CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`022255Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`

`

`MEMORANDUM
`
`TO:
`NDA 22-255
`FROM:
`Wendy I. Wilson-Lee, Review Chemist
`SUBJECT: CMC Review of Revised Carton and Container Labels
`DATE:
`CC:
`
`4/19/2010
`Susan Daugherty, HFD 120 RPM; Don Henry, ONDQA PM; Martha Heimann, ONDQA CMC Lead; Ramesh Sood, ONDQA
`Branch Chief
`
`Revised Carton and Container Labels
`
`Schwarz provided revised carton and container labels based on FDA comments forwarded to the sponsor on 14-APR-2010.
`Based on further review, and in concert with DMEPA, we requested the sponsor remove the expression of total lacosamide
`content per total volume as it may confuse the patient. Figures 1 and 2 represent the final draft carton and container labels.
`
`
`
`1 Page of Draft Labeling has been Withheld in Full Immediately
`Following this Page as B4 (CCI/TS)
`
`

`

`
`
`Overall Recommendation
`
`
`
`
`
`
`
`
`
`The revised carton and container labels are adequate, from a CMC perspective.
`
`
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`
`
`
`
`_______Wendy I. Wilson-Lee_______
`
`
`
`
`
`
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`
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`
`
`
`
`
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`
`
`Wendy I. Wilson-Lee, Ph.D.
`Review Chemist
`ONDQA DPA-I
`
`3
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22255
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WENDY I WILSON
`04/19/2010
`
`MARTHA R HEIMANN
`04/19/2010
`for Ramesh Sood
`
`

`

`
`
`Date:
`
`To:
`
`Thru:
`
`From:
`
`Subject:
`
`Drug Name(s):
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`April 7, 2010
`
`Russell Katz, MD, Director
`Division of Neurology Products
`
`Carlos Mena-Grillasca, RPh, Team Leader
`Denise Toyer, PharmD, Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`
`Judy Park, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Medication Error and Labeling Review
`
`Vimpat (Lacosamide) Oral Solution
`10 mg/mL
`
`Application Type/Number: NDA 022255
`
`Applicant:
`
`OSE RCM #:
`
`
`
`UCB, Inc.
`
`2009-2157 and 2009-2158
`
`

`

`
`
`1
`
`CONTENTS
`INTRODUCTION................................................................................................................... 3
`1.1
`Regulatory History......................................................................................................... 3
`1.2
`Product Information....................................................................................................... 3
`2 METHODS AND MATERIALS ............................................................................................ 3
`2.1
`Adverse Event Reporting System (AERS) .................................................................... 3
`2.2
`Packaging, Labels and Labeling .................................................................................... 3
`3 RESULTS................................................................................................................................ 4
`3.1
`Medication Error Cases.................................................................................................. 4
`3.2
`Packaging, Labels and Labeling .................................................................................... 4
`4 DISCUSSION ......................................................................................................................... 4
`4.1
`Vimpat Oral Solution New Concentration..................................................................... 4
`5 CONCLUSIONS AND RECOMMENDATIONS.................................................................. 4
`5.1
`Comments to the Division.............................................................................................. 4
`5.2
`Comments to the Applicant............................................................................................ 5
`6 REFERENCES........................................................................................................................ 6
`APPENDICES................................................................................................................................. 7
`
`
`
`
`
`
`
`2
`
`

