CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
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`APPLICATION NUMBER:
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`022567Orig1s000
`
`OTHER REVIEW(S)
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`Submission date:
`Review date:
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` 7/7/10
` 1/7/11
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`PGxHealth, LLC
`
`Vilazodone
`
`Serotonin reuptake inhibitor
`
`Major depressive disorders
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`
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`1
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`Medical Officer's Consultative Review of NDA 22-567
`Ophthalmology Consult
`
`
`NDA 22-567
`
`
`Ophthalmology Consult
`
`Sponsor:
`
`Drug:
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`Pharmacologic Category:
`
`Proposed Indication:
`
`Requested:
`The sponsor has submitted an original NDA (22567) for vilazodone in the treatment of depression. Vilazodone has two
`serotonergic mechanisms of action: it is an SSRI as well as an agonist at the 5-HT1A receptor. We would appreciate your
`assessment of the ophthalmologic findings and conclusions submitted by the sponsor.
`
`Background:
`The sponsor has provided data from five 8-week clinical studies and one 52-week open-label study of vilazodone. In addition,
`the sponsor has provided an independent expert’s review of the ophthalmologic data. In the sponsor’s opinion, the results of the
`ophthalmologic assessments did not demonstrate clinically significant changes in ‘eye health’ or ocular function in subjects
`treated with vilazodone. The report indicates that the presence of treatment-emergent cataracts was identified by slit-lamp
`biomicroscopy in 22 subject-eyes among 12 subjects. For cortical, nuclear sclerotic, and posterior subcapsular cataract types,
`the number of subject-eyes that shifted from negative at baseline to positive at the end of treatment was ‘small’. Of 110
`subjects with cataract at baseline, the overall cataract severity was determined to have worsened for 14 (12.7%) subjects and to
`have remained stable (change in summed score <0) for 96 (87.3%) subjects at end of treatment.
`
`In a zip file, we have included: two previous ophthalmology consults, two safety summaries containing relevant
`ophthalmologic data, and the study report for the 52-week clinical study.
`
`We have the following questions:
`1) What is your assessment of the ophthalmologic findings?
`2) Has the sponsor adequately assessed the ophthalmologic safety profile of vilazodone?
`3) Could the ophthalmologic risks be managed through labeling? Would you recommend any specific labeling?
`4) Would you recommend that we request any additional information from the sponsor?
`
`The Clinical reviewer is Cheri Lindberg, M.D., and the TL is Robert Levin, M.D.; the Pharmacology/Toxicology (non-clinical)
`reviewer is Violetta Klimek, Ph.D., and the TL is Linda Fossom, Ph.D. Let me know if you have any questions to send to the
`sponsor. The link to the NDA original application can be found at: \\CDSESUB1\EVSPROD\NDA022567\022567.ENX
`We will also send a zip file that contains relevant summaries and data.
`
`
`
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`Reviewer's Comments: Responses in this consult will be limited to areas of ophthalmologic concern.
`
`
`NDA 22-567
`Reference ID: 2888794
`
`Ophthalmology Consult
`
`Vilazodone
`
`

`

`
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`Phase 2 Studies:
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`
`2
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`Reviewer's Comments:
`Multiple dose levels demonstrate decreasing tear product following use of
`vilazodone. Tear film deficiencies may account for some of the decreased vision and some of the corneal
`abnormalities.
`
`
`The following funduscopy findings were reported:
`Retinal hemorrhage – 3 reports
`Floaters -1 report
`Abnormal cup – 2 reports
`Vitreous detachment – 1
`Microaneurysm – 1
`
`
`
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`
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`Reviewer's Comments:
`The relatively few reports and the nature of the reports do not suggest any
`retinal or vitreous problem related to the drug product.
`
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`NDA 22-567
`Reference ID: 2888794
`
`Ophthalmology Consult
`
`Vilazodone
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`

