Evaluations ......................................................................... 119
`7.6.1 Human Carcinogenicity............................................................................ 123
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 123
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 124
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 124
`8 POSTMARKET EXPERIENCE............................................................................. 125
`
`9 APPENDICES ...................................................................................................... 126
`9.2 Labeling Recommendations ........................................................................... 126
`9.3 Advisory Committee Meeting.......................................................................... 126
`
`
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`Reference ID: 2893768
`
`4
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`From a clinical perspective, approval is recommended (with revisions to the proposed
`label) of NDA 022567 Viibryd (vilazodone) for the treatment of Major Depressive
`Disorder in adult patients.
`
`
`1.2 Risk Benefit Assessment
`
`The efficacy of vilazodone was demonstrated in two (2) of seven (7) controlled trials
`designed to evaluate vilazodone as a treatment for Major Depressive Disorder in adult
`outpatients. Review of the safety data submitted by the applicant reveals a safety
`profile that is similar to other serotonin reuptake inhibitors; with the exception of
`ophthalmologic abnormalities, there were no unexpected findings.
`
`The efficacy of only one dose of vilazodone, 40 mg qd, was explored. It is the opinion of
`this reviewer that the dose-response relationship of vilazodone has not been adequately
`characterized. This should be explored as a post-marketing commitment with a fixed-
`dose design to provide a valid and rigorous examination of dose-response relationships
`for efficacy as well as safety and tolerability.
`
`Post-marketing commitments will help elucidate tolerance and withdrawal effects of
`vilazodone and provide a more thorough understanding of the drug in patients with renal
`and hepatic impairment.
`
`The labeling should include recommendations to
`
` Although in the
`placebo-controlled database, the mean change from baseline and outliers for heart rate
`and blood pressure were not significantly different for vilazodone compared with
`placebo; this reviewer concurs with recommendations of the QT-IRT to monitor blood
`pressure and pulse rate in patients with hypertension or pre-existing heart disease.
`Concurrence is based on the opinion that it is necessary to further characterize the
`pharmacokinetic profile of vilazodone with regard to drug-disease interactions and dose
`response. In the thorough QT study, at the 80 mg dose of vilazodone, 18% of patients
`met tachycardia outlier criteria as compared with 5% in the placebo group. Current data
`regarding food effect, dose-response, and drug-disease interaction (severe hepatic and
`severe renal impairment) indicate that it may be difficult to predict exposure.
`
`
`
`
`Reference ID: 2893768
`
`5
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`(b) (4)
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`Overall, in view of the potential clinical benefit, the risk-benefit assessment is favorable
`for vilazodone 40 mg/day for the treatment of Major Depressive Disorder in the adult
`population.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`In accordance with section 505-1(a) of FDCA, it has been determined that a REMS is
`necessary for antidepressant medications to ensure the benefits of the drug outweigh
`the increased risk of suicidality in children, adolescents, and young adults as observed
`in short-term studies of major depressive disorder (MDD) and other psychiatric
`disorders. No specific risk was observed within this clinical development program;
`however, a Medication Guide REMS is required for all members of this therapeutic
`class.
`
`The REMS must include a timetable for submission of assessments that shall be no
`less frequent than 18 months, three years, and seven years after the REMS is initially
`approved.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Because the efficacy of only one dose of vilazodone, 40 mg qd, was studied, the dose-
`response of this drug has not been adequately explored. Therefore, the applicant
`should conduct a clinical trial evaluating vilazodone compared with placebo in fixed
`doses of 10 mg/day, 20 mg/day, 30 mg/day, and 40 mg/day.
`
`The applicant should also conduct a placebo-controlled, randomized withdrawal trial to
`assess the occurrence of withdrawal and rebound during taper and discontinuation.
`
`The applicant should also adequately characterize vilazodone with regard to hepatic
`and renal impairment. The current trials have assessed a small number of patients with
`mild to moderate impairment of hepatic and renal impairment; no patients with severe
`impairment have been studied.