`

`
`
`1
`INTRODUCTION
`This review responds to a request from the Division of Neurology Products (DNP) for the
`Division of Medication Error Prevention and Analysis (DMEPA) to evaluate the new proposed
`concentration for the Vimpat oral solution (10 mg/mL) and revised container labels, carton and
`insert labeling submitted on October 16, 2009 for potential medication errors.
`
`1.1 REGULATORY HISTORY
`Vimpat (Lacosamide) Tablets and Injection were approved on October 28, 2008. The oral
`solution dosage form of Vimpat received a Complete Response on October 28, 2008. The Agency
`was concerned with the potential for dosing errors with the solution concentration
`
`and limitations
` (see OSE Review #2007-1610 dated May 15,
`2008). We reviewed the labels and labeling for the oral solution in OSE Review #2008-633 dated
`May 15, 2008. The Applicant submitted a new concentration for the oral solution (10 mg/mL)
`and revised labels and labeling on October 16, 2009 in response to Complete Response letter.
`
`1.2 PRODUCT INFORMATION
`Vimpat tablets and oral solution are indicated for partial-onset seizures as adjunctive therapy in
`patients aged > 17 years. The injection is indicated for short-term replacement when oral
`administration is not feasible in these patients. The recommended dose for partial onset seizures
`is 50 mg twice daily initially, then increased at weekly interval by increments of 100 mg per day,
`based on clinical response and tolerability, to 200 mg per day to 400 mg per day in two divided
`doses. When switching from oral to intravenous dose, the initial total daily intravenous dosage
`should equal the oral total daily dosage and frequency. The parenteral formulation of Vimpat can
`be administered without further dilution or may be mixed in a compatible diluent and should be
`administered intravenously over 30-60 minutes. Vimpat is available in tablets (50 mg, 100 mg,
`150 mg, and 200 mg), solution for injection (200 mg/20 mL). The Applicant is proposing to add
`an oral solution (10 mg/mL) to the existing Vimpat product line.
`
`2 METHODS AND MATERIALS
`
`2.1 ADVERSE EVENT REPORTING SYSTEM (AERS)
`Because Vimpat Tablets and Injection are currently marketed products, DMEPA conducted a
`search of the FDA Adverse Event Reporting System (AERS) database on February 1, 2010 for
`any medication errors relevant to the labels or labeling of Vimpat using the following criteria:
`Active Ingredient “Lacosam%” and Trade Name “Vimpat%” and the MedDRA reaction terms
`“Medication Errors” (HGLT) and “Product Quality Issues” (HLGT).
`The reports were manually reviewed to determine if medication errors occurred involving factors
`related to either labels or labeling. Those cases that did not describe a medication error, and those
`that were determined to be irrelevant, were excluded from further analysis.
`
`2.2 PACKAGING, LABELS AND LABELING
`DMEPA used Failure Mode and Effects Analysis (FMEA)1 in our evaluation of the new
`concentration and revised container labels, carton and insert labeling submitted on October 16,
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`2009 (see Appendices A and B). We also evaluated the recommendations pertaining to the
`previous labels and labeling in OSE Review #2008-633.
`
`3 RESULTS
`
`3.1 MEDICATION ERROR CASES
`The AERS search retrieved a total of 9 reports involving Vimpat on February 1, 2010. However,
`none of these cases were related to issues concerning the labels or labeling of Vimpat. These
`cases involve suicide attempts, lack of efficacy, overdose (causality not given), and reports of
`tablet breaking per physicians’ recommendations.
`
`3.2 PACKAGING, LABELS AND LABELING
`We compared the revised labels and labeling to the previously reviewed labels and labeling in
`OSE Review #2008-633 dated May 15, 2008. We note that our previous recommendations were
`incorporated in the revised labels and labeling.
`
`4 DISCUSSION
`
`4.1 VIMPAT ORAL SOLUTION NEW CONCENTRATION
`. We were concerned that this
`Previously, the Applicant proposed a concentration
`concentration could not measure the recommended dose in whole milliliter units. We were also
`concerned with the medication error potential of the Applicant’s
`
`(see OSE Review #2007-1610). The new concentration addresses this
`concern since the new concentration allows for dosing in whole milliliter units (5 mL, 10 mL,
`15 mL and 20 mL). This amount can be accurately measured with non-product specific
`measuring cups available in pharmacies.
`
`. We concur with the Applicant that a
`specialized, drug-specific measuring dosing cup is not warranted.
`
`
`
`5 CONCLUSIONS AND RECOMMENDATIONS
`
`5.1 COMMENTS TO THE DIVISION
`The new proposed concentration for Vimpat oral solution (10 mg/mL) and the revised labels and
`labeling submitted by the Applicant adequately addresses our previous concerns regarding the
`inability to measure the recommended dose in whole milliliter units. Additionally, the Applicant’s
`revisions to the labels/labeling or the new concentration did not introduce any additional areas of
`vulnerability that could lead to medication errors.
`We note that ONDQA had requested the addition of the total drug content/total volume in all
`labels and labeling. However, DMEPA disagreed and expressed concerns that such presentation
`might be confusing and could potentially lead to medication errors. After discussion, ONDQA
`agreed with DMEPA's recommendation to remove the statement of total drug content/total
`volume from all labels and labeling.
`Please copy the Division of Medication Error Prevention and Analysis on any communication to
`the Applicant with regard to this review. If you have any further questions or need clarifications,
`please contact Sarah Simon, OSE Project Manager, at 301-796-5205.
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`5.2 COMMENTS TO THE APPLICANT
`We acknowledge the previous request from the Agency to add the total drug content/total volume
`to all labels and labeling. However, such presentation might be confusing and could potentially
`lead to medication errors. Thus, it should be deleted from all labels and labeling.
`
`
`
`
`5
`
`