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`
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`3
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`Study CLDA-07-DP-04
`
` A
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` One Year Open-Label Study Assessing the Safety and Tolerability of Vilazodone in Patients with
`Major Depressive Disorder
`
`Ophthalmologic examinations were performed at baseline (Visit 1) and subsequently at Visits 11
`(Week 24) and 18 (Week 52). Exams were performed at the early termination visits for patients
`withdrawing from the study. Evaluations included assessment of best corrected visual acuity as measured
`by manifest refraction and Snellen scoring, as well as slit-lamp biomicroscopy of the conjunctiva, iris,
`cornea, and lens. Dilated fundoscopy examinations of the macula, disc, and retinal vessels were
`performed and the presence/absence of pigments/naevi, exudates, microaneurysms, and/or hemorrhages
`were noted. Intraocular pressure was also measured at baseline and Week 52 (or at Early Termination
`[ET]).
`
`Treatment emergent Adverse Events pertaining to the eye occurred in 97 patients (16.2%), the most common of
`which included dry eye (4.7%), vision blurred (4.0%), and lacrimation increased (1.2%).
`
`Reviewer's Comments:
`
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`Corneal Findings
`Visit 11/Week 24
`
`Dry eye can be contribute to both blurred vision and increased lacrimation.
`
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`Baseline
`N
`310 Normal
`Abnormal
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`Vilazodone Treatment Result
`
`
`Right Eye
`
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`Left Eye
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`Normal
`Abnormal
`Normal
`Abnormal
`288
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`5
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`288
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`5
`2
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`15
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`3
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`14
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`Visit 18/Week 52
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`247 Normal
`Abnormal
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`231
`2
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`4
`10
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`227
`3
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`8
`9
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`Reviewer's Comments:
`
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`Lens/Cataract
`Visit 11/Week 24
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`310
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`Visit 18/Week 52
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`247
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`These corneal findings are likely to be a result of the dry eye abnormalities.
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`
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`Absent
`Present
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`Absent
`222
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`10
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`Present
`5
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`73
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`Absent
`227
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`9
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`Present
`4
`70
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`Absent
`Present
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`171
`8
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`6
`62
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`175
`7
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`6
`59
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`Change from Baseline to End of Treatment in Overall Cataract Severity
`All Patients with Cataracts at Baseline
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`Eye
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`Right
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`Left
`More Severe
`
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`Reviewer's Comments:
`A 9-10% rate of cataract progression in one year is considered high. It is
`not possible to distinguish without a control group whether this is due a higher than normal rate in this
`population or due to the drug product.
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`N
`110
`110
`110
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`Stable
`100 ( 90.9%)
` 99 ( 90.0%)
` 96 ( 87.3%)
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`Worsened
`10 ( 9.1%)
`11 ( 10.0%)
`14 ( 12.7%)
`
`NDA 22-567
`Reference ID: 2888794
`
`Ophthalmology Consult
`
`Vilazodone
`
`

`

`
`
`4
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`Stable
`
`2 Level Decrease
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`>2 Level Decrease
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`268
`212
`117
`382
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`264
`210
`112
`375
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`0
`1
`0
`1
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`3
`4
`2
`6
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`2
`0
`1
`2
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`2
`0
`1
`2
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`N
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`270
`213
`118
`385
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`269
`214
`115
`383
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`Right Eye
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`Visit 11/Week 24
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`Visit 18/Week 52
`Visit 18/Early Termination
`End of Treatment
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`Left Eye
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`Visit 11/Week 24
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`Visit 18/Week 52
`Visit 18/Early Termination
`End of Treatment
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`
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`Other Ocular Adverse Events:
`Among rare TEAEs, 1 subject (0.2%) reported an abnormal sensation in eye, considered mild in severity. Mild
`blepharitis was reported by 1 subject (0.2%). Mild eye irritation was reported by 2 subjects (0.3%). Increased
`lacrimation, rated as mild or moderate in severity, occurred in 7 subjects (1.2%). One subject temporarily
`discontinued study drug due to increased lacrimation. Photophobia was reported by 4 subjects (0.7%), and was
`considered to be mild or moderate in severity. No subject discontinued due to photophobia. Mild punctate keratitis
`was reported in 1 subject (0.2%). Reduced visual acuity, mild in intensity, was reported in 4 subjects (0.7%). Other
`reported events included moderate blepharospasm (1, 0.2%), mild-to-moderate transient blindness/temporary loss
`of vision (2, 0.3%), mild to moderate eye pain (4, 0.7%), mild eye swelling (2, 0.3%), mild eyelid disorder (2, 0.3%),
`mild eyelid margin crusting (2, 0.3%), mild myodesopsia (1, 0.2%), “mild” oculogyric crisis (1, 0.2%), mild eye
`pruritus (3, 0.5%), accommodation disorder (1, 0.2%), arteriosclerotic retinopathy (1, 0.2%), cataract (3, 0.5%),
`cortical cataract (1, 0.2%), conjunctival hemorrhage (3, 0.5%), conjunctivitis (4, 0.7%), allergic conjunctivitis (2,
`0.3%), corneal infiltrates (1, 0.2%), corneal neovascularization (1, 0.2%), acquired dacryostenosis (1, 0.2), eye
`discharge (2, 0.3%), eye hemorrhage (1, 0.2%), giant papillary conjunctivitis (1, 0.2%), lacrimal disorder (1, 0.2%),
`ocular hyperaemia (2, 0.3%), ocular hypertension (1, 0.2%), retinal hemorrhage (1, 0.2%), and retinal tear (1,
`0.2%)and mild-to-moderate visual impairment (4, 0.7%). One subject temporarily discontinued, and another subject
`permanently discontinued due to moderate visual impairment.
`
`Reviewer's Comments:
`There is no particular pattern to these events and the frequency is
`consistent with events typically seen in a population of this age range (Mean Age was 43 ±13, Range
`18-70, Median 44).
`
`
`
`NDA 22-567
`Reference ID: 2888794
`
`Ophthalmology Consult
`
`Vilazodone
`
`