`
`
`Reference ID: 2893768
`
`6
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
` 2
`
` Introduction and Regulatory Background
`
`2.1 Product Information
`
`USAN: Vilazodone hydrochloride
`Molecular Formula: C26H27N5O2HCl
`
`
`
`
`
`Vilazodone hydrochloride is a new molecular entity with putative antidepressant activity
`as a serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. Vilazodone has
`greater in vitro potency and selectivity for serotonin reuptake than fluoxetine. In vitro
`binding studies also indicate that vilazodone has a greater potency at the 5-HT1A
`receptor than specific 5-HT1A ligands such as buspirone, an accepted adjunctive
`treatment for Major Depressive Disorder.
`
`Proposed Trade Name (established name): Viibryd is the proposed trade name and
`vilazodone HCl is the established name adopted by the United States Adopted Names
`(USAN) Council.
`
`Chemical Class: New Molecular Entity – belongs to the structural chemical group of
`the indolalkylamines and is formulated at 10, 20, and 40 mg tablets for oral
`administration.
`
`Pharmacologic Class: Selective Serotonin Reuptake Inhibitor
`
`
`
`
`
`Proposed Indications: Treatment of Major Depressive Disorder
`
`Proposed Age Group: Adults
`
`
`Reference ID: 2893768
`
`7
`
`(b) (4)
`
`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`Proposed Dosage and Administration: The recommended dose for vilazodone is 40
`mg once daily. Vilazodone should be titrated to the 40 mg dose, starting with an initial
`dose of 10 mg once daily for 7 days followed by 20 mg once daily for an additional 7
`days. Vilazodone should be taken with food.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`A number of antidepressant medications are available for the treatment of Major
`Depressive Disorder, including:
`
`Tricyclic Antidepressants
`
`imipramine, desipramine, amitryptiline, nortryptiline,
`doxepin, amoxapine, trimipramine, protryptiline,
`maprotiline.
`phenylzine, tranylcypromine, isocarboxazid,
`maprotiline, selegiline patch
`fluoxetine, fluvoxamine, sertraline, paroxetine,
`citalopram, escitalopram
`venlafaxine, duloxetine, desvenlafaxine
`
`Monoamine Oxidase
`Inhibitors (MAOI)
`Selective Serotonin Reuptake
`Inhibitors (SSRI)
`Serotonin and Norepinephrine
`Reuptake Inhibitors
`Other Antidepressants
`
`
`Electroconvulsive therapy is also available for the treatment of MDD.
`
`bupropion HCl, bupropion HBr, trazadone, nefazodone,
`mirtazapine
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`This product is a new molecular entity under development for licensing by the applicant
`and is currently not marketed in the United States. The applicant indicates that the drug
`product would be readily available in the United States.
`
`
`2.4
`
`Important Safety Issues with Consideration to Related Drugs
`
`Vilazodone is in the therapeutic class of serotonin specific reuptake inhibitors (SSRI).
`Although no specific safety issues related to the following items were identified in the
`vilazodone clinical development program SSRIs, as a class, have been associated with
`the following safety concerns:
`• Suicidality
`• Serotonin syndrome
`• Seizures
`• Abnormal bleeding
`• Activation of mania or hypomania
`• Hyponatremia
`
`Reference ID: 2893768
`
`8
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`• Discontinuation syndrome
`
`These issues are specifically addressed in Section 7, Review of Safety.
`
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`
`
`Type of
`Meeting/Correspondence
`(Meeting Date)
`[Correspondence
`Finalized]
`
`Initial IND
`54613
` (11/21/1997)
`[12/21/1997]
`
`
`
`
`
`
`
`IND 54613
`Type C Meeting
`(August 7, 2006)
`[August, 15 2006]
`
`
`
`IND 54613
`Type B Meeting
`(May 11, 2009)
`[May 19, 2009]
`
`
`
`FDA recommendations/comments
`
`• Per telephone conversation of 12/21/1997,
`recommend ophthalmology monitoring because of
`corneal opacities in the six-month dog study.
`• Request verification of 26 week rat study mammary
`gland findings.