`

`
`
` REFERENCES
`
` 6
`
`1. Adverse Events Reporting System (AERS)
`AERS is a database application in CDER FDA that contains adverse event reports for
`approved drugs and therapeutic biologics. These reports are submitted to the FDA
`mostly from the manufactures that have approved products in the U.S. The main utility
`of a spontaneous reporting system that captures reports from health care professionals
`and consumers, such as AERS, is to identify potential post-marketing safety issues.
`There are inherent limitations to the voluntary or spontaneous reporting system, such as
`underreporting and duplicate reporting; for any given report, there is no certainty that the
`reported suspect product(s) caused the reported adverse event(s); and raw counts from
`AERS cannot be used to calculate incidence rates or estimates of drug risk for a particular
`product or used for comparing risk between products.
`2. OSE Review #2007-1610 Proprietary Name, Label, and Labeling Review for Vimpat;
`Park, J.; May 15, 2008.
`3. OSE Review #2008-633 Labels and Labeling Review for Vimpat; Park, J.; May 15,
`2008.
`
`
`
`6
`
` 3 Pages Draft Labeling Withheld in
`Full Immediately Following this Page
`as B4 (CCI/TS)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22255
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JUDY J PARK
`04/07/2010
`
`CARLOS M MENA-GRILLASCA
`04/07/2010
`
`DENISE P TOYER
`04/07/2010
`
`

`

`
`
`Date:
`
`To:
`
`Thru:
`
`From:
`
`Subject:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`May 15, 2008
`
`Russell Katz, MD, Director
`Division of Neurology Products
`Bob Rappaport, MD, Director
`Division of Anesthesia, Analgesia and Rheumatology Products
`
`Kellie Taylor, PharmD, MPH, Team Leader
`Denise Toyer, PharmD, Deputy Director
`Division of Medication Error Prevention
`
`Judy Park, PharmD, Safety Evaluator
`Division of Medication Error Prevention
`
`Labeling Review
`
`Drug Name(s):
`
`Vimpat (Lacosamide) Tablets, Oral Syrup, and Injection
`
`Application Type/Number: NDA 22-253, NDA 22-254, NDA 22-255,
`
`
`
`Applicant:
`
`OSE RCM #:
`
`
`
`Schwarz Biosciences, Inc.
`
`2008-633
`
`(b) (4)
`
`

`

`
`
`CONTENTS
`EXECUTIVE SUMMARY............................................................................................................. 3
`1 BACKGROUND..................................................................................................................... 3
`1.1
`Introduction.................................................................................................................... 3
`1.2
`Product Information....................................................................................................... 3
`2 METHODS AND MATERIALS ............................................................................................ 3
`3 RESULTS................................................................................................................................ 4
`4 DISCUSSION ......................................................................................................................... 5
`5 CONCLUSIONS and recommendations................................................................................. 5
`5.1
`Comments To The Division........................................................................................... 6
`5.2
`Comments To The Applicant......................................................................................... 6
`APPENDICES................................................................................................................................. 8
`
`
`
`
`
`
`
`2
`
`