`

`
`
`5
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`Responses to Questions:
`Question 1) What is your assessment of the ophthalmologic findings?
`
`Response:
`The increase in dry eye seems to be real and consistent with other products which cause dry eyes such as
`many antihistamines. The retinal abnormalities do not appear to be any different than the expected rates
`in a normal population. The cataract progression rate is higher than I would have expected, but without
`a concurrent control group, it is not possible to determine whether the product definitely increases the
`rate of cataracts or the population being studied had a higher than expected reported rate because they
`were looking for it.
`
`
`Question 2) Has the sponsor adequately assessed the ophthalmologic safety profile of vilazodone?
`
`Response: Yes
`
`
`Question 3) Could the ophthalmologic risks be managed through labeling? Would you recommend
`any specific labeling?
`
`Response: Yes, the ophthalmologic risks can be managed through labeling.
`
`
`Question 4) Would you recommend that we request any additional information from the sponsor?
`
`Response: While it is possible to include information on cataract progression, it would be useful to
`distinguish whether the higher cataract rate observed in this population is a function of the drug product,
`a reflection of the baseline rate of cataract formation in the intended population or both. A controlled
`clinical trial in which patients were maintained on therapy for a period of two years or more would be
`necessary to make this determination.
`
`
`
`
`
`
`Wiley A. Chambers, M.D.
`Supervisory Medical Officer, Ophthalmology
`
`
`NDA 22-567
`Reference ID: 2888794
`
`Ophthalmology Consult
`
`Vilazodone
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILEY A CHAMBERS
`01/07/2011
`
`Reference ID: 2888794
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`January 6, 2011
`Thomas Laughren, MD, Director
`Division of Psychiatry Products
`Kristina A. Toliver, PharmD, Team Leader
`Carol A. Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis (DMEPA)
`Loretta Holmes, BSN, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis (DMEPA)
`Label and Labeling Review
`Viibryd (Vilazodone) Tablets
`10 mg, 20 mg, and 40 mg
`NDA 022567
`PGxHealth, LLC
`2010-826
`
`Date:
`To:
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`Through:
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`From:
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`Subject:
`Drug Name:
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`Application Type/Number:
`Applicant:
`OSE RCM #:
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`Reference ID: 2887706
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`1
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`

`

`Contents
`INTRODUCTION .................................................................................................................. 3
`1
`2 METHODS AND MATERIALS............................................................................................ 3
`3
`RECOMMENDATIONS........................................................................................................ 3
`3.1
`Comments to the Applicant............................................................................................ 3
`APPENDICES................................................................................................................................. 7
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`Reference ID: 2887706
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`2
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`

