CENTER FOR DRUG EVALUATION AND RESEARCH
AIroval Package for:
APPLICATION NUMBER:
20-690/8011
Trade Name: Aricept
Generic Name: Donepezil
Sponsor: Eisai Inc.
Approval Date: May 4, 2004
Indications: Indicated for the treatment of mild andmoderate dementia of Alzheimer's type.
CENTER FOR DRUG EVALUATION ANDRESEARCH
APPLICATION NUMBER:
20-690/8011
CONTENTS
Reviews / Information Included in this NDA Review.
Approval Letter X
Approvable Letter . XLabelin2 XMedical Review(s) XChemistry Review(s)
Pharmacolo2Y Review(s)Statistical Review( s)MicrobioloJO Review(s)
Clinical Pharmacoloev/ Biopharmaceutics Review(s) XAdministrative/Correspondence Document(s) X
CENTER FOR DRUG EVALUATION ANDRESEARCH
APPLICATION NUMBER:
20-690/8011
APPROVAL LETTER
_~stM.VI('.r.r.v""- &.s
( .JDEPARTMENT OF HETH & HUMAN SERVICES,::~\- Public Health Service
Food and Drug AdministrationRockvile, MD 20857
NDA 20-690/8-011
Eisai Inc.Attention: Rhea Willams, MPHGlenpointe Centre West500 Frank W. Burr BlvdTeaneck, New Jersey 07666-6741
Dear Ms. Wiliams:
Please refer to your supplemental new drug application dated submitted under section 505(b) of theFederal Food, Drug, and Cosmetic Act for AriceptQ! (donepezil) 5 mg and 10 mg Tablets.
We acknowledge receipt of your submissions dated April 8, 2004 and April 19,2004.
Your submission of November 21,2003 constituted a complete response to our July 29, 2003 actionletter.
This supplemental new drug application provides for changes to the Precautions (Drug -DrugInteractions and Carcinogenesis) section of labeling and the addition of a Geriatric use subsection.
We completed our review of this supplemental new drug application. It is are approved, effective onthe date ofthis letter, for use as recommended in the final printed labeling (FPL) submitted on April19,2004. .If you issue a letter communicating important information about this drug product (i.e., a "Dear HealthCare Professional" letter), we request that you submit a copy of the letter to this NDA and a copy tothe following address:
MEDWATCH, HFD-410FDA5600 Fishers LaneRockvile, MD 20857
We remind you that you must comply with the requirements for an approved NDA set forth under21 CFR 314.80 and 314.81. .
NDA 20-690/S-0 11Page 2
If you have any que~tions, call Melina Griffis, R.Ph., Sr. Règulatory Project Manager, at (301) 594-5526.
Sincerely,
(See appended e!cClí'()llìc s(gnaiure page!
Russell Katz, M.D.DirectorDivision of Neuropharmacological Drug ProductsOffce of Drug Evaluation ICenter for Drug Evaluation and Research
--_.......----------_..__.-------_..-------------_....--_...---_....--_....-------_..----_...--..------_....------_..This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.--------_..------------........._............................._.....-_..._--_.-...__............_-_.._-_.._------_..-/s/
Russell Katz5/4/04 05: 27 : 3 0 PM
CENTER FOR DRUG EVALUATION ANDRESEARCH
APPLICATION NUMBER:
20-690/8011
LABELING
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ARICEP'f DOT(Donepuzil Hydrohlorlde)
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CENTER FOR DRUG EVALUATION AND. RESEARCH
APPLICATION NUMBER:
20-690/8011 .
APPROV ABLE LETTER
+t-'t SU.VIC'ESo"
( -t DEPARTMENT OF HEALTH & HUM SERVICES,::Public Heai:~service
,
Food and Drug AdministrationRockvile, MD 20857
NDA 20-690/SLR-Oll
Eisai Medical Research, Inc.Attention: Rhea WiliamsGlenpoint Centre West500 Fran W. Burr BlvdTeaneck, NJ 07666
Dear Ms. Willams:
Please refer to your supplemental new drg application dated January 30,2003, receivedFebruary 3,2003, submitted under section 505(b)/pursuant to section 505(b)(2) of the Federal
Food, Drug; and Cosmetic Act for ArceptCI(donepezil hydrochloride) Tablets.