`

`
`
`EXECUTIVE SUMMARY
`The results of the Label and Labeling Risk Assessment found that the presentation of information
`and design of the proposed carton and container labels appears to be vulnerable to confusion that
`could lead to medication errors. The Division of Medication Error Prevention believes the risks
`we have identified can be addressed and mitigated prior to drug approval, and provides
`recommendations in Section 5.2 that aim at reducing the risk of medication errors.
`
`1 BACKGROUND
`
`1.1
`INTRODUCTION
`This consult was written in response to a request from the Division of Neurology to evaluate the
`container labels and carton labeling of Vimpat for its potential to contribute to medication errors.
`The proprietary name, Vimpat, and the insert labeling were evaluated under a separate review
`(OSE Review #2007-1611).
`
`1.2 PRODUCT INFORMATION
`Vimpat (Lacosamide) is a new molecular entity indicated for partial-onset seizures as adjunctive
`therapy in patients aged
`years and older,
`
`. The recommended dose for partial onset seizures
`is 100 mg per day twice daily initially, then increased to 200 mg per day to 400 mg per day.
`
`
`
`The dose can be
`increased at weekly intervals by increments of 100 mg per day based on clinical response and
`tolerability. The maximum daily dosage of Vimpat is
` per day. When switching from oral
`to intravenous dose, the initial total daily intravenous dosage should equal the oral total daily
`dosage and frequency. The parenteral formulation of Vimpat can be administered without further
`dilution or may be mixed in a compatible diluent and should be administered intravenously over
`. Vimpat will be available in 50 mg, 100 mg, 150 mg, 200 mg,
`
`
` oral syrup, and 10 mg/mL solution for injection.
` For partial seizure indication, tablets, oral syrup
`
`and injectables are indicated.
`
`2 METHODS AND MATERIALS
`This section consists of two sections which describe the methods and materials used by the
`Division of Medication Error Prevention staff conducting a label, labeling, and/or packaging risk
`assessment. The primary focus of the assessments is to identify and remedy potential sources of
`medication error prior to drug approval. The Division of Medication Error Prevention defines a
`medication error as any preventable event that may cause or lead to inappropriate medication use
`or patient harm while the medication is in the control of the health care professional, patient, or
`consumer. 1
`The label and labeling of a drug product are the primary means by which practitioners and
`patients (depending on configuration) interact with the pharmaceutical product. The container
`labels and carton labeling communicate critical information including proprietary and established
`
`
`1 National Coordinating Council for Medication Error Reporting and Prevention.
`http://www.nccmerp.org/aboutMedErrors html. Last accessed 10/11/2007.
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`name, strength, form, container quantity, expiration, and so on. The insert labeling is intended to
`communicate to practitioners all information relevant to the approved uses of the drug, including
`the correct dosing and administration.
`Given the critical role that the label and labeling has in the safe use of drug products, it is not
`surprising that 33 percent of medication errors reported to the USP-ISMP Medication Error
`Reporting Program may be attributed to the packaging and labeling of drug products, including
`30 percent of fatal errors.2
`Because our staff analyze reported misuse of drugs, our staff are able to use this experience to
`identify potential errors with all medication similarly packaged, labeled or prescribed. We use
`FMEA and the principles of human factors to identify potential sources of error with the proposed
`product labels and insert labeling, and provided recommendations that aim at reducing the risk of
`medication errors.
`For this product the Applicant submitted on April 9, 2008 following labels and labeling for our
`review (see Appendices A, B, C, D, E, F, and G for images):
`• Retail Container for Injection: 10 mg/mL (20 mL vial)
`• Retail Carton for Injection: 10 mg/mL (20 mL vial)
`• Retail Container for Oral Syrup:
`• Retail Carton for Oral Syrup:
`
` 465 mL)
` 465 mL)
`
`• Retail Container for Tablets : 50 mg, 100 mg, 150 mg, 200 mg
` counts)
`
` (60,
`
`3 RESULTS
`A review of the container labels and carton labeling identified several potential sources of
`medication error.
` above the letter “A” of the proprietary name on the container
`We noted a
`labels and carton labeling. Additionally, the established name and dosage form appears smaller in
`size and prominence than the proprietary name while the company logo is similar in prominence
`as the proprietary name.
`The retail labels and labeling for all strengths of tablets have the same trade dress except for the
`strength colors. The differentiating strength colors for 50 mg, 100 mg, and 150 mg tablets look
`almost identical since they are presented in similar shades of pastel and are bordered in black.
`For the injectable dosage form, we noted the total drug content (200 mg/20 mL) and the
`concentration (10 mg/mL) of the injectable have the same prominence. Additionally, the
`container label for the injectable does not list the inactive ingredients qualitatively and
`quantitatively and the carton labeling does not list the quantitative amount of the inactive
`ingredients.
`
`
`2 Institute of Medicine. Preventing Medication Errors. The National Academies Press: Washington DC.
`2006. p275.
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`Lastly, the precautionary statement for Phenylketonurics on oral syrup label
`
`confusing because it is unclear
`.
`
`
`
` is
`
`
`
`
`
`4 DISCUSSION
`The results of the Label and Labeling Risk Assessment found that the presentation of information
`and design of the proposed container labels and carton labeling appears to be vulnerable to
`confusion that could lead to medication errors.
`We noted inadequate differentiation among the proposed product strengths of the tablet
`formulation. The visual similarities of the container labels and carton labeling can lead to product