`

`1
`INTRODUCTION
`This review summarizes DMEPA’s evaluation of the container labels, carton and insert labeling
`for Viibryd (Vilazodone HCl) Tablets, 10 mg, 20 mg, and 40 mg (NDA 022567). The Division
`of Psychiatry Products requested DMEPA’s assessment for medication error potential.
`
`2 METHODS AND MATERIALS
`DMEPA uses Failure Mode and Effects Analysis (FMEA) and lessons learned from
`post-marketing experiences to evaluate container labels, carton and insert labeling. This review
`focuses on the container labels, carton and insert labeling submitted by the Applicant on
`December 13, 2010 (see Appendices B through F).
`• Trade (10 mg, 20 mg, and 40 mg tablets)
`o Container labels: 30-count, 90-count, 500-count
`o Blister card labels: 10-count
`o Carton labeling: Ten 10-count blister cards
`o Patient Starter Package: (contains 10 mg, 20 mg, and 40 mg tablets), 30-count
`• Physician Sample Package (contains 10 mg and 20 mg tablets), 14-count
`
`3 RECOMMENDATIONS
`Our evaluation noted areas where information on the container labels, carton and insert labeling
`can be improved to minimize the potential for medication errors. Section 3.1 Comments to the
`Applicant contains our recommendations for the container labels and carton labeling. We request
`the recommendations in Section 3.1 be communicated to the Applicant prior to approval.
`Appendix A provides our recommendation concerning the insert labeling that was previously
`communicated to the review division in a Viibryd labeling meeting held on November 30, 2010.
`Please copy the Division of Medication Error Prevention and Analysis on any communication to
`the Applicant with regard to this review. If you have further questions or need clarifications,
`please contact OSE Regulatory Project Manager, Sandra Griffith, at 301-796-2445.
`
`3.1 COMMENTS TO THE APPLICANT
`A. General Comments for All Container Labels and Blister Carton Labeling
`1. Ensure the established name is at least ½ the size of the proprietary name, taking into
`account all pertinent factors including typography, layout, contrast and other printing
`features [21 CFR 201.10(g)(2)].
`2. The dosage form statement “Tablets” appears more prominent than the active
`ingredient statement. The dosage form statement is a part of the established name,
`therefore, ensure it is commensurate in size, font, etc. to the active ingredient
`statement.
`B. Container Labels, 10 mg, 20 mg, and 40 mg (30-count, 90-count, and 500-count)
`1. The net quantity statement is too prominent. Therefore, we request you decrease the
`prominence by unbolding the statement and reducing its size.
`2. The Medication Guide statement is not prominent. Separate the Medication Guide
`statement from the Usual Dosage and “Dispense in...container” statements (e.g., use a
`
`
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`Reference ID: 2887706
`
`3
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`

`

`line to separate these statements). Additionally, increase the prominence of the
`Medication Guide statement with the use of bold type.
`3. The statement “Each tablet contains...” is located on the principal display panel and
`detracts from important product identifying information such as the proprietary name,
`established name, and strength. Relocate this statement to one of the side panels.
`C. Blister Carton
`1. The active ingredient statement “vilazodone HCl” is printed in a light grey color that
`lacks sufficient contrast against the white background and is, thus, difficult to see.
`Additionally, the dosage form statement “Tablets” appears more prominent than the
`active ingredient statement because it appears in a dark green font color. The active
`ingredient and dosage form statements make up the established name and, thus,
`ensure they appear in the same color and are commensurate in size, font, etc.
`2. The statement of strength is left justified on the front and two side panels. For
`improved readability, center the statement of strength on these panels. In order to
`make space for this, relocate the “Each tablet contains...” statement to the back panel.
`D. Blister Labels, 10 mg, 20 mg, and 40 mg (10-count unit dose blisters)
`1. Increase the prominence of the proprietary name and established name.
`2. Relocate the statement of strength to the usual position which is immediately below
`the established name. In its current position, it looks like the blister number rather
`than the product strength.
`3. Decrease the prominence of the lot number and expiration date.
`4. The blister labels look identical for all three strengths. Differentiate the strengths
`with the use of color, different box shapes, or some other means.
`5. Delete the statement “Each tablet contains...” This statement crowds the label and it
`is not necessary because the label is too small.
`E. Patient Starter Package and Physician Sample Package
`1. As currently presented, the tablet layout is confusing for the following reasons:
`• The tablets to be taken for each week are lined up in vertical columns that are
`adjacent to one another and there is no line or other demarcation to separate
`them.
`• Under each vertical column there is a boxed statement of strength and it is not
`immediately clear why they are positioned under the vertical columns.
`It is not immediately clear where a patient should start and in which direction a
`patient should go as the tablets are taken (i.e., should a patient progress across in
`a row or down in a column).
`We request you provide data to support the proposed configuration. Provide the
`results of an FMEA and usability testing that demonstrate the current layout is not
`confusing and patients can follow the dosing schedule as provided. If you do not
`have data to support your proposed configuration, we recommend you revise the
`format as follows:
`Reconfigure the tablet layout so that one week of therapy is contained on one panel
`or each week of therapy is separated and distinct from the other (see example below).
`
`•
`
`
`
`Reference ID: 2887706
`
`4
`
`