This supplemental new drg application provides for changes to the Precautions (Drug -DrugInteractions and Carcinogenesis) section of labeling a.ri,a-tle adØition of a Genatrc usesubsection.
We completed our review of this application and it isapprovable. Before this application may be.approved, however, it wil be necessary for you to submit drft labeling revised as follows:
1. The proposed revisions to the subsectiòn of the label entitled "Effect of Arcept onMetabolism of Other Drugs" (under Clincal Pharmacokinetics (Drug Interactions) &Precautions) areacceptable. In addition, the revisions to the label updating the number ofpatients with renal impairent that received the drg in protocol E2020-E044-00 11 areaccèptable.
2. The proposed revision to the subsection of the label entitled "Effect of Other Drugs on theMetabolism of Arcept" (under Clincal Pharmacokietics (Drug Interactions) &, Precautions)is not acceptable. Ths section should read as follows:
"In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mgq.d.) increasedmean donepezil (5 mg q.d.) concentrations (AUCo-24 and Cmax) by 36%.
We note that you have proposed that the above statement reflect a: ' in AUCo-24 and a-However, our calculations reflect ~increase in both. We believe the
discrepancy is due to a mathematical error on yoUr part. .
NDA 20-690/SLR-OllPage 2
3. The Geriatrc Use subsection oflabeling should be edited to read as follows:
Alzheimer's disease is a disorder occurrng primarily in individuals over 55 years of age.The mean age of patients enrolled in the clinical studies with ARICEPT~ was 73 years; 80%of these patients were between 65 and 84 years old and 49% of patients were at or above theage of75. The efficacy and safety data presented in the clinical trials section were obtainedfrom these patients. There were no clinically signficant differences in most adverse eventsreported by patient groups ¿ 65 years old and.: 65 years old.
4. The Carcinogenesis, Mutagenesis, Impairment of Fertility subsection oflabeling should beedited to read as follows:
No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study ofdonepezil hydrochloride conducted in CD-l mice at doses up to 180 mglg/day(approximately 90 times the maximum recommended human dose on a mg/m2 basis), or in a .1 04 week carcinogenicity study in Sprague-Dawley rats at doses up to 30mglg/day(approximately 30 times the maximum recommended human
dose on a mg/m2 basis).
Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouselymphoma forward mutation assay in vitro. In the chromosome aberration test in cultues ofChiese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil wasnot clastogenic in an in vivo mouse micronucleus test and was not genotoxic in an in yivounscheduled DNA synthesis assay in rats.
Donepezil had no effect on fertility in rats at doses up to 10 mglg/day (approximately 8
times the maximum recommended human dose on a mg/m2 basis).
We note that you have proposed animal-to-human mg/m2 safety factors for the mouse and ratcarcinogenicity. studies as. . , respectively. Since our calculations differ from yours please
explain in your response how you derived these factors.
If additional information relating to the safety or effectiveness of this drug becomes. available,revision of the labeling may be required. -----
Withi 10 days after the date of ths letter, you are required to amend ths application, notify usof your intent to file an amendment, or follow one of your other options under 21 CFR 314.110.If you do not follow one of these options, we wil consider your lack of response a request to -
witharw the application under 21 CFR 314.65. Any amendment should respond to all thedeficienCies listed. We wil not process a parial reply as a major amendment nor wil the reviewclock be reactivated until all deficiencies have been addressed.
This product may be considered misbranded under the Federal Food, Drug, and Cosmetic Act ifit is marketed with this change before approval of this supplemental application.
NDA 20-690/SLR-OllPage 3
If you have any questions, call Melina Griffs, R.Ph, Senior Regulatory Project Manager, at(301) 594-5526.
Sincerely,
(See appended electronic signatue page 1
Russell Katz, M.D.Dire~torDivision of Neuropharacological Drug Products
Office of Drug Evaluation I 'Center for Drug Evaluation and Research
,.
This is a representation of an electronic.record that was signed electronically andthis page is the manifestation of the electronic signature.
/s/Thomas Laughren7/29/03 09: 30: 40 AMSigned for Russell Katz, M.D.