`• Regarding adequacy of the Phase 1 studies: “the
`adequacy of the studies will be a review issue. It is
`suggested the sponsor consider exploring the
`relationship between vilazodone exposure (e.g.
`concentration, dose) and response (e.g. efficacy,
`safety).”
`• The sponsor should also refer to the Guidance on
`drug interaction studies on the FDA website.
`
`• Discussion of pivotal trial CLDA-07-DP-02
`• The sponsor agreed to send… the identifying data on
`the 2 phase II studies that have already been
`submitted. The information from three trials
`undertaken by GSK will be submitted, however, the
`sponsor reported that some appendices were unable
`to be located. We requested that the primary efficacy
`results including the Montgomery-Asberg Depression
`Rating Scale (MADRS) endpoint and the 17-item
`Hamilton Rating Scale for Depression (HAM-D17)
`endpoint be sent to us. The sponsor confirmed that
`all data will be submitted as part of the filing to the
`new drug application.
`• We consider Study CLDA-07-DP-02 the first pivotal
`
`Reference ID: 2893768
`
`9
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`
`
`IND 54613
`Type B Teleconference
`(June 17, 2009)
`
`trial to confirm the findings on
` genetic
`marker… findings need to be replicated before they
`could be considered in support of a labeling claim.
`
`• The data from the two pivotal studies will be
`presented separately and discussed in the clinical
`summary of efficacy. PGxHealth does not intend to
`pool the efficacy data from the two pivotal studies
`other than for the purposes of subgroup analyses.
`• Data from the five Phase II studies conducted under
`the sponsorship of Merck and GSK are not
`considered supportive for the proposed dose and
`indication.
`
`
`
`From PGxHealth, regulatory affairs “I wanted to clarify that
`we have removed the Pharmacogenetics data from the NDA
`planned for Q4 of 2009.”
`
`
`
`
`
`
`
`
`
`
`
`
`
`IND 54613
`Email
`[July 31, 2009]
`
`2.6 Other Relevant Background Information
`
`
`The ownership of vilazodone has been transferred among several sponsors, as
`indicated below:
`
`
`November 11, 1997
` Initial IND 54613 Submission
`Lipha Pharmaceuticals, Inc
`(an Associate of Merck)
`
`August 26, 1998
`Transfer of ownership from Lipha Pharmaceuticals, NY to Merck KGaA, DE
`Authorization of PPD Pharmaco as US Agent for IND 54613
`
`
`
`May 1, 2001
`Transfer of Ownership from Merck to GSK
`February 11, 2003
`Transfer of ownership from GSK to Merck KGaA
`November 7, 2003
`Notice of establishment of EMD Pharmaceuticals, Inc. as IND Agent
`
`Reference ID: 2893768
`
`10
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`(b) (4)
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`October 25, 2004
`Transfer of ownership of IND 54613 from EMD to Genaissance Pharmaceuticals (GNSC)
`
` 3
`
` Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The submission was appropriately organized to allow information to be reviewed in an
`acceptable manner. The responses of PGxHealth to all of FDA’s requests were timely
`and well organized.
`
`
`3.2 Compliance with Good Clinical Practices
`
`According to statements included in the reports for the pivotal trials the applicant
`certified that the studies were conducted in compliance with the following: good clinical
`practice standards as outlined in the Declaration of Helsinki or the International
`Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, with the
`institutional review board regulations as per 21 CFR (56), and the informed consent
`regulation as per 21 CFR (50).
`
`The Division of Scientific Investigation (DSI) inspected four clinical sites that participated
`in the pivotal Phase 3 trials and did not find any regulatory violations over the course of
`the audits of these sites. Audits of the applicant revealed no discrepancies or regulatory
`violations in terms of oversight and monitoring of the pivotal Phase 3 studies, test article
`accountability, qualifications of investigators or site monitors, transfer of obligations,
`adverse event reports, or handling of data.
`
`During this inspection, records and documents included, but were not limited to:
`organization and personnel; conduct of regulatory responsibilities; appropriate transfer
`of regulatory responsibilities, contracts, work orders, and agreements; investigator
`selection; FDA 1572's; clinical investigator training; monitoring procedures; data
`verification; adverse event reporting procedures; primary efficacy process and
`verification; eligibility assessment; data collection and computerized systems and use of
`e-CRF's; test article accountability and reconciliation; and sponsor correspondence.
`
`One Form FDA 483 was issued to Dr. Arifulla Khan, an investigator in Protocol CLDA-
`07-DP-02, one of the two phase 3 efficacy studies. The Form FDA 483 was issued
`because the investigation was not conducted in accordance with the investigational
`plan, and that the investigator did not maintain adequate histories or data pertinent to
`the research investigation. Dr. Khan responded adequately to the inspectional findings
`
`Reference ID: 2893768
`
`11
`
`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`in a letter dated July 13, 2010. The minor regulatory violations are not considered to
`have an impact on data integrity and patient safety. The study appears to have been
`conducted adequately, and the data generated by this site may be used in support of
`the respective indication.
`
`One Form FDA 483 was issued to Dr. Jerry C. Steiert, an investigator in Protocol CLDA-
`07-DP-02, one of the two phase 3 efficacy studies. The Form 483 was issued because
`the investigation was not conducted in accordance with the investigational plan.
`Specifically, there was lack of full documentation that the washout period for an herbal
`medication was completed. Dr. Steiert responded adequately to the findings.
`
`The DSI inspection reports indicate that the applicant appears to have executed
`responsibilities appropriately, and no significant issues were noted. The studies appear
`to have been conducted adequately, and the data generated appear acceptable in
`support of the proposed indication.
`
`3.3 Financial Disclosures
`
`Form 3454 (version 10/09) was included in the submission. For the Phase 3 studies the
`applicant has adequately disclosed financial arrangements with the investigators; no
`specific issues that raise doubt about the integrity of the data are identified.
`
`Vilazodone was licensed to two previous sponsors (Merck and GSK). Two of the five
`Phase 2 trials did not collect financial disclosures. PGxHealth obtained a letter from a
`previous sponsor regarding financial disclosures. The division’s response indicated that
`this is acceptable only if the two Phase 2 trials without financial disclosure are not
`pivotal studies that support the labeling claims in the NDA. None of the Phase 2 trials
`are considered pivotal studies for this application.
`
`4 Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`4.1 Chemistry Manufacturing and Controls
`
`The chemistry, manufacturing and controls data were reviewed by Dr. Pei-I Chu. The
`reviewer considered the NDA approvable from a CMC perspective pending satisfactory
`responses from the applicant regarding questions regarding the drug substance and
`drug product. At the time of this writing, the response had not been received.
`
`There are no recommendations for post-marketing commitments, agreements, or risk
`management steps.
`
`
`Reference ID: 2893768
`
`12
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`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`The Office of Compliance has determined that pre-approval inspections for the drug
`substance, drug product and packaging sites are not needed based on the drug profile.
`
`
`4.2 Clinical Microbiology
`
`Not applicable.
`
`
`4.3 Preclinical Pharmacology/Toxicology
`
`The pharmacology/toxicology data was reviewed by Violetta Klimek, Ph.D. At the time
`of this writing, the review was not available. The review team held several status
`meetings during the course of this NDA and no significant issues were identified by the
`pharmacology/toxicology reviewer.
`
`4.4 Clinical Pharmacology
`
`The clinical pharmacology data were reviewed by Bei Yu, Ph. D. At the time this review
`was completed, the clinical pharmacology review was not available. The review team
`held many status meetings during the course of this NDA and no significant issues were
`identified by the clinical pharmacology reviewer.
`
`
`4.4.1 Mechanism of Action
`
`The applicant reports “vilazodone is a potent and selective inhibitor of serotonin
`reuptake and a potent and selective partial agonist at the 5HT-1A subtype of serotonin
`receptors.” It is thought to optimize the regulation of the 5-HT circuitry at both pre- and
`post-synaptic sites to augment 5-HT transmission, putatively producing antidepressant
`effect.