`

`Ensure that for each day of therapy, the numerical day of the week is stated (i.e., Day
`1, Day 2, Day 3, etc.) and placed in close proximity to the respective dose (see
`example below) rather than the current presentation of “Days X-Y”.
`Week 1
`Day 1 Day 2 Day 3 Day 4
`Day 5 Day 6 Day 7
`
`Week 2
`Day 1 Day 2 Day 3 Day 4
`Day 5 Day 6 Day 7
`
`
`2. The letters “A” and “B”, and “A”, “B”, and C” are on the patient starter package and
`physician sample package, respectively. Each letter is accompanied by a circle that
`encloses one of the tablet strengths, however, there are no instructions that explain
`the meaning of these letters. Explain the intended meaning of these letters and
`whether these letters were tested to ensure they can be understood. If tested, provide
`the results of the testing.
`3. The instructions to the patient about how the package should be used do not appear
`complete. These are some of the questions that should be answered in the
`instructions to the patient:
`a. What is the procedure for removing the tablets from the package?
`b. Where does the patient start (e.g., show the patient which tablet, week, and day to
`start with; consider using the statement “start here” along with an arrow pointing
`to the tablet that should be used first)?
`In the instructions under “How to take Viibryd (vilazodone HCl) Tablets”, the tablet
`strengths have a dash between the number and unit of measure (i.e., 10-mg, 20-mg,
`40-mg). This may be confusing. Delete the dash that separates the number and unit
`of measure (e.g., 10 mg, 20 mg, and 40 mg)
`4. The package does not state the number of weeks or days of therapy it contains.
`Revise to include the number of weeks or days of therapy that the package contains
`and place this statement on the principal display panel.
`5. The starter package and physician sample do not have a net quantity statement. The
`principal display panel contains only the three strengths without reference to how
`many tablets of each strength are contained in the pack. Revise to include a net
`quantity statement on the principal display panel. Revise the statement of strength to
`reflect the number of tablets of each strength included in the package. For example:
`Each starter pack contains:
`XX tablets containing XX mg—Week 1
`XX tablets containing XX mg—Week 2
`XX tablets containing XX mg—Week 3
`
`
`
`
`Reference ID: 2887706
`
`5
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`

`

`6. It is not clear how the tablet strengths will appear on the packages. Each tablet
`position is represented by a circle and inside the circle the respective tablet strength is
`specified (i.e., 10, 20, or 40). However, it is unclear whether this information will be
`printed on the package or how it will appear on the marketed package. Please clarify.
`We recommend you print the individual tablet strengths on the front card
`immediately below each tablet in order to help minimize confusion by ensuring that
`the information is easily seen. Additionally, ensure the dosage unit is also specified
`(e.g., revise “10” to read “10 mg” and “20” to read “20 mg”, etc.)
`7. The active ingredient statement “vilazodone HCl” is printed in a light grey color that
`lacks sufficient contrast against the white background and is, thus, difficult to see.
`Additionally, the dosage form statement “Tablets” appears more prominent than the
`active ingredient statement because it is presented in a dark green font color. The
`active ingredient and dosage form statements make up the established name and,
`thus, ensure they appear in the same color and are commensurate in size, font, etc.
`
`
`
`Reference ID: 2887706
`
`6
`
`8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LORETTA HOLMES
`01/06/2011
`
`KRISTINA C ARNWINE
`01/06/2011
`
`CAROL A HOLQUIST
`01/07/2011
`
`Reference ID: 2887706
`
`