CENTER FOR DRUG EVALUATION. ANDRESEARCH
APPLICATION NUMBER:
20-690/8011
MEDICAL REVIEW
Review and Evaluation of Clinical Data
NDA (Serial Number)Sponsor:Drug:Proposed Indication:Material Submitted:Correspondence Date:Date Received 1 Agency:Date Review CompletedReviewer:
20690. (SLR-011)EisaiDonepezilAlzheimer's DiseaseDraft Labeling Supplement8/30/998/31/9910/29/99Ranjit B. Mani, M.D.
1. BackgroundThis submission contains a draft labeling supplement for donepezil.
Donepezil(Aricepte) is a centrally-acting, piperidine-based, cholinesterase inhibitormarketed in this country for the treatment of mild to moderate dementia of theAlzheimer's type.
2. Changes to LabelingAll changes to labeling involve the "Precautions" section. One of the changes is alsoin the "Drug-Drug Interactions" section. The changes are under the followingheadings:
2.1 Drug-Drug InteractionsThe changes summarize the results of-a multiple dose interaction study betweendonepezil and ketoconazole conducted in healthy volunteers (Protocol 62020-A001-012). The results of this study Were submitted to NDA 20690 on 2/23/98.
The addition to the label is as follows:"In a 7-day cross-over study in - healthy volunteers, ketoconazole increased mean donepeiilconaentration (AUCo-24 ).
This change has been included in both the "Ciinical Pharmacology" and. ."Precautions" sections under this heading
2.2 Carcinogenesis, Mutagenesis, Impairment of FertiltyThe draft package insert now additionally describes the results of:· 88-week mouse and 104-week rat carcinogenicity stùdies· Mutagenicity studies in mouse lymphoma and rat hepatocyte cultures
The results of these studies are described as negative. i have not reproduced thetext of the change
Ranjit B. Mani, MD, HFD-120 Medical ReviewND 20690 (SLR-D11), Donepezil, Eisai
Page 2 of 210/29/99
2.3 Geriatric UseA Geriatric Use subsection has been added to comply with an Agency Guidance.The wording of this subsection is provided below:
"Alzheimer's Disease is a disorder occurrng pnmanly in individuals over 55 years of age. The meanage of patients enrolled in clinical studies with Ancept(JwasT of these patientswere between 65 and 84 years old and- of patients were above the age of 75 years. Theeffcacy and safety data presented in the clinical tnals section were obtained from these patients.There were no clinically significant differences in adverse events reported by patient groups - 65years old and 0: 65 years old. n
A table from the original NDA is provided as the basis for the demographic dataabove
3. Comments and Recommendations. Pharmacology and biopharm reviews of this draft labeling supplement are
pending. In the Geriatric Use subsection, 2 minor inaccuracies need to be corrected
. The stated percentage of patients betWeen 65 and 84 years is mildly inaccurate based on
the table supplied by the sponsor: the correct figure is 80 %. The stated percentage of patients above the age of 75. years is also somewhat inaccurate:
what can be estimated from the table is the proportion: '
. In regard to the Geriatric Use subsection, the sponsor has supplied no data to
support the assertion that "there were no clinically significant differences inadverse events reported by patient groups- 65 years old and c: 65 years old."The sponsor should either supply data to support that assertion or delete thestatement
Ranjit B. Mani, M.D.. Medical Reviewer
R. Levin, M.D.
rbm10/29/99cc:HFD-120NDA 20690 (SLR-011)electronic copy-LevinMalandrucco
I recommend that the geriatric section read:Thé effcacy and safety data described in thelabeling reflect the use of the drug in an elderlypopulation. The mean age of patients enrolledin the clinical trials waS'. . Approximately80% of patients were between 65 and 84 years.
Biopharm and pharmtox reviews are pending.
Reviêw and Evaluation of Clinical Data
NDA (Serial Number)Sponsor:Drug:Proposed Indication:Material Submitted:Correspondence Date:Date Received 1 Agency:Date Review CompletedReviewer:
20690 (SLR-011)
EisaiDonepezilAlzheimer's DiseaseAmendment To Labeling Supplement11/21/0311/241033118104Ranjit B. Mani, M.D.
1. BackgroundThis submission contains the second amendment to a supplemental New DrugApplication (NDA) for donepezil hydrochloride (Aricept().
This supplemental NDA proposes changes to the product labeling and wasoriginally submitted on August 30,1999; the Division responded to thatsubmission in an Approvable letter, dated August 28, 2000. Please refer to myreview of that submission for full details.
The first amendment to this labeling supplement was submitted on January 30,2003; an Approvable letter was issued on July 29, 2003; again, please refer tomy review of that submission for full details.
Donepezil(Aricept(I) is a centrally-acting, piperidine-based, acetylcholinesteraseinhibitor, that has been marketed in this country for the treatment of mild tomoderate dementia of the Alzheimets type since 11/25/1996.
In this review i wil first summarize the previous 2 submissions under this labelingsupplement and the Division's response (in the form of Approvable letters) tothem. I wil then describe the current submission. .
2. Original Labeling SupplementBoth the labeling changes proposed and the Division~s response in anApprovable letter are summarized below
2.1 Changes ProposedThe changes to labeling that were proposed by the sponsor in the originalsubmission of this labeling supplement (correspondence date of 8/30/1999) wereunder the following headings: .
.. \() Page(s) Withheld
§ 552(b )(4) Trade Secret / Confidential
§ . 552(b )(5) D'eliberative Process. .
X § 552(19)(4) Draft Labeling
-----------------~--------------------------------------------------------------------~------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.---------------------------------------------------------------------------------------------------------------------/s/
Ranj it Mani7 / i 7 / 0 3 0 i : i 7 : 3 3 PMMEDICAL OFFICER
Armando Oliva7 / i 7 /03 0 i : i 8 : 43 PMMEDICAL OFFICER
Review and Evaluation of Clinical Data
NDA (Serial Number)Sponsor:Drug:Proposed Indication:Material Submitted:Correspondence Date: .Date Received / Agency:Date Review CompletedReviewer:
20690 (SLR-011)
EisaiDonepezilAlzheimer's DiseaseAmendment To Labeling Supplement1/30/032/3/036/18/03Ranjit B. Mani, M.D.
1. BackgroundThis submission contains an amendment to a labeling supplement for donepezil.
The original labeling supplement was submitted on August 30, 1999; the Divisionresponded in an Approvable letter, dàted August 28, 2000. The currentsubmission responds to the Division's letter of August 28,2000.
Donepezil(AriceptQD) is a centrally-acting, piperidine-based, cholinesteraseinhibitor marketed in this country for the treatment of mild to moderate dementiaof the Alzheimets type, since 11/25/1996.
In this submission I will address the following in the same order as below:. The contents of the original labeling supplement
. The text of the Division's Approvable Letter of August 28, 2000.
. The contents of the current submission
2. Original Labeling SupplementThe following is a summary of the labeling supplement, as originally proposed inthe submission of August 30, 1999.. .The changes to labeling that were proposed were under the following headings:
.2.1 Drug-Drug Interacüons .The changes summarized the results of a multiple dose interaction studybetween donepezil and ketoconazole conducted in healthy volunteers (ProtocolE2020-A001-012). The results of this study were submitted to NDA 20690 on2/23/98.
The proposed adØition to the label was as follows:
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-_.-------......_......_--------------------------.---_..------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.---------------------------------------------------------------------------------------------------------------------lsi
Ranj it Mani3/18/04 12: 54: 17 PMMEDICAL OFFICER
CENTER FOR DRUG EVALUATION ANDRESEARCH
APPLICATION NUMBER:
20-690/8011
ADMINISTRATIVE and CORRESPONDENCEDOCUMENTS
REGULATORY PROJECT MANAGERLABELING REVIEW
NDA:DRUG:Sponsor:Supplements:
20-690Arcept (donepezil Hc1) TabletsEisaiSLR-Oll
Materials Reviewed:Current approved product labeling for Aricept (October 2003)Curent proposed labeling incorporated in SLR- 011
REVIEW
SLROllDated: August 30, 1999, amended Januaiy 30, 2003, November 21,2003, April 8, 2004and April 19, 2004Class: Prior Approval
This supplemental application provides for updated labeling to the Precautions (Drug -Drug Interactions and Carcinogenesis) section of labeling and the addition of a Geriatrcuse subsection (see attched document comparison of proposed changes).
CONCLUSIONS
In the attched electronic comparison (provided by the sponsor) between the lastapproved labeling and the curent proposed labeling only the changes highlighted weremade. All changes have been approved by the medical, phanntox and biopharmreviewers. I recommend approval of the above listed supplement.
Melina Grffs, RPhRegulatoiy Project Manager
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---------------------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.---------------------------------------------------------------------------------------------------------------------/s/
Melina Griffis4/23/Ó4 09: 06: 00 AMeso
CENTER FOR DRUG EVALUATION ANDRESEARCH
APPLICATION NUMBER:
20-690/8011 '
CLINICAL PHARMACOLOGY ANDBIOPHARMACEUTICS REVIEW(S)
CLINICAL PHARACOLOGYIBIOPHARCEUTICS REVIEW
NDA:Sponsor:Drug:Formulation:Proposed Indication:Material Submitted:Correspondence Date:Reviewer:
20-690/SLR -011EisaiDonepezil (Arcept)
Oral tabletsAlzheimer's Disease
Response to Approvable Letter1130/03Sally Usdin Yasuda, MS, Pharm
Background:
Arcept( donepezil) is a reversible inibitor of acetylcholinesterase that is indicated forthe treatment of mild, to moderate Alzheimer's tye dementia.
The Sponsor submitted a supplemental NDA for Arcept(donepezil) 5 and 10 mg tabletsin August 1999 that proposed changes to the Precautions (Drug-Drug Interactions andCarcinogenesis) section of labeling and the addition of a Geriatrc use subsection.Following review of the application, the Agency requested 1) specific revisions to thedraft labeling, 2) revision of the label to reflect the final number of patients with renalimpairent that received the drg in protocol E2020,-E044-001 " A single-dose study to
compare the pharmacokinetics ofE2020 and its metabolites in subjects with moderate toseverely impaired renalfiction", 3) evidence to address the question of differences inresponse between elderly and younger adults, and 4) clarfication of the results öftheUDS toxicity assay.
The present review wil evaluate the pharmacokietic portions ofthe Sponsor's response.
Sponsor's Response: ')
1. Revision to subsection of label entitled "Effect of Aricept on Metabolism of Other
Drugs" - The requestedrèvision has been made to read: "Formal
pharacokinetic studies evaluated the potential of Arcept for interaction withtheophylline, cimetidine, warfar, digoxin, and ketoconazole. No effect ofArcept on the pharacokinetics of these drugs - 'observed".
2. Revision to subsection of label entitled "Effect of Other Drugs on the Metabolism
of Aricept" - The Agency requested that this section reflect a 36% increase indonepezil AUCo-24 and Cmax when administered with ketoconazole. The Sponsor
has proposed that this statement reflect a_'ii!t ii 2 I wand a -
.. According to the OCPB review of December 8, 1999 in thedrg-drg interaction study investigating the potential changes of doIiepezil andketoconazole pharacokietics, an increase of abou - was observed in both
AUCo-24 and Cmax for donepezil after 7 days of repeated dosing compared to asingle dose of donepezil alone. In that review, it was noted that the Sponsor'scalculations of the magnitude of interaction are questionable.
The parameter in question is the AUCo-24 for which the mean values in theabsence and presence of ketoconazole were 501.1 ng*hr/ml and 680.91 ng*hr/ml,respectively. Although the Sponsor calculates this
_ The discrepancy between the Sponsor's proposed labeling and
the Agency's change is due to a mathematical error on the part of the Sponsor.Therefore, the change requested by the Agency should be made.
This section should read:
"In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.)increased mean donepezil (5 mg q.d.) concentrations (AUCo-24 and Cmax)by 36%.
3. Revision to the.label updating the number of patients with renal impairment thatreceived the drug in protocol £2020-E044-001 - The proposed label has beenrevised as requested in the OCPB review ofDec~mber 8, 1999.
Conclusions and Recommendations:
From the perspective of Clinical Pharmacology and Biopharaceutics, the Agency's.requested label change regarding the magnitude ofthe ketoconazole~induced increase(36%) in donepezil AUCo_24 and Cmax is stil required. Please forward this comment to
the Sponsor.
Sally Usdin Yasuda, MS, PharReviewer, Neuropharmacological Drug Section, DPE IOffce of Clinical Pharacology and Biopharmaceutics
Concurence: Ramana Uppoor, PhD
Team Leader, Neuropha.acologiCal Drug Section,DPE I
Offce of Clinical Pharacology and Biopharmaceutics
..,."
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cc: HFD-120
HFD-860
NDA 21-690/S-011CSO/J. WarelBiopharmS. YasudaITL Biopharm. Uppoor
, IDD DPEIIM. Mehta, C. Sahajwalla
References
(1) Tiseo PJ, Perdomo CA, Friedhoff LT. Concurrent administration of donepezil HCl
and ketoconazole: assessment of pharmacokinetic changes following single andmultiple doses. Br J Clin Pharmacol1998; 46(Suppll):30-34.
-.._._-_.__._-----------------------.----------------------------_._-------------------------------------------------This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.---------------------------------------------------------------------------------------------------------------------/s/
Sally Yasuda5/5/03 03: 46 : 4 9 PMBIOPHARMCEUTI CS
Ramana S. Uppoor5/5/03 i 0 : 28 : 52 PMBIOPHACEUTICS
CLINICAL PHARACOLOGYIBIOPHARMCEUTICS REVIEW
NDA:Sponsor:Drug:Formulation:Proposed Indication:Material Submitted:Correspondence Date:Reviewer:
20-690/SLR -011EisaiDonepezil (Aricept)Oral tabletsAlzheimer's Disease
Supplement AmendmentNovember 21,2003Sally Usdin Yasuda, MS, Phar
Background:
Arcept (donepezil) is a reversible inhibitor of acetylcholinesterase that is indicated forthe treatment of mild to moderate Alzheimer's tye dementia.
The Sponsor submitted a supplemental NDA for Arcept (donepezil) 5 and 10 mg tabletsin August 1999 that proposed changes to the Precautions (Drug-Drug Interactions and'. Carcinogenesis) section of labeling and the addition of a Geriatrc use subsection.Pertinent to the present supplement amendment, following review of the application, theAgency requested specific revisions to the draft labeling in the subsection entitled"Effect of Other Drugs on the Metabolism of Arcept" (under Clinical Pharacokinetics- Drug Interactions and Precautions). This was followed by a request by the Division onJuly 29,2003 that the proposed revision be changed to read as follows:
"In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.)increased mean donepezil (5 mg q.d.) concentrations (AUCo-24 andCmax) by 36%.
This recommendation was based on an error by the Sponsor in calculating the magnitudeof the increase.
Sponsor's Response:
The Sponsor has acknowledged its error in calculating the increase in AUCo-24 and Crnax. and has revised the labeling accordingly to reflect a 36% increase in both. In the presentsubmission, the Sponsor proposes the following alterIate language (change is in bold):
"In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.)increased mean donepezil (5 mg q.d.) concentrations (AUCo-24 and Crnax) by 36%.
The clinical relevance of this inèrease in concentration is unknown."
Conclusions and Recommendations:
From the perspective of Clinical Pharmacology and Biopharmaceutics, the Sponsor'sproposed language is acceptable. Please forward this comment to the Sponsor.
Sally Usdin Yasuda, MS, PharmDReviewer, Neuropharmacological Drug Section, DPE IOffice of Clinical Phamiacology and Biopharmaceutics
Concurence: Ramana Uppoor, PhD
Team Leader, Neuropharmacological Drug Section, DPE IOffice of Clinical Pharmacology and Biopharmaceutics
HFD-860
NDA 21-690/S-0 11CSOIM. GriffislBiopharS. Yasuda
rrL Biophar. UppoorIDD DPEIIM. Mehta, C. Sahajwalla
cc: HFD-120
This is a representation of an electronic record that was signed electronically andthis page is the manifestation of the electronic signature.
/s/Sally Yasuda12/18/03 06: 56: 04 AMBIOPHACEUTICS
Ramana S. Uppoor12/18/03 10: 35: 56 AMBIOPHARMCEUTICS