`selection errors because all strengths are usually stocked side-by-side on a pharmacy shelf. We
`are concerned with the similar strength colors of the 50 mg, 100 mg, and 150 mg tablets, in
`addition to identical trade dress for all strengths. The minimal differences in the strength color
`may not afford adequate differentiation of the product strengths.
`Per 21 CFR 201.10(g)(2), the established name should be at least ½ the size of the proprietary
`name and have the prominence commensurate with the prominence of the proprietary name,
`taking into account all pertinent factors, including typography, layout, contrast, and other printing
`features. The proposed labels do not present the established name in accordance with the
`regulations.
` on the container labels and carton labeling. This is distracting
`We noted the use of
`and draws attention away from important product information such as drug name and product
`strength. The
` contributes to the overall visual similarity of the labels. The company
`logo should also be diminished in size and color since it competes with other important
`information such as the drug name and strength.
`The same prominence of the total drug content (200 mg/20 mL) and the concentration
`(10 mg/mL) of the injectable makes it difficult to identify the total drug content. The differences
`between total drug content and concentration would be more evident if the concentration is
`presented under the total drug content and has less prominence.
`Additionally, the injectable container label does not list the inactive ingredients qualitatively and
`quantitatively and the carton labeling does not list the quantitative amount of the inactive
`ingredients as it should per 21 CFR 201.100(b)(5).
`
`Lastly, the precautionary statement for Phenylketonurics on oral syrup is confusing because it is
`unclear
`
`
`.
`
`5 CONCLUSIONS AND RECOMMENDATIONS
`The Label and Labeling Risk Assessment findings indicate that the presentation of information
`and design of the proposed container labels and carton labeling introduces vulnerability to
`confusion that could lead to medication errors. We believe the risks we have identified can be
`
`
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`addressed and mitigated prior to drug approval, and provides recommendations in Section 5.2 that
`aim at reducing the risk of medication errors.
`
`5.1 COMMENTS TO THE DIVISION
`Based upon our assessment of the labels and labeling, we have identified areas needed of
`improvement. We have provided recommendations in Section 5.2 and request this information be
`forwarded to the Applicant.
`We would appreciate feedback on the final outcome of this review. Please copy us on any
`communication to the Applicant with regard to this review. We would be willing to meet with
`the Division for further discussion, if needed. If you have further questions or need clarifications,
`please contact Daniel Brounstein, Project Manager, at 301-796-0674.
`
`5.2 COMMENTS TO THE APPLICANT
`The Label and Labeling Risk Assessment findings indicate that the presentation of information
`and design of the proposed container labels and carton labeling introduces vulnerability to
`confusion that could lead to medication errors. The Division of Medication Error Prevention
`believes the risks we have identified can be addressed and mitigated prior to drug approval, and
`provides recommendations below that aim at reducing the risk of medication errors.
`Overall, our Risk Assessment is limited by our current understanding of medication errors and
`causality. The successful application of Failure Modes and Effect Analysis depends upon the
`learning gained for a spontaneous reporting program. It is quite possible that our understanding
`of medication error causality would benefit from unreported medication errors; and, that this
`understanding could have enabled the Staff to identify vulnerability in the proposed name,
`packaging, and labeling that was not identified in this assessment. To help minimize this
`limitation in future assessments, we encourage the Applicant to provide the Agency with
`medication error reports involving their marketed drug products regardless of adverse event
`severity.
`
`5.2.1 General Comment
`1. We recommend removing
`on all container labels and carton labeling.
`2. Per 21 CFR 201.10(g)(2), ensure that the established name is the same font size as
`the dosage form and at least ½ the size of the proprietary name, and have the
`prominence commensurate with the prominence of the proprietary name, taking
`into account all pertinent factors, including typography, layout, contrast, and other
`printing features.
`3. Decrease the prominence of the company logo in size and color so that it does not
`compete with other important information such as the drug name and strength.
`
` above the proprietary name
`
`5.2.2 Tablets
`1. The current proposed presentation of the labels lack adequate differentiation since
`all the labels have the same trade dress. Although we recognize that the strength
`color correlates to the tablet colors, the proposed strength colors on labels for
`50 mg, 100 mg and 150 mg look particularly similar to one another because they
`are presented in similar pastel colors and bordered in black. Provide additional
`visual differentiation of the labels so that each strength is clearly differentiated
`from the remainder of the strengths.
`
`
`
`6
`
`(b) (4)
`
`

`

`
`
`2.
`
`5.2.3 Oral Syrup
`1. Revise the precautionary warning statement for Phenylketonurics
`
`
`
`
`
`
`
`5.2.4 Injectable
`1.
`Increase the prominence of the total drug content (200 mg/20 mL). Relocate the
`concentration (10 mg/mL) to below the total drug content.
`
`
`
`
`
`7
`
`(b) (4)
`
`(b) (4)
`
`3 Pages of Draft Labeling have been Withheld
`in Full Immediately Following this Page as B4
`(CCI/TS)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Judy Park
`5/15/2008 10:11:10 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Kellie Taylor
`5/15/2008 10:45:46 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`5/15/2008 12:35:59 PM
`DRUG SAFETY OFFICE REVIEWER
`
`