`

`
`M E M O R A N D U M
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`
`Subject:
`
`January 5, 2011
`
`Thomas Laughren, M.D., Director
`Division of Psychiatry Products
`
`Michael Klein, Ph.D., Director
`Controlled Substance Staff
`
`Chad J. Reissig, Ph.D. Pharmacologist
`Lori A. Love, M.D., Ph.D., Lead Medical Officer
`Controlled Substance Staff
`
`Vilazodone (NDA 022-567)
`Indication: Major Depressive Disorder
`Dosages: 40 mg daily
`Sponsor: PGx Health, LLC
`
`
`Materials reviewed: NDA submission located at: \\CDSESUB1\EVSPROD\NDA022567
`Abuse potential materials including Appendix 7: “Assessment of drug abuse potential”, a
`self-administration study, physical dependence study, and conditioned place preference
`study in rodents.
`Medical officer review by Cheri Lindberg, M.D.
`Pharmacology/toxicology review by Violetta Klimek, Ph.D.
`
`
`
`
`Table of Contents
`SUMMARY ......................................................................................................................................... 1
`A. BACKGROUND................................................................................................................................... 1
`B. CONCLUSIONS:.................................................................................................................................. 2
`C. RECOMMENDATIONS:........................................................................................................................ 3
`II. APPENDIX.......................................................................................................................................... 4
`D.
`PHARMACOLOGY OF DRUG SUBSTANCE AND ACTIVE METABOLITES ................................................. 4
`E. CLINICAL PHARMACOLOGY............................................................................................................... 8
`F. CLINICAL STUDIES.......................................................................................................................... 10
`G.
`INTEGRATED ABUSE POTENTIAL ASSESSMENT................................................................................. 14
`
`I.
`
`
`I. Summary
`A. Background
`
`
`Reference ID: 2887051
`
`
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`1 of 19
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`

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`This memo responds to the Division of Psychiatry Products consult regarding the
`abuse potential of vilazodone (NDA 22-567). Vilazodone is a new chemical
`entity (NCE). According to the Sponsor, vilazodone is an orally administered,
`dual-acting, selective serotonin reuptake inhibitor and 5-HT1A receptor partial
`agonist. Vilazodone is being developed for the treatment of major depressive
`disorder.
`
`There is evidence suggesting the involvement of serotonin (5-HT) in several
`psychiatric disorders including depression. Depression may be due, in part, to a
`deficiency of 5-HT neurotransmission. Selective serotonin reuptake inhibitors
`(SSRI’s) are thought to achieve therapeutic efficacy via an increase in 5-HT
`neurotransmission. However, the increase in 5-HT may result in feedback
`inhibition via autoinhibitory 5-HT1A receptors.
`
`According to the Sponsor, the combination of an SSRI and 5-HT1A partial
`agonist may more robustly normalize 5-HT neurotransmission relative to either
`mechanism of action alone, and alleviate the symptoms of major depression.
`
`B. Conclusions:
`1. Receptor binding studies indicate that vilazodone does not have significant
`affinity for receptor sites associated with abuse potential.
`2. Drugs with a mechanism of action similar to vilazodone such as selective
`serotonin reuptake inhibitors (SSRI’s) and 5-HT1A agonists have a low abuse
`potential.
`3. Vilazodone produces antidepressant-like behavioral effects in preclinical
`models of depression.
`4. Animal self-administration studies indicate that vilazodone has a low potential
`for abuse.
`5. Animal conditioned place preference studies indicate that vilazodone has a
`low potential for abuse.
`6. Animal physical dependence studies indicate that vilazodone produces
`physical dependence. However, physical dependence is unlikely to contribute
`to the abuse potential of vilazodone at clinically relevant doses.
`7. The Sponsor has not studied vilazodone for abuse potential in a human abuse
`potential pharmacology laboratory study.
`8. However, an analysis of abuse-related AEs from completed clinical studies
`suggests that vilazodone affects CNS activity, but does not indicate that
`vilazodone has the potential for abuse, in that minimal euphoria and
`hallucinations were reported. Vilazodone produces somnolence and sedation
`in humans.
`9. In summary, preclinical and clinical data indicate the vilazodone produces
`CNS depressant effects, but appears to have a very low potential for abuse.
`
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`Reference ID: 2887051
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`C. Recommendations:
`CSS recommends that the following text be added to section 9.2 of the label: “An
`analysis of abuse related adverse events from clinical studies suggests that
`VIIBRYD has a low potential for abuse”.
`
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`Reference ID: 2887051
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`II. Appendix
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`
`
`D. Pharmacology of drug substance and active metabolites
`
`1. Product description
`Upon approval, vilazodone will be available in 10, 20, and 40 mg immediate-
`release, oval, film-coated tablets manufactured from a
` with total
`tablet weights of 103 mg, 206 mg and 412 mg, respectively. The 10 mg tablets
`are pink; the 20 mg, orange; and the 40 mg, blue. The tablets are debossed with
`the strength on one side and plain on the other. The tablets are packaged in 30-
`count, 90-count and 500-count high-density polyethylene (HDPE) bottles, and in
`film/aluminum foil blisters.
`
`2. In vitro studies
`The pharmacology of vilazodone has been studied to characterize its serotonin (5-
`hydroxytryptamine; 5-HT) reuptake inhibition, receptor binding profile, and
`regulation of 5-HT neurotransmission. Sponsor information and DPP reviews are
`summarized below:
`
`• Receptor binding studies
`According to the pharmacology and toxicology review by Violetta Klimek, Ph.D.,
`Vilazodone binds with high affinity to the serotonin reuptake site (Ki=
`0.1 nM), but not to the norepinephrine (Ki=56 nM) or dopamine (Ki=37 nM)
`reuptake sites. Vilazodone inhibits reuptake of serotonin (IC50 = 1.6 nM and
`binds to 5HT1A receptors with similar affinity (IC50 = 2.1 nM) and is 5HT1A
`receptor partial agonist.
`
`Additional information summarized by the Sponsor appears below:
`
`In study GPP-007-NCD- PCL-1999-065, the affinity of vilazodone for various
`receptors was assessed. Vilazodone has high affinity for 5-HT1A receptors from
`rat cerebral cortex (IC 50 = 1.6 nM) and human recombinant 5-HT1A receptors
`expressed in CHO cells (IC 50 = 2.1 nM). Vilazodone also displays high affinity
`(0.14 nM) for the 5-HT reuptake transporter and does not demonstrate significant
`affinity for any other receptor subtypes in this study.
`In study GPP-007-NCD-PCL-1995-046, vilazodone demonstrates high affinity for
`5-HT1A (IC 50 = 0.5 nM) receptors, D3 receptors (IC 50 = 140 nM), 5-HT4
`receptors (IC 50 = 100 nM) and σ receptors (IC 50 = 16 nM). In this study,
`vilazodone has higher affinity for rat hippocampal 5-HT1A receptors than the
`prototypical 5-HT1A agonist 8-OH-DPAT, and the anxiolytics ipsapirone and
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`buspirone. This study also demonstrates vilazodone’s activity in inhibiting 5-HT
`uptake (IC50 = 0.2 nM).
`The receptor binding profiles of the three major metabolites of vilazodone (EMD,
`87409, EMD 80 546, and EMD 122 230) were also assessed. All were shown to
`have less affinity or be less potent than the parent compound.
`
`3. Safety pharmacology findings
`• General behavioral responses
`Studies examining the ability of vilazodone to produce physical dependence and
`withdrawal are described below (see: Animal behavioral studies).
`
`The Sponsor examined the effect of vilazodone on locomotor activity and
`8‑OH‑DPAT-induced hyperlocomotor activity in male rats (study GPP-007-
`NCD-PCL-2003-134). The locomotor study did not include a positive control
`with a known abuse potential. Because a positive control was not used in the
`locomotor study, the results do not provide information directly applicable to the
`abuse potential assessment of vilazodone.
`
`Male rats were administered vilazodone (3.0, 10, or 30 mg/kg p.o.) or vehicle
`prior to an injection of either 8-OH-DPAT (0.1 mg/kg s.c.) or vehicle. Animals
`were then placed into runway boxes under red light conditions and the number of
`travels monitored for 30 minutes. No dose of vilazodone had a significant effect
`on locomotor activity. In contrast, 8-OH-DPAT significantly increased the
`number of travels recorded.
`
`These data demonstrate that vilazodone does not affect locomotor activity at the
`doses tested. The locomotor study data also suggest that vilazodone produces
`behavioral effects that are distinct from the prototypical 5-HT1A agonist, 8-OH-
`DPAT. The preceding suggestion is consistent with the partial agonist profile of
`vilazodone at the 5-HT1A receptor