`
`Reviewer comment: The in vivo 5-HT1A receptor binding study of vilazodone failed to
`provide compelling evidence of 5-HT1A binding activity. The meeting minutes from the
`End of Phase 2 Meeting on December 20, 2005 indicate: “The Office of Clinical
`Pharmacology noted that the PET study utilizing a 40 mg dose produced mean receptor
`occupancy of < 30%, whereas the common thought is that at least 80% occupancy may
`be needed for antidepressant efficacy.”
`
`
`
`
`Reference ID: 2893768
`
`13
`
`(b) (4)
`
`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`4.4.2 Pharmacodynamics
`
`The clinical study report indicates vilazodone binds in vitro with high affinity to the
`human 5-HT reuptake site (5-HT transporter) with a Ki=0.1nM and shows lower affinity
`for the norepinephrine and dopamine reuptake sites. Vilazodone also potently binds to
`the rat 5-HT transporter and inhibits with high affinity both rat and human 5-HT
`reuptake. Functionally, vilazodone is a centrally-active 5-HT reuptake inhibitor.
`
`The study report also indicates that vilazodone binds with high affinity to the rat and
`human 5-HT1A receptor binding sites and is 60 times more potent than buspirone.
`In vivo studies provide a functional profile for vilazodone that is characteristic of a 5-
`HT1A partial agonist.
`
`In cardiovascular studies, vilazodone was not active in a human hERG (human ether-a-
`go-go related gene) channel assay, nor did it have activity indicative of potential
`proarrhythmogenic effects in guinea pig papillary muscles.
`
`4.4.3 Pharmacokinetics
`
`Absorption
`Vilazodone is absorbed after oral administration with Tmax occurring at 4 to 6 hours.
`Vilazodone has linear pharmacokinetics with single doses of 2.5 mg to 80 mg and with
`repeated doses of 20 mg to 80 mg. In the presence of a high fat breakfast the Cmax
`values are approximately 150% higher and AUC values approximately 60-90% higher.
`
`Distribution
`Vilazodone is highly protein bound, ranging from 96-99% in human serum.
`
`Metabolism
`Vilazodone is extensively metabolized by the liver. CYP3A4 is the major enzyme
`responsible for vilazodone metabolism with minor contributions from CYP2C19 and
`CYP2D6. The use of vilazodone 10 mg with ketoconazole 200 mg resulted in a 50%
`increase in Cmax and AUC. The use of vilazodone with inducers of CYP3A4 may
`reduce vilazodone concentrations.
`
`Excretion
`The elimination half-life is, on average, about 24 hours. The range in various studies is
`from 8.5 to 36 hours. The half-life for vilazodone following a single 40 mg dose in
`healthy young adults ranged from 13 – 30 hours. Shorter half-lives were seen in studies
`where drug concentrations were measured for only 24 hours post-dose. Some studies
`reported half-lives from approximately 24 – 29 hours with multiple dosing while another
`study reported a range of 28 – 37 hours. The majority of vilazodone is eliminated in the
`feces, presumably via secretion of the parent and metabolites into bile.
`
`
`Reference ID: 2893768
`
`14
`
`

`

`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`5 Sources of Clinical Data
`
`5.1 Tables of Studies/Clinical Trials
`
`The clinical development program of vilazodone for the treatment of MDD in adults
`included 24 Phase 1 studies, five Phase 2 studies, and three Phase 3 studies during
`which 2898 subjects received vilazodone.
`
`Table 5.1 Phase 1 Clinical Trials in Healthy Subjects
`
`
`Protocol
`
`
`Study Design
`
`
`Subjects
`M/F (ITT)
`
`Treatment Arms
`
`
`Duration/Applicant’s
`Conclusions
`
`
` 1
`
` day in each of 2
`periods
`
`Conclusion:
`Clear demonstration of
`food effect – higher
`exposures with food.
`
`
`1 day in each of 3
`periods
`
`Conclusion:
`Bioavailabilities were
`similar among the three
`formulations
`
`1 day in each session
`
`
` 1
`
` day in each of 3
`sessions
`
`Conclusion:
`Bioequivalence criteria
`met.
`
`
`1 day in each of 3
`sessions
`
`
`
`
`EMD 68 843-007
`
`Single dose
`Food Effect
`
`
`
`Single-center
`OL, R, 2-way
`crossover of
`fed and fasting
`
` SB-659746/004
`
`Single dose
`Bioavailability
`
`Open-label,
`randomized,
`3- period
`crossover
`
`OL, R, 2
`session
`crossover
`
`SB-659746/013
`
`Single dose
`Bioequivalence
`
`
`
`
`
`
`
`16/0
`Healthy
`Subjects
`
`
`
`
`
`2/12
`Healthy
`subjects
`
`2/13
`Healthy
`subjects
`
`
`2/11
`Healthy
`subjects
`
`18/10
`Healthy
`subjects
`
`19/10
`Healthy
`subjects
`
`
`
`
`Vilazodone 20mg
`
`
`
`Oral
`
`
`
`
`
`
`Vilazodone 10mg
`micronized tablet
`
`
`Vilazodone 10mg
`non-micronized
`tablet
`
`
`
`Vilazodone 10mg
`micronized capsule
`
`Vilazodone 20mg
`phase II capsule
`
`
`Vilazodone 20mg
`Phase III capsule
`
`
`SB 659746/047
`
`
`OL, R, 3
`session
`
`17/9
`
`
`Vilazodone 20mg
`Phase II capsule
`
`Reference ID: 2893768
`
`15
`
`

`

`
`
`
`
`
`
`Conclusion:
`
`
`
`
`
`
`
` 1
`
` day in each of 2
`periods
`
`Conclusion:
`BE criteria met
`
`
`
`
`
`
` 1
`
` day in each of 2
`periods
`
`Conclusion:
`BE criteria met (high
`drop out rate d/t nausea
`and vomiting)
`
` I
`
` day in each of 3
`periods
`
`Conclusion:
`Food increased oral
`bioavailability
`
` I
`
` day in each of 2
`periods
`
`Conclusion:
`BA of oral:IV was
`72%:81% per dose
`normalized AUC
`
` 1
`
` day
`
`
`Conclusion:
`85% radioactivity
`recovered, 20% urine,
`65% feces
`
`
`
`16/12
`
`
`17/13
`
`Healthy
`subjects
`
`
`
`13/17
`
`
`12/16
`
`Healthy
`subjects
`
`
`50/23
`
`
`
`50/26
`
`Healthy
`subjects
`
`11/9
`
`Healthy
`subjects
`
`
`7/5
`
`
`7/5
`
`Healthy
`subjects
`
`7/0
`
`Healthy
`subjects
`
`
`Vilazodone 20mg
`Form IV capsule
`
`Vilazodone 20mg
`
`
`
`Vilazodone 20mg
`tablet
`
`Vilazodone 20mg
`Phase III tablet
`
`
`
`Vilazodone 40mg
` tab
`
`
`Vilazodone 40mg
`
`
`
`tab
`
`
`Vilazodone 20mg
`tablet
`
`
`Vilazodone 20mg
`tablet
`
`Vilazodone 5 mg IV
`formulation
`
`
`Vilazodone 20 mg
`solution (oral) μCi
`radiation
`
`Clinical Review
`Cheri Lindberg, M.D.
`NDA 022567
`Vilazodone
`
`
`crossover
`
`Single dose
`Bioequivalence
`
`
`
`
`
`
`SB-659746/050
`
`Single dose
`Bioequivalence
`
`
`OL, R, 2
`period
`crossover
`
`R06-1586
`Single dose
`Bioequivalence
`
`
`DB, R, 2-way
`crossover
`
`PGX-08-P1-05
`Single dose
`Food Effect
`Bioavailability
`
`
`OL, R, 3
`period
`crossover
`
`PGX-08-P1-08
`Single dose
`Bioavailability
`
`
`OL, R, 2
`period
`crossover
`
`PGX-08-P1-07
`PK - ADME
`
`
`OL
`
`Reference ID: 2893768
`
`16
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`10 days:
`3 day on CYP drugs
`only, wash-out followed
`by 7 days of