RECEIVED

OFFICEOFPETi-flONS
Elan Pharmsceuticrls, tnc. Skclaxd 0netaulcne)

Protocol No ELN151607.106

A STUDY TD EVALUATE THE PHARMACOKlNETiCS OF SKELAXIN. (METAXALONE) 2x400 MG TABLET ADMINISTERED TO YOUNG AND ELDERLY VOLUNTEERS UNDER FED AND FASTED CONDtTlONS ELNlJl607-105 CLINICAL STUDY REPORT IND Number: Name of Product: Phase of Dcvelopmsnr Date Study Inltirted: Date of Last Observation: Design: Skelaxine (metaxalone) Phase t April 9.2002 May20,2002 Single center. open tabei. single dose, randomized, two-period, two way cross-over trial in volunteers Elan Phamaceuticals, Inc. 7475 Lusk Boulevard San Diego, CA 92121 Investigator: Mark J. Allison, M.D. MDS Phanna Services 4639 south 36” street Phoenix, AZ 85040 Tel: (602) 4376097 PRACS Instiiute, Ltd. April q6,2003 I !

Sponror:

Principal

Prepared by: Date of Report:

This study was performed in accordance with Good Clinical Pracke guidelines. The final study report incorporates ICH 1996 Guidelines and is archived at Elan Pharmaceuticets, Inc.

Page 1

MI1 6/03

ELAN-K-06-000038

Elan Phrmwutds, Skelaxin’ (mrt8xslone)

Inc. SIGNATURE PAGE

Protocol No ELNl51607-106

A STUDY TO EVALUATE THE PHARMACOKINETICS OF SKELAXINe (MET-LONE) 2x400 MG TABLET ADMINISTERED TO YOUNG AND ELDERLY VOLUNTEERS UNDER FED AND FASTED CONDlTiONS ELN151607-105 Sponsor Name: Document Vereion: Elan Pharmaceuticals, Inc. 1

Prepared at PRACS Institute, Ltd. by: d/b/O3 Date Reviewed at MDS Pharma Services by: Mark J. Allison, M.D. Principal investigator

it&&=-o$%bh Date

Reviewed by Quality Assurancs at PRACS Institute, Ltd. by: Thomas E. Ary, Ph.D. c/ Director, Cuaiity Assurance

iGL4T?w~Ls

I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and results of this study. Approved by:

Michael C.. SC&, Ph.D. Vice President, Global Regulatory Affairs

Page 26

W116/03

ELAN-K-06-000039

Elan PharmaCwbCals Skemd (mrtaxaktnr)

11%

Protocol

No. ELNlS1607.105

SIGNATURE

PAGE

A STUDY T O EVALUATE THE PHARMACOKlNETlCS Of SKELAXIN’ (METAXALONE) 2x400 M G TABLET ADMINW-ERED T O YOUNG AND ELDERLY VOLUNTEERS UNDER FED AND FASTED CONDfTlONS ELN151607.105

ELNl51607.105 Sponsor Name: Elan Pharmacauficals Inc

This is to ceftify that Guintjies (10245 Hlckmen Mills Onvt. P.O. Box 9708. Kansas Cfty, M O 64134-0706) has made a comparison of th@ pharmacoktnetics paramelers calculated by PRACS in Appendices 16.255 through 16.2.5.8 with those calculeted independently by Quintilss. The original analysis by PRACS is considered lo be acceptable and can be used as IS.

ic&kG=. , ..
Vice President, Clinicel pharmacology

//&i/o 3

Page 2b

ELAN-K-06-000040

Elan Phafmaceutids, Inc. Skaluin* (nwta%Mnt)

Pmtocol NO. ELN151607-105

2.0

SYNdPSlS INDIVIDUAL STUDY SYNOPSIS Page 1 of 3 I INDIVIDUAL STUDY (FOR NATIONAL REFERRING TO AUTHORtTY PART OF DOSSJER USE ONLY) Volume:

NAME OF COMPANY: Elan Phannaceuticels, Inc. NAME OF FINISHED PRODUCT: Skelaxine NAME OF ACTIVE INGREDfENT: Metaxalone

Pegr:

Title of Study: 4 Study to Evaluate the Phannacokinetics of Skeiaxin* (metaxalone) 2x400 mg Tablet Administered to Young and Eldcrty Volunteers Under Fed and Fasted Conditions Date of Protocol: Investtgrtors: Principal Investigator. Sub-Investigator: Study Cen;ters: MDS Phanna Services 4639 South 36” Street Phoenix, A2 85040 Tel: (602) 437.0097 Study Period: 3ate of First Treatment: >a!e of Last Observation: March 28, 2002 Mark J. Allison, M.D. Irving E. Weston, M.D.

April 9.2002 May 20,2002

Phase of Development: Phase i

Wmary Objoctlve: The primary objectives are to evaluate? the effect of age and-food on the >harmecokinetics of Skeiaxin’ (metaxalone) when administered to two dtierent age groups.

Page 3

04116m

ELAN-K-06;000041

Elan Phrnnaceutkalr. Inc. Skelrxin* (metucalone)

ProtocolMO.ELN151607.105

Methodology: This study was a single center, open iabcl, singtc dose, two-period (per age group), nndomized, two way crossover trial in young volunteers between the ages of 18-55 years old (average age 39.3 f 10.8) and the elderly, 65 and older, (average age 7t.5 * 6). On Study Days f and 8, a single oral dose (2 x 400 mg) of Skei%xin* (metaxaione) was administered, once fed and omxfasted, to each of the subjects. Blood sampling (19 per subject each period) for drug content analysis occurred within on@ hour prior to dosing (0 hour) and after dose administration on Days 2 and 8 at 0.5. 1. 1.5. 2.2.5.3, 3.5,4,4.6, 5, 68, 12, 16, 24,30,36, and 48 hours Number of Subjects: Forty-eight healthy subjects were enrolled in the study (24 males, 24 females). Forty-four subjects successfully completed the study and were used for the pharmacokinetic and statistical analyses. The following subjects completed Period I but did not complete Period II, Subject 29 was dropped for eiev%ted ALT and Subject 33 was dropped for anemia. Subject 34 did not return for Period II check-in, and Subject 45 was dropped on Day 3 of Period 1 due to noncompliance. All subjects who received treatment were included in the safety analysis. Diagnori% and Main Crfteria for Inclusion: Agreed to voluntarily participate and sign informed consent document; volunteen over the age of 18; within 20% of ideal body weight accordrng to the Metropolitan Height and Weight Table; childbearing female subjects must not be pregnant or lactating and willing to use contraception. Test Product, Dose, and Mode of Administration, 0atch No.:

Treatment A: 2 x 400mg Skelaxin’ (metaxalone) with food Lot No.: 34851A, Exp.: 31.Jan-05 Treatment B: 2 x 4OOmg Skelaxine (metaxalone) without food Lot No.: 3485119, Exp.: 3%Jan-05 3uration of frertmont: 4 single dose was administered on Study Day 1 and Study Day 8. deference Therapy, Dose, and Mode of Administration, Uone Batch No.:

Criteria for Evaluation: The following pharmacokinetic parameters were calculated for metaxalone: W&t,. ALG,p,, Cm.,, T,, K., and Tin

1
0(/l 6103

Page 4

Elan Pharmaceytlclls, Inc. Skelad (meomne)

Protocol No. ELN151607.105

Statistical Methods: For each age and treatment group, descriptive statistics of plasma concentrations at each sampling time were reported. Descriptive statistics for the pharmacokinetic parameters were presented by age and treatment group as well. The age, treatment, and sge-by-treatment effects for each pharmacokrnetic parameter were tasted using an ANOVA model with age, subject within age, treatment, and the agaby-treabnent interaction as factors. Summary of Resulta:

Pharmacokinrtiu: During the study there were no protocol deviations to confound the pharrnacokinetic and bioavaiiabilty anatyses. Young Subjects: Mean f Standard Deviation for Non-lr?nsformed Fasted Parameter Fed 19636.24 +, 7836.05 20462.38 f 7545.11 A’ JGw 20489.57 i 79?0.28 20814.57 i 7589.14 AUCmn 2719.02 + 1237.54 2915.27 f t591.87 C ITa1 Elderly Subjects: Mean i Standard Deviation for Non-Tnnrformed Fastad Parameter Fed 23797.04 +, 10623.52 24340.43 f 11664.95 AUCtm, 24194.13 f tO689.44 24704.17 f 11662.03 AU&n 3167.89 2 1345.06 3680.21 f. 2161.75 C flux P-Values Based on Ln-Transformed Data Effecf AU%n AU&m %X 0.3569 0.3891 0.2037 Age 0.6968 0.4353 0.5618 Treatment 0.9600 0.3986 0.4935 Interaction There were no statistically significant diffarences detected for AU&r). AUCpng, or Cm, baaed on age, treatment, or the interaction of age.by-treatment. Safety: A total of 54 adverse events wore reported over the course of the study: 23 adverse events were considered unrelated by the nveatrgatorts) and 31 adverse events were considered related to the study drug Data

Data

J

Page5

04~6lO3

ELAN-K-06-000043

Elm Phwmaceutials. Inc. Sketaxm* (mmmlone)

Protocol No. El,N151607-105

Conclusions:
There were no statistically significant

age effects detected for any of the

phafmacokinetic parameters. All study treatments were well tolerated by all subjects. Date of Report: 04/16/03

Page 6

M/l 6m3

ELAN-K-06-000044

Elan Phmnaceutruls, Inc. Sk&xln* (metrxabne)

Protocol No ELN151607-105

TABLE OF CONTENTS 1.0 2.0 3.0 4.0 5.0
5.1

TITLE PAGE.. ............................................................................... SYNOPSIS . . ................................................................................. TAEitE OF CONTENTS ................................................................... LIST OF ABBREVIATIONS AND DEFiNlltON

1 3 7

OF TERMS w.................. .l t ......... 12 .12 2
.12

ETHICS .......................... ..~..................~....-.....-......................“..” Emrw

5.2
6.3

INSTITUTIOML REVIEW @CURD(IRB) ........................................................ CONDUCTOF THE SNaY..............................................................l %.BJECl INFORMATIONAND CONSENT.. .....................................................

6.0 7.0 8.0 9.0
9.1 9.2

INVESTlGATORS INTRODUCTfON

AND STUDY ADMINISTRA’ WE

STRUCTURE ....... ..13 14 15

....................................................................................... ..............................................

STUDY OBJECTIVE ... ..-...........................I INVESTIGATIONAL

PLAN ... .._“......................................~

........................ 15

9.3 16 9.31 Inclusion CM& ................................................................................ 16 9.3.2 Exclusion Critetia ............................................................................... 9.3.3 RemoWl of Subjects from Therapy or Assessment ........................... 17 17 9.4 TRMNWTS ............................................................................................ 17 9.4.? Trctetments Adminisi8md ................................................................. 18 9.4.2 /d~ntilyOffnWStigrlianSf~UCf.. .................................................. 9.4.3 Method of Assigning Subjects to Treatmen! Gmup.. ........................ 18 18 9.4.4 Sektion of Doses in the Study ....................................................... 9.4.5 S8lection 81?d liming of DOS8 for Each Subject ............................... 19 19 9.4.6 Blinding ............................................................................................ ;; 9 4.7 Prior and Concomitsnt Therapy 9.4.8 Tmatmsnt Complience . ...........................................................................................................................
9.5 EPFICACY AND SAFEWVARMBLES ............................................................ 19

.: ........... 15 OVERAUSTUDYDESIGNANDPLAN.. ............................................. D!SCuSSfON Of !~TuDY DESIGN.. ............................................................... .16 SELECTION of STUDY POPUUTION ........................................................... .16

9.5.1 Eflcacy and Safety Measurements Assessed and Flow Chart ........ 19 9.5.2 Appropriet8ncPSS of ~8~SUlWRl8nt.S................................................. .22 9.5.3 Drug Concentration Measurements ................................................. 22 22 9.6 DATA QUALITY ASSURWCE .......................................................................
9.7 STATISTICAL MNODS PUNNED IN THE PROTOCOL AND DETERM~~UTIONOF 22 SMPLE SIZE ............................................................................................

9.7.1

Statistical and Analysis Plans .........................................................

.22

Page 7

04/16/03

ELAN-K-06-000045

Eian Pharmwutiars,
Sk&win (metaxalonr)

Inc.

Protocol No ELN151607.105

Detemfination of Sample Size.. ....................................................... 9.7.2 .23 9.0 CHANGES IN THE CONDUCT OF THE SNOY OR PLANNEO ANALYSES .............. 23 10, STUDY SUBJECTS .” ................................................................................ 23 .23 25 .. ..2 6 26
.31 .32 10.1 DlsPOSlTloN OF SuWECtS ....................................................................... 10.2 PROTOCOL DWIAT~ONS .............................................................................

11. 12.

PHARMACOKINETIC

AND PHARMACODYNAMIC

PARAMETERS..

11.1 f’ tURt4ACOlON~CS ......................................

I.. .........................................

SAFETY EVALUATION ........................ ..O....~.......................” .................. 31

12.1 EXTENT OF EXPOSURE .............................................................................
12.2 ADVERSE EVENTS ....................................................................................

72.2.1 Brie? Summery of AUvene Events ................................................... Events.. ............................................................ 12.2.2 Displ8yofAdverse 12.2.3 Analysis of Adverse Events. ............................................................. 12.214 Listing of Advetse Events by Subject .............................................. 12.3 DEATHS, DTHER SERIOUS ADMRSE EVENTS, AND OTHER SIGNIFICANT
AO~ERSE Em .....................................................................................

32 .32

32
.32 32 .32 .32
.33

12.4 CLINICALLA~ORATDRY EVAUtAllON .......................................................... 72.4. I Evaluation of Each Leboretoty Parameter ...................................... 12.5 VITAL SIGNS, PWSICM FINDINGS, ECG, AND OTHER OBSERVATIONS 12.6 Srsm 13. 14.
RELATED TO SAFE ................................................................................ CONCLUSIONS .............................................................................

.33

DISCUSSION AND OVERALL CONCULUSIONS

...... ...” ........................ 34 3s

TABL.ES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT .........................................................................

14.1 SAFEN DATA SUMMARY FIGURES AND TAEILES...........................................

35 7 4.7.1 Displ8ys of Adversb Even& ............................................................ .35 14.1.2 tistings of Deaths, Other Serious and Significant Advene Events . . 38 14.1.3 Nat-Wives of De8thS, Other Senbus and Cert8in Other Significant Adveme Events ................................................................................ 38 14.1.4 Abnormal Lsboratory Velues.. ......................................................... .39 REFERENCE LIST ..” ............................................................................... APPENDICES -TABLE OF CONTBNTS ................................................. 46 47 .50 .51 97 141 759 170 172

15. 16.

16.1 STUDY ~NFOFMA~ON ................................................................................

161.1 Pmtocolgnd Pmtocol Amendments.. .............................................. 16.7.2 Sample Csse Report f onn .............................................................. 16.7.3 Institutional Review Board and Representative Informed Consent Documents ..................................................................................... 16.1.4 List oflnvestigators.. ...................................................................... 7 67.5 Signature of Pfincipel lnvestrgator ................................................. 16.1.6 Randomization Scheme .................................................................

Page 8

Mll6m3

ELAN-K-06-000046

Elan Phsrmacwticalr. Inc. Skelaxd (metaxalona)

Pmlacol No. ELN151607-105

f 6.7.:’ Certithte of Anelysis ..................................................................... 175 I 6, I, 8 Documentslion of Statistical Methods.. .......................................... 178 16.1.9 Documentation of Inter-Labomtoty St~ndardiration Methods and Procedures ..................................................................................... 179 16.1. ;rOPublications Based on the Study .................................................. .263 16.1.11 Important Publicetions Refemnced in Repott.. .............................. .264 16.2 SUWECTDATA LIWINOS ........................................................................ .265 16.2. :I Discontinued Subjects ................................................................... 266 16.2.2 Pmtoco! Devis lions ....................................................................... -267 7 6.2.:~ Subjects Excluded from the Phatmecokinetic Analysis ................. -268 16.2.4 Demographic d&a.. ....................................................................... .269 16.2.5 Ptasms Concentration Date and Pharmacokinetic Data ............... .272 7 6.2.6 individual Adverse Event Listings.. ................................................. 362 16.2.7 Listing of Individual Labomtoty Measurements.. ............................ 356 ...........................................................................42g 16.3. CASE REPORTFORMS.. 7 6.3.7 Case Report Forms (for desths, other serious adverse events, and withdmvals due to &verse events) ............................................... 430 16.3.2 Other Case RepofiFonns.. ............................................................ 431 16.4 INDIVIDUAL SUBJECTDATA LISTINGS ......................................................... 432

Page 9

W16/03

ELAN-K-06-000047 -- -_

Elan Phamaceut~cals. Inc. Skeluin* (metaxalone)

Protocol No. ELN151607.105

List of In-Text-Tables Table lO.l’ Subject Demographic Descriptive Statistics for YOUng Subjects .l: (12 Young Males; 12 Young Females; 24 Young Subjects) . . . . . . . . . . . . . . . . . .._.....24 Table 10.1.2: Subject Demographic Descriptive Statistics for 65 and Older Subjects (12 Older Males; 12 Older Females; 24 Older Subjects) .,....._....... 24 Table 10.1.3: Subject Demographic Descriptive Statistics for All Subjects (24 Mates; 24 Females: 48 Subjects Total) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. . . . . . . . 25

I: (ng-hr/mL) Skelaxin* Table 11 .l .‘ Mean and Coeffkient of Variation for AK&J (metaxaione) when Administered Wtih and Without Food . . .. . . ...-.............. 28
Table 11 .1.2: Mean and Coefficient of Variation for A&M (ng-hr/mL) Sketaxin* (metaxalone) when Administered With and Without Faod . . .. . . ..*..............*... 29 Table 11.1.3: Mean and Coefficient of Variation for C,, (nglmi) Skelaxin* (metaxalone) when Administered VVIth and Without Food . . . . . . . . . .. . . . . . . . . . . . . . . . . 30 Table 11.1.4: Summary of Statistical Results . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Table 11 .l.ti: Median and Range for T, (hr) Skelaxine (metaxalont) when Administered Wfih and Without Food I....................................,....... *. . . . . . . . . . . . 31 List of tn-Text-Figurrs Figure 11 .?.l: Mean Plasma Concentration (0 - 48 hours) . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 27 Figure 11.1.2: Mean +I- Standard Deviation by Age Group and Treatment Group for AUCftiu(, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 26 Figure 11 .1.3: Mean +/- Standard Deviation by Age Group and Treatment Group Inn...............................................................................................,,... 29 for AUC ‘ Figure 11 .1.,4: Mean +/- Standard Deviation by Age Group and Treatment Group for C, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Page 10

04/l

6/m

ELAN.K-06.000048

Etan PharmPceuticalr, Inc. Sketad (nwtaulone)

Protocol No ELN151607.105

4.0 AE

LIST OF ABBREVIATIONS

AN0 OEFINITION OF TERMS

AUCw, AUC(nr) CRF ~msx CS ECG FDA GCP GLP HIV ICH IRB IGI NCS PK QA SAE SD T1n TllUl

Adverse Event Experimental area under the CUIVC calculated to the last quantifiable concentration according to the linear trapezoidal rule Area under the curve extrapolated to infinity Case Report Fon Maximum plasma concentration Clinically Significant Electrocardiogmm Food and Drug Administration Good Clinical Practice Good Labomtory Practica Human lmmunodeficiency vtrus International Conference on Harmonisation Institutional Review Board Slope of the renninal linear portion of the concentration versus time curve Not Clinicalty Significant Phannacokinetic Quality Assurance Serious Adverse Event Standard Deviation Terminal half-liie Time to reach the maximum plasma concentration

Page 11

04/16m3

ELAN-K-06-000049

ELIn Phamacoutkah. Skclrxd (rnemxrbne) 5.0

Inc.

Protocol No. ELW51607-105

RHICS 5.1 institutional Review Board (IRE)

Prior to the initiation of the study, the investigator sent the study protocol, consent and the Physician’ Desk Reference Reprint to the MDS Phana s Services institutional Review Board (IRB). The investigator obtained signed evidence of protocol and informed consent approval from the tRB and fonvarded the approval letter to the Sponsor. MDS Phatma Sewices IRE; members is presented in Appendix 16.1.3. The March 26,2002 protocol and informed consent document were approved by the MDS Pharma Services IRB on April 9,2002. The April 11, 2002, revisions and certifications of translation from English to Spanish to the informed consent document, were approved by the MDS Pharma Services IRB on April IJ,2002. 5.2 Ethical Conduct of the Study

The study was conducted in accordance with the ethical principles of the Declaration of.Helsinki, and other principles of the ICH Good Clinical Practice Guideline’ 2. * 6.3 Subject tnfonation and Consent

Prior to study enrollment the study specific informed consent (Efan Pharmaceuticals, Inc. ELNl51607-105) was reviewed with the subject emphasirlng the nature of the study, the drug product tested, potential adverse events, conduct of the study, and dates of confinement and ambulatory procedures. [Appendu 16.1.3). All subjects gave written informed consent to participate in the Elan Pharmaceuticals, Inc. ELNl5 1607-105 study and were aiiowed to ask and have answered questions concerning the conduct of the study prior to enrollment in the study.

Page 12

om6/03

ELAN-K-06-000050

Elan Pharmwcu!icals, Inc. Skelaxd (rnetaxabne)

Protcd

No. ELNl51607.105

6.0

lNVESTlGATORS Qi+al

AND STUDY ADMINJSTRATIVE

STRUCTURE

Research Investigators and Facilities: Mark ,I. Alliion, M.D., Principal Investigator (Appendix 16.1.4 and Appendix 16.1.5) Irving E. Weston, M.D., Sub- Investigator (Appendix 16.1.4) MDS Pharma Services Phoenix, AZ 85040 Activities: Study management, on-site protocol activities, dosing, and sample collection, physical examination, medical record review and medical investigator on-site and on-call professional services

Clinical taboratory Facilities: Robert A Earl, Ph.D. MDS Phama Services Lincoln, NE 68516

[Hematology, Chemistry hinalysis, Drug Screen, Pregnancy Hepatitis B surface antigen, Hepatitis C antibody, HIV antibody] Activities: Certfiad reference clinical laboratories, clinical lab sample analysis

AnPlytical Investiator & Facility: Gary Erdmann, Ph.D. PR&S Institute. Ltd. Fargo, ND 58104 Activities: Responsible for bioanalytlcal analyses. Statistical Analysis: Brenda L. Krogen, MS. PRACS Institute, Ltd. Fargo, ND 58104 AcWties: Responsibkz for pharmacokinetic analyses.

and statistical

Page 13

0.m 6/03 ELAN-K-06-000051

--

Elan Phomacautwls. Inc. Skclaxin’(rmtaxalone) 7.0 INtRODUCflON

ProtocolNo. ELNl51607.105

Metaxaione is a car&al nervous system depressant that has sedative and skeletal muscle relaxant effects. Metawalone is indicated as an adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute, painful mUSWlOSkel8tal conditions’ The recommended dose for adults . and children over 12 years of age is two tablets (400 mg per tablet, 800 mg total dose) three to four times a day.’ The mechanism of action of mataxalone in humans has not been established, but may be due to general central neNouS System depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.’ Metaxalone is metabolized by the liver.’ Precautions indude the following: metaxaione must be administered with great care to patients with pm-existing liver damage; false positive Benedict’ tests due to an unknown reducing s substance have been noted: Safe use has not been established with regard to possible adverse effects upon fetal development it is unknown whether it is secreted in human milk, and the safety and effectiveness in children 12 years of age and below has not been 8stabiiShed. In the elderly, reduction in the metabolic capacity of the liver is commonly seen.’ This is often the resut of a reduction in hepatic blood flow as well as a reduction in hepatic mass and volume. w Further, there are pharmacokinetic changes associated with aging. There can be attered responsiveness to the absorption, distribution, metabolism and excretion of drugs.‘ This is often the result of .’ attered physiology.’ For example, the apparent Vd of lipid soluble drugs can be ratsed due to changes (usually’ increase) in fat-to-lean body composition ratlo.7d The aiteration (decrease) in renal blood flow can also greatly impact the excretion of dogs.” Drug toxicity ca used by increased free drug levels due to impaired drug protein binding or displacement from protein binding sites can be seen.6 The most ,frequent reactions to metaxalone include nausea, vomiting, gastrointevtmal upset, drowsiness, dizziness, headache, and nervousness or ‘ irritability”. Other adverse events are hyperSensitivrty reaction, characterized by a light rash with or without pruritls: kukopenia. hemolytlc anemia; and jaundice. I

Page 14

04l16103 ELAN-K-06-000052

Elm Phsrnwt:adult. Inc. Skslexd (mtltaxalona)

Protocol No. ELN151607.?05

8.0

STUDY OB.JECTlVE The primav objectives are to evaluate the effect of age and food on the pharmacokinefics of Skelaxin’ (metaxalone) when administered to young and elderly age groups.

9.0

INVESTIGATIONAL 9.1

PLAN

Overall Study Design and Plan

This was single canter, open label, single dose, two-period (per each age group), randomizad. two way crossover trial in healthy subjects between the ages of 1855 yean old (young) and the elderly (65 and older); treatments were follows: Treatment A: Skeiaxin* (mefaxaione) tablet 2 x 400 mg tablet administered with food Treatment 6: Skelaxin’ (metaxalone) tablet 2 x 400 mg tabfef administered without food A standardized breakfast was given to the subjects 45 minutes prior to dosing and was consumed within a 30 minute period. The dose of study drug was administered to the subjects 15 minutes after the breakfast was finished. The breakfast consisted of the following: 2 2 2 4 1 eggs (fried in butfer) strips of bacon slices of toast with butter ouncas of hash brown potatoes g&s whole milk (8 ounces)

Nineteen blood samples wera cofiecfad, starting with baseline (0 hour) and iat the foliowing time points: 0.5, I, t .5, 2, 2.5, 3, 3.5. 4.4.5, $6, 6, 72, 16.24, 30, 36, and 48 hours. In Period II. a blood sample at approximafefy 168 hours wes collccfed to ensure the study drug was eiiminated from the body. A total of 48 subjects (24 males and 24 females) were enroiled. Forty-four of 46 subjects completed both treatments and the plasma samples were assayed and used in the pharmacokrnetic analysis. Four subjects completed only one treatment and were not used In the pharmacokinetlc analysis.

Page 15

541~6/03

ELAN-K-06-000053

Elan PhairmuceutJcaJs. Inc. SWuin* (n?epxrW)

Protocol No. ELN151607-105

9.2

Discussion of Study Design

This was a single center, open label, single dose, tM+petiod (per each age group), randomized, two way crossover trial in heatthy subjects, between the ages of 18-55 years old (young) and the elderly (65 and older). 9.3 Selection of Study Population 9.3.1
l

Inclusion Criteria Agreed to participate voluntarily and signed and dated an IR5approved written, subject informed consent form; At least 18 yean old at the time of screening ; Wtiin t 20% of ideal body weight according to the Metropolitan Height and Weight Tables: Female subjects of childbearing potential were not pregnant or lactating and were willing to use a medically appropriate form of contraception for the duration of the study. Exclusion Criteria
l l

l l

l

9.3.2

l l

l l l

Not competent to provide informed consent; Displays clinically significant abnormalities on screening evaluations which consist of: physical examination, heart rate and sitting (1 minute) blood pressure, temperature. 12 lead ECG, and clinical laboratory tests. Deviatrons from the established normal ranges may be acceptable for study participation lf, in the opinion of the investigator and Sponsor, they are not dinically meaningful or are viewed as normal for that individual. Individual screening tests may be repeated by the investigator to confirm accuracy of the original determinations or to further evaluate the dinical significance of deviations; Clinically significant ilhess wtthin 4 weeks of screening: Known to be HN positive. hepatitis 5 antigen positive, or hepatitis C antibody posJtive; History of drug or alcohol addiction or abuse: Use of tobacco products within the last 6 months; Use of any drugs including food supplements, herbal remedies and non-prescribed drugs known to induce or inhibit hepatic drug metabolism within 30 days prior to screening as listed in Appendix A of the protocol (Appendix 16.1.1);

Page 16

04116103

ELAN-K-06-000054

Ebn Phwmacaukais. Inc.
Skaiax!n* (mataxabnt)

Pmtocol No.

ELN151607.105

. History of clinicaily significant drug allergies or allergic responses to metaxalone or related drugs; . Femaks who are pregnant or breastfeeding; l Blood donation within 30 days of screening or plasma donation within 14 days of screening; . Participation in a ctinical trial of an investigational drug or device within 30 days of the treatment phase: l Considered by the investigator to be unsuitable for study participation, for any reason. 9.3.3 Removal of Subjects from Therapy or Assessment

Subjects could have been discontinued or withdrawn from the study for any of the following reasons:
l l

l

At the subject’ s At the discretion appropriate, for At the discretion for any reason

request of the Investigator, if deemed any reason of the Sponsor, if dsemed appropriate,

Four subjects, subjects 29, 33, 34, and 45 were discontmued or withdrawn after Period I dosing. 9.4 Treatments 9.41 Treatments Administered

A single dose of Skelaxine 400 mg tablet (2 x 400 mg) was administered to each subject according to the randomization scheme and according to the specific instructions for administration. The study drug was administered as follows: Treatment Treatment A: 2 x 400mg Skelaxin* (metaxalone) with food B: 2 x 400mg Skelaxine (metaxalone) without food

Breakfast was given to the subjects approximately 45 minutes prior to dosing and consumed within a 30 minute period. The dose of study drug was administered to the subjects approximately 15 minutes after the breakfast was finished. The breakfast consisted of the following: 2 eggs (fried in butter) 2 strips of bacon 2 slices of toast with butter 4 ounces of hash brown potatoes 1 gtass whole milk (8 ounces)
Page 17 04/16/03

ELAN-K-06-000055

Elan Phormrcauticals. Inc. Skelaxm* ImMaxalone)

Protocol No. ELN1S1607r10S

Subjects were sequentially dosed at 1 minute intervals. All fortyeight subjects received one dose of Skelaxin? Dosing was completed as scheduled in 44 of 48 subjects. The following subjects did not receive a second dose of Skeiaxin* Subjed 29 was dropped for elevated ALT and Subject 33 was dropped for anemia. Subject 34 did not return for Period II checkin, and Subject 45 was dropped on Day 3 of Period I due to noncompliance. Under the investigator’ direction, an accurate dispensing log was s maintained to record dates and emoun! of medication drspenseci to each subject in the trial. In addition. an entry on the case report form for each subject provides a record of this activity. All unused study product is accounted for and was returned to Elan Biophartnaoeuticals. Subjects were continuously monitored by MDS Pharma Sewices staff throughout the confinement portion of the study. 9.4.2 Identity of Investigational Product Name: Substenoe: Dosage Form: Content: Route: Batchnot No.: Expiration Date: Manufacturers 9.4.3 Skelaxine Mctaxalone Tablet 400 mg Oral 34851A 31-Jan-05 Mallinckrodt

Hobart

Method of Assigning Subjects to Treatment Group

All subjects received 2 tablets of Skelaxino (metaxalone) 400 mg. The randomization schedule is located in Appendix 16.1.6. 9.4.4 Sebotion of Doses in the Study is the recommended

The dose selected (2 x 400 mg Skelaxrnq dose for this product.

Page 18

M/16/03

ELAN-K-06-000056

Elan PharmaceubcaIS. Sketaxin* [m&xalonO)

Inc.

Protocol No ELNlS1607-105

9.4.5 Selection and Timing of Dose,for Each Subject Subjects were sequentially dosed at 1 minute intervals under fasting or fed conditions, dependent on randomization. Food was restricted 10 hours predose (fasting group). 9.4.6 Blinding Not Applicable 9.4.7 Prior and Concomitant Therapy The investigator’ staff obtained information about concomitant s illnesses and therapeutic interventions. The investigator’ staff s recorded the dates of onset and remission of all symptoms and diagnosed conditions, as well as the name, daily dose and dates of self medications. 9.4.8 Treatment Compliance At admission to the clinical research facility, all subjects were questioned regarding their compliance to the protocol since their previous visit. Subjects were continuously monitored by MDS Phana Services staff throughout the confinement portion of the study. 9.5 Efficacy and Safety Variables 9.51 Efficacy and Safety Measurements Assessed and Flow Chart untii 4 hours post-dose

Efkacy was not an objective of the study design. Safety measurements performed over the course of the study were as follows: 1. A medical history and a physical examination were performed at the screening visit and at the post-study vistt. 2. Vii signs (sitting (1 minute)) blood pressure. pulse, and oral temperature) were measured at all visits and on the PK profile days at pre-dose and approximately 2. 6, 12, and 24 hours post dose.

Page 19

M/16/03

ELAN-K-06-000057

Elan Pharmrceu&als. Inc. Skelaxitl* (metax8kme)

Prorc~~01 No. ELNl51607.105

3.

4. 5.

Clinical laboratory tests, including a serum pregnancy screen (females on\y). were performed at screening and on Days -1,7, and at the post-study visit. A 12 lead ECG was performed at the screening and poststudy visits. Adverse events were recorded.

Page 20

04/16M3

ELAN-K-06400058

Elan Pharmaceuticals, Inc. Skclud (metmalona)

Pr~Locol No. ELN151607-105

r

SCHEDULE OF EVENTS
Screen Treatment Psnoct 1 Warhout Treetmant Penod 2 Post SW

,

I

Fast overnight (10 hours) Hcrnatology. chemrrty, unnatysis Serum Pregnancy Dru#alcohcJ screon PK samdes X

X X
: .I

X X
I

X

X’ X

X X x2 I

X X i x’ I

X

X

I / I I 1 I I I I ‘ Okwn VlO) signs predose and 2.6. 12 and 24 hours post-study drug admtnrstrat!on 8. 12. 16.24.30. 36 and ‘ Ohm PK SwWas at pro-dose, 0.5. 1. 1.5.2, 2.5, 3, 3.5,4,4.5,5,6. 46 houn post430sa. Paw 21 M/16/03

I

ELAN-K-06-000059

Dan Pharrnaceticah. Skelaxm* (rnwxalone)

Inc.

Prolccd

No. ELN’ ISWY-105

9.5.2 Appropriateness

of Measurements

The measurements performed are standard procedures for the conduct of pharmacokinetic studies. 9.5.3 Drug Concentration Measurements Blood tampks for the measurement of metaxalone plasma concentrations were colkoted at the following time points: l Baseline (0 hour) (IO mL blood sample) 9 0.5, 1, 1.52.2.5, 3, 3.5,4,4.5, 5, 6,8, 12. 16, 24, 30, 36, and 48 hours after drug administration (1 x 10 ml. blood sample). The total blood volume taken per subject for pham\acokinatic analysis and clinical labontofy testing was approximatety 444 mL for maie subjects and 480 for female subjects over a pericd of approximataly 30 days, Samples were collected and stored In an ice bath. Plasma samples were separated by certtrifugation, frozen at approximately -20%. and kept frozen, packed in dry ice, and sent to PRACS Institute, Ltd., in Fargo, North Dakota. 9.6 Data Quality Assurance

All parts of the clinical phase of the study and all documentation were subject to inspection by Elan’ independent quality assurance (QA) unit. s Non-clinical (analytical) parts of the study were also subject to QA audit. 9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size 9.7.f Statistical and Analysis Plans

For each age and treatment group, descriptive statistics of plasma wncsntrations at esch sampling time was reported. Descriptive statistics for the phatmacokinetic parameter8 were presented by age and treatment group, as well. The age, treatment, and age-bytreatment effects for each pharmacokinetic parameter were lested using an ANOVA model with age, subject within age, treatment, and the age-by-treatment Interaction as factors.

Page 22

04/l 6x13

ELAN-K-06-000060

Elan Pharmacetiwis, Inc. Skelaxd (metaxalone)

Protocol No E~N151$07-t05

9.72

Determination of Sample Size

This was a descriptive study to determine the pharmacokinetics of 2 x 400 mg Skelaxine(metaxalone) tablets when administered to volunteers between the ages of 18-55 and in volunteen’ 65 years of age and older in both the fed and fasted state. Due to the descriptive nature of the study, no power oalcutation was
pWfOf!Tt&.

9.8

Changes in the Conduct of the Study or Pfanned Analyses

No changes wera made during the conduct of the study or with the planned analyses that could have aitered the study outcomes, 10. STUDY SUBJECTS 10. I Disposition of Subjects

The study was SUCCeSSfullyCompleted by 44 of 48 subjects enrolled. At enrollment, all 48 subjects met study inclusion and exdusion criteria as documented by an acceptable medical history, medication history, physical examination, sitttng blood pressure, heart rate, electrocardiogram. clinical laboratory evaluations, a non-reactive HIV antibody acraen, and negative screen3 for Hepatitis S surface antigen, Hepatitii C antibody, pregnancy (females only), and drugs of abuse fourteen days prior to. Period I dose administration. All female subjects had a negative pregnancy screen prior to dose administration. All subjects gave written informed consent and were allowed to ask and have answered questions concerning the conduct of the study pnor to enrollment in the study. The trial was conducted under medical supervision. Tables 10.1.1, 10.1.2, and 10.1.3 summarize the demographic characteristics for young subjects, older subjects, and for both age groups combined.

Page 23

Mll6m3

ELAN-K-06-000061

Elan Phrmacsuttcalr. tnc. Sketaxlr? (memUlOIW)

Protocol No. ELNlSlSO?-105

Table fO.l.1: Subject Demographic Descriptive Statistics for Young Subjects (12 Young Males; 12 Young Females: 24 Young Subjects)

Data Source: Append= 16.2.4

Table 10.1.2: Subject Demographic Descriptive Statistics for 65 and Older Subjects (72 Older Males; 12 Older Females; 24 Older Subjects) I f- Elderly Male I Ekleriy Frmrle 1 Eiderly All
r
Etdarly Male

I

Age

) 1 Meant Sunamd y4an 71.4 i 4.5 Dq~ruon ( Mmmum 1 71 years 1 Maxtmum 1 66yean i Medun 81 yean j 71.5 f 5.1 yarn / 65 yean 1 70yean / 81 years 1 71.5 f 5 ycrrrs I 65 years 1 70 yran 1 81 yean I Welght Meant Standard Dew&on 1 Minimum 173.7 f 24.6 Ibs. 1 116ibS. 141.3t21.9 Jbs. I 112 tbs. 157.5 r 28.1 tbs. I 112 Ibs. 1 1 I / / j 1 j

i Etdcrly Fwmr /-3ldU#iy Aa I

Median i MaxImum 180.010s. I ZrHIbS 138.0 tbs. 1 185 Ibs. 159.0Ibs [ 204 Ibs
1 / Manmum 1 72Otn. I 70.5 In 72.0 in.

I 1 Mean f Standard Dowabon EIderty Mob j 69.3f 1.9n-t. Elderry Femab ) 64.4 t 3.2 in iElderly All j 66.8 : 3.6 tn. Data Source. Appendu 16.2.4

namrlt. -. . Mmimum 1 Medtan 66.0 in. 1 69.0n. 60.5 In 64.0 m 60.5 in 1 67.5 m

Page 24

04/l wo3

ELAN-K-06-000062

Elan Phummceuticals, Inc. Skclaxm’ (metaxalone)

Protocol No ELNl51607-105

Table 10.1.3: Subject Demographic Desctiptive Statist& for All Subjects (24 Males; 24 Females; 48 Subjeots Total)

The weight of the volunteers was not more then f 20% of ihe ideal for height 8fid body frame as par the Desirable Weights for Men or the Desirable Weights for Women - Metropolitan Height and Weight Table. Appendix 46.2.4 includes 8 t8ble presenting the demographic data for 48 subjects enrolled in the study. 10.2 Protocol DeVi8tiOns The following protocol deviations occurred during the conduct of this study: [ Sub. NO.
I Devtntion all

45

31 31 I 27

Aocordlng to the protocol. Post-study events were to include the following: vitat signs, a Physical exam. cfiniuf laboratory tests, and an ECG. Subject’ early termination s events were all completed prior to release except for an ECG. According to the PmtOCtA, blood rampk was to k obtarned at a 4.5 houra postdose. Dunng Period 1, the 45hour sample was not obtainad due to a difficult venipuncture. According to the protocol, a blood sample was to ba obtamad at 1.5 houn post-dose. Dunng Period 2. the 1 S-hour sample was not obtained due to a difficutt venipuncture. According to the PrOtOeOl, blood sample was to be obtained at a 3.5 and 4.5 hours posi-dosc. During Period 2, the 3.5 and 4.5 hour samolcs were not obtained due to difficult vcnlpuncture.

Page 25

04/l

6103

ELAN-K-06-000063

Elan Pharm8cruticals. Inc. Skelaxm* (metitxdm)

Protocol No. ELNl51607-105

11.

PHARMACDKtNETFC 11 .I Pharmacokinetics

AND PHARMACODYNAMIC

PARAMETERS

The pharmacokinetic pammaters were calculated using VVinNoniin~. Version 3.1. software designed specificaky for analyzing pharmacokinetic data. WinNonlin’ Model 200 for extravascular input was utifiad. All other amputations wera completed using SAS*, Version 8.2 for Wrndows. Microsoft6 Ex& 97 was used to produce tables and graphs. The following phannacokinetic parameters were computed fram the plasma concentration data using the actual sample collection times: Time to maximum concentration; i-’ ,,& Observed maximum concentration; lk: fL% of terminal linear portion of concentration-time Ttn: AUCre,$ AU&i: Hatf-ltfe of metaxalone calculated as: 0.693/K.,; Area under the curve to last quantifiable concentration as measured by the trapezoidal rule; The AUC value cxtrapotated to infinity calculated as: AUCca = AUCN) + C(t)last/K.r where C(t)last IS the last measurable concentration.

Natural logarithmic (in) transformations were computed for AUCcIUo. AUC(,r, and C, and were employed for the statistical analysis. An analysis of variance (ANOVA) was performed on each of the following pharmacokmetic pammeters using SASe software: non-transformed T,, C ,,,=, k.,, Tto, AUCfmr, and Al&q; and In-transformed AU&,,), AU&Q. and C&. ANOVA models included factors for age, subjects within age, treatment, and the treatment-by-age interaction were utilired in comparing the age, treatment and age-by-treatment effects. Effects were declared statistically significant at the 6% level of significance. The lower limit of quantitation for metaxalone was 10 nglmL. For statistical enalysii. subject sample values below the lower limit of quantitation (BLQ) were reported as zero. Figure 11.1 .l illustmtes the mean plasma concentration curves by treatment and age from time 0 to 48 hours after dosing on a linear stale.

Page 26

04/l b103

ELAN-K-06-006064

Elan Pha~uceut~cals. Inc. Skelaxr? (metaxalone)

Protocol No ELN151607.105

Figura 1 j.1 .l : Mean Plasma Concentration (0 - 48 hours)

The mean plasma concentration curves appear to be somewhat different between young and elderly subjects and between fed and fasted conditions in each of the two age groups. However, the differences do not appear to be substantial. Tables 11.1 .l - 11 .t .3 present descriptive statistics (arithmetic mean and coefkient of vanation) by age and treatment groups for AIJC~rurl~AUC<an, and Cmu, respectively. Figures 11 .1.2 - 11.1.4 display the arithmetic mean plus or menus the standard deviation by age and treatment groups for AUC(@,,,,.AUCcing, and C,, respediely.

Page 27

M/16/03

ELAN-K-06-000065

-

Elan Phafn%%wtm!S, Skcluin* (mataxalone)

Inc.

Protocol Ho. ELN151607-105

Table 11.1 .l: Mean and Coefficient of Variation for AU&,,, .(ng-hr/mL) Skeiaxin’ (metaxalone) when Administered Wtth and Wrthoui Food Administered With Food 2W2.38 n$hr/mL (37.33%) 24340.43 ng-hrfmL Elderly Subjem (46.01%) (N=23) Da@ source: Appendix 16.255 - 16.2.5.8 AdminIstered Wnhou! Food 19836.24 ng-hrtml (39.52%) 23797.04 ng-hr/mL (44.64%)

Figure ll.lJ1: Mean +I- Standard Deviation by Age Group and Treatment Group for AUCwI,

O! f%d

F&

Based on Tabk 11.1.1 and Figure 11.1.2, there appears to be a slight age effect since the mean AUCtluo values are slightly greater for the elderiy subjects when compared to the young subjects for either treatment There appears to be at most a small treatment effect given the amount of change in the mean AUCms values between fed to fasting treatments for either age group.

Page 20

04HWOJ EL/WK-06.000066

Elan Phannaceut~olr. Inc. Skalrx!n* (meuxalone)

Proto& No. El.N151607-105

Table 11.1.2: Mean and Coefficient of Variation for AUCn,o (ng-hr/mL) Sketaxin’ (mctaxalone) when Administered With and WIthout Food

Dsta Sourea:Appandu 16.2.5.5- 16.2.5.6 Figure 11.1.3: Mean +I- Standard Deviation by Age Group and Treatment Group for AUC,,0

Based on Table 11.1.2 and Figure 11.7.3 there appears to be a slight age effect since the mean AUCm values are slightly greater for the elderiy subjects when compared to the young subjects for either treatment. There appears to be at most a small treatment effect given the amount of change in the mean AU&) values from fed to fasting treatments for either age group.

Page 29

rwl6/03 ELAN-K-06-000067

Elan PharmecWiu)z, Inc. Skrlaxin’ (rnetaxalone)

Proto& No ELM 51607-i 05

r

Table 11.1.3: Mean and Coefficient of Variation for C, (nglml) Bkelaxine (metaxalont) when Administered Wtth and Wtthout Food

I

Administered W&h Food
2915.27 rtgiml

Admintstcred WIthout Food 2719.02 ng/mL (45.51%) 3167.89 nglml (42.46%)

/

(54.60%) 3680.21 nglmL (58.74%)

I

I

Elderly Subjects (N=23)

Dau Source: Appendix 16.2.5.5 - fILZ6.8

Figura 11.1.4: Mean +I- Standard Deviation by Age Group and Treatrrwnt Group for C,

0 Fed

FSt
-4-Ycmg4BwyJ

Based on Table 11 .1.3 and Figure 11-l .4, there appears to be a slight age effect since the mean L vaiues are slightly greater for the elderly subjects when comparad to the young subjects for either treatment. There appears to ba at most a small treatment effect given the amount of change between the mean Crmr vatues for fed and fasting treatments for erther age group.

page 30

iwwo3

ELAN-K-06-000068

Elan Phaffnaceutrals. Inc Skelaxd (metaubne)

Protocol No ELNlSlSOf-105

Table 11.1.4 summarizes the statistical resutts for age, treatment, and interaction (age-by-treatment) effects for AUCM,~~, AUCr,a. and Cmu. There were no statistically significant age, treatment, or age-by-treatment interaction effects detected for any of the in-transformed pharmacokinetic p;wameters. Table 11 .1.4: Summary of Statistical Resufts

Diitl Souse: Apprndu 162.5, pp. 349 - 351

Table 11 .1.5 presents the median and range for T,, treatment groups.

by age and

Table 11.1.5: Median and Range for T- (fir) Skeiaxin’ (metaxalone) when Administered Wfih and W&hour Food Administered With Food Young SubJea (N=Zl) 6.00 hr (2.00 hr to 24.00 hr) 1 Administered Wnhoui Food 2.53 hr (1 .OOhr to 5.00 hr) 2.50 kr (I.00 hr to 4.53 hr)

Etderly Subjects 6.00 hr (N=23) (2.50 hr to 24.00 hr) %a Same: A@prndtx 16.2.5.5- 16.2.6.6

Appendix 162.5 contains the plasma concentration levels and pharmacokinetic parameters by age and treatment The overlay graphs as well as the individual graphs are also inuluded. 12. SAFETY EVALUATION l;!. 1 Extent of Exposure The drug product received from Elan Pharmaceuticals, fo8lows: Inc. was as

Page 31

WH6m

ELAN-K-06-000069

Ekn Phwmaceuticals. Inc. Skelum* (~metsxalone)

Protocol No ELN151607.105

Skelgxir? 400 mg Tablets - 1 Bottle of 499 tablets by Mallinckrodt Hobart; Lot No. 3485114; Exp. Date: 31-Jan-05 All subjects received the study product (Skelaxine 400 mg tablet) adminrstered with and without food, dependent on randomizatron scheme, 12.2 Adverse Events Brief Summary of Adverse Events

12.2.1

During the study, adverse events were mild in severity and no serious or severe adverse events were reported. A total of 54 adverse events were reported by 25 of 48 subjects enrolled. Thirty-one of the adverse events reported were considered related to the study drug. The most frerquently reported adverse event was headache (Tables 14.l ,I. 1 74.1.1.4) 12.2.2 Display of Adverse Events Adverse events are listed in tables by age group and treatment group InTables 14.1.1.1 - 14.1.1.4. ‘ 12.2.3 Analysis of Adverse Events Of the 84 reported adverse events, 31 were considered related to study medication. In the opinion of the investigators, the other 23 adverse events were unrelated to study medication. None of the adverse events were considered sonous. 12.2.4 Listing of Adverse Events by Subject

All advene events are listed in Appendix 182.6. 12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events No deaths, other serious adverse events, or other signiftcant adverse events ocouned. 12.4 Clinical Laboratory Evaluation 12.4.1 Evaluation of Each Laboratory Parameter Refer to Appendix 18.2.7.1 - 182.78 for indivrdual laboratory Mngs for the following tests: Hematology, Chemistry, Urinalysis,

Page 32

Wl6103

ELAN-K-06-000070

Ehn PhamccubcPb. WIG. Skelaxm* (meWWons)

Protocal NO. ELNt5360?-305

Drugs of Abuse, HEP B&C and Pregnancy Screens. There were no ciinicatfy significant changes in the*clinical laboratory parameters over the course of the study. Due to the sensitMy associated with HtV tests, MDSPS prafen to keep results as secure as passibte as it is not part of normal operations to release the results. unless requested by the client. 12.5 Mal Signs, Physical findings, ECG, and Other Observations Related to Safety

No changes were noted from the screening to the post-study physical examinations that were considered clinically significant by the Medical Investigator. No clinically significant changes ware noted from the screening to the post-study electrocardiogram. The blood pressure and heart rate vaiues reporied over the course of the study were considered ‘ normal’ for a group of healthy subjects. (Appendix 16.4) 12.6 Safety Conclusions

The clinical portion of the project was COmpltted without any significant sequdae attributable to the invastigationai drug. In general, aft blood sample collections were successfully completed as per protocol design.

Page 33

cut16103 ELAN-K-06-000071

Etan Pherrnaceuticals. Inc. Skelaxd (metPxrlon8)

Protocol No ELN151607.105

13.

DISCUSSION AND OVERALL

CONCLUS!ONS

Ase Effect Efderlv subjects had slightly higher values for AUGW, AUC~,~, and C,,,,, when-corndared to the ialies for young subjects. These diffeiences were not found to be statistically significant. Food Effect In the onsence of food, the C,. AUC&~, and AIJCM were increased in ~. buth a$e groups, atthough th&& differences did not leach statistical siQnificance. Safety Fifty-four adverse events were reported by 25 subjects enrolled in this study. Thirtyone were considered to be drug reiated (57.4%). The most common dnig-related adverse event reported was headache (10 reports, 32.3%). The most adverse events were reported by elderly fed subjects (19 reports, 35.2%). All adverse events, however. were considered to be mild in nature. Further the investigator concluded that Sketaxtn” is safe and well.tolerated. Conclusions
l

Age had no significant effect on any pharmacokinetic measured, Skeiaxin” was safe and welf tolerated by the subjects.

parameter

l

Page 24

WlWO3

ELAN-K-06-000072

Elan PhrtmaceubcaIr. Inc. Skcluona (mstaxalana)

Proiocol No ELN151607.105

14.

TAELES, FIGURES, AND GRAPHS REFERRED TO BUT NOT lNCLUDED IN THE TEXT 14.1 Safety Data Summary Figures and Tables 14.1 .l Displays of Adverse Events

Table 1.4.1.1.1: Adverse Events (Count, Percent of Subjects, and Subject Identification) for Young Subjects under Fed Conditions (Nr21) Mild Moderate SWUO TOW
Even! RoWed’ NR’
TOtSI

Releted-

NR-

Related-

NR”

Refrtad’ NR1J

-1

2

2
1

4
I

‘ Rek~ted to Study Drug (Likely, Pmbably, or Paswbty) -Not Related to Study Drug (Unlikely or Unrelated) (oh) Denotes me parcentof !oIal sub)ects withIn age-by-treatment group WxRefers to the sub~ecl study number Data Source. Appendix 16.2.6.1

Page 35

04/1M)3

ELAN-K-06-000073
___

Elan Pharwcaubcsh, Skelaxin= (Wtaxalon)

inc.

Protocol No ELNl51607.106

T&h 14.1.1.2: Adverse Events (Count, Percent of Subjects, and Subject Identification) for Elderly Subjects under Fed Conditions (N=23) Mcdcmte Mild Severe ‘ TOW Event Total
NRRelelec? NRRelatad’ NRRdoted’ NR-

2
1

2 1

l Relaecl to study Dfug (Likely. Probably. or potslbty) “Not Rata&U to Study Dntg (Unlikely br Unrelattdj (%) Danotea tha perccnl of total rubjacts wlhn age-by-treatment group. #Refers to thr subject stu6y number Data Source Appends 16.2.6.1

Page 36

04I16/03

ELAN-K-06-000074

-

Elan Phamwceutwb. inc. SkeWin* (metamlone)

Protocol No. ELN151607-105

Table 14.1.1.3: Adverse Events (Count, Percent of Subjects,

‘ Releted to Study Drug (Likely, Probably. or PossWy) “Not Related to Study Drug (Unlikely or Unrelated) (X) Denotes the percent of total subjects WCmk, egcbymatment ## Refers to the subject study number Data Source: Appmdtx 16.2.6.1

group

Page 37

M/l 6/03

ELAN-K-06-000075

Elan Ph8rmac~tWs. Inc. Skataxln* (metarrronc)

Protocol No ELN151607-105

fable f4.1.f.4: Adverse Events (Count, Percent of Subjects, and Subject Idcntiication) for EMtrly Subjects under Fasting Conditions (N=23) Modente Total sevcrc MM
Event
R&ted NR” Related’ NR” R4ftd NRReleted’ NR” 1

Total

FItl#K!
Pam . -1 aed Pm . .I ! , ! /

(Il.?%)
41.41 (4.:K) 43

2

2 1

1 r I I 2 I , 1

(6.R) 46,41

2 I

I I I I I ‘ Retateci to Study Dr$ (Llkety. Probabty. or PoasWy) “Not Related to Study Drug (Unlikely or Unrelated) (Ye) Denotes the percent of total subwlthin age-by-treatment group 31 Rcfen to the subject study number
Data Source Appcnatx 16 2.6.1

I

I

14.12

Listings of Deaths, Other Events

Serious

and Significant Adverse

There were no deaths, or other serious an&or significant adverse events in thii study. 14.1.3 Narratives of Deaths. Other Serious and Certain Other Significant Adverse Events

There were no deaths, or other serious and/or certain other

significant adverse events in this study.

Page 38

04/l 6/03

ELAN-K-06-000076 ---

Elan Pharrnacwircrls, inc. Skckxine (metaxebnc)

Protocol NO. ELNlS1607-105

14.1.4 Abnormal Laboratory Values Table 14.1.4.1: Listing of Abnormal Hematology Laboratory Values at Screening by Subject The following hematology laboratory test results were outside the reference range at screening. The results were deemed not clinically significant by the medical investigator, and subject enrollment was allowed r SubJecI L8borMory

t

No. 19 x: 31 31

P1mmeter WBC HCT HGB HCT HGB

Rcfersmce Range

3.2 - 9.8 Thouiu~
43.9 T4.8 45.7 15 3 5.06 10.8 44.1 3X9-43.6% lO.S- 14.6% g/dL 31.9 -43.6% lO.S- 14.6 g/dL 3.5 - 5.05 MUUL tO.S- 14.6 g/dL

:: 36 36 39 39

RBC Et!

RBC HCT HGB HCT 41 HGB 41 41 PM&et count HGB 42 HCT 43 HGB 43 HCT 44 HGB 44 HCT 45 HGB 45 RBC 45 HCT 48 HGB 40 RBC 48 au Source: Appendix 16.2.7.1

5.26
45.5

31.9 -43.6% 3.5 - 5.05 MiUuL
31.9-43.6X

15,2
44.5 15.2 438 15 45.8 15.2 45 1s 45.7 15.3 51 46.3 15.1 5 I5

10.9 - 14.6 gfdL
31 .S - 43.6Oh lO.S- 14.6 gm. 120 - 42s -rhou/uL lO.S- 14.6 g/dL 31.9 - 43.6K 10.9 - 14.6 @dL 31.9 -43.6% lO.S- 14.6 g/dL 31.9-43X% lC.S- 14.6 sJdL 3.5 - 5.05 MiUuL 31.9-43.6% 10 9 - 14 6gIUL 3.5 - 5.05 MlUUL

,.

Page 39

04/16/03

ELAN-K-06-000077

Elan Phatmrcetrttals. Skelaxln* (rrdaxaloae)

Inc.

Pfotoe~i No. ELN151607-105

Table 14.1.4.2: Listing of Abnormal Hematology Laboratory Values During Study Period I by Subject The following Period 1 check-in hematology laboratory test results were outside the reference range and deemed not clinically significant by the medical investigator.
Laboratory Ptt@KUWV NO. VVBC 22 WEC 29 HGB 33 HOE 39 HCT 41 HGE 41 Platelet Count 41 HCT 42 tiGB 42 WC 42 HCT 43 HG8 43 HGB 45 WCT 40 HGB 48 RBC 46 Oata Source. Appendix 16.2.7.1

subfeit

- Labomtofy

Rtsun
10.1 10.4 10.7 14.9 44.2 15 436 63.7 14.7 10.7 44.4 14.9 14.9 46.6 15.6 5.18

Relerenct

Range

3.2 - 9.8 ThouIu~ 3.2 - 9.8 ThouIuL 10.9 - 14.6 g/d1 10.9 - 14.6 gldL 31.9-43.6% 10.9 - 14.6 g/dL 120 - 425 ThouluL 31 9 - 43.m 10.9 - 14.6 g/dL 3.2- 9.8Thou/uL 31.9-43.6% 10.9- 14.6 gidL 10.9 - 14.6 E)/dL 31.9-43.6% 10.9 - 14.6 g/dL 3.5 - 5.05 MIUUL

Table $4.1.4.3: Listing of Abnormal Hematology Laboratory Values During Study Period It by Subject

The following Period II check-in hematology laboratory test results were outside the referencc range and deemed not clinically significant by the medical investigator.
Subject No. 12 :i Labolatory PDIWMW WBC La8oratory Result 10.3 Reference Range 3.2 - 9.8 Thw/uL 437.2 - 50.2% - 5.70 MiUuL

RBC HCT

:i

Page 40

04/l 6/03

ELAN-K-06-000078 ---

Elan Pharmaccut~cals. Inc. Skelaxir? (metaxstone)

Protocol No ELN151607-105

Table 14.1.4.4: Listing of Abnormal Hematology Laboratory Values at Study Exit by Subject The following hematology laboratory test results were outside the reference range at study exit. The results were deemed not clinically significant by the medical investigator, and no repeat measurements were reouested. L8bWptO~ Labomtory Subfl Reference Range
No. 1s :: Pwametrr

13

RBC
RBC WBC Platele! Count HC8 Hc38 HCT

mutt
3.67 3.97 11.1 465 10.6 10.8 47 15.9

ii 45

45 %E 48 HCT [ 48 HGB Data Source: Appendix 16.2.7.1

5.2 44.9
14.9

4 - 5.7 MiUuL 4 - 5.7 MiUuL 3.2 - 9.8 Thou/uL I20 - 42!iThou/uL 10.9 - 14.6 g/d1 10.9 - 14.6 gldL 31.9 -43.6% 10.9 - 14.6 g/dL 3.5 - S.OJ MiVuL 31.9 - 43.6% 10.9 - 14.6 g/dL

Table 14.1.4.5: Listing of Abnormal Chemistry Laboratory Values at Screening by Subjuct The following screening clinical chemistry laboratory test results were outside the reference range and deemed not clinically signitkant by the medical investigator. Subject enrollment was allowed.
Subject No. 1 : 4 3 I2 :: 15 19 LIboralOfy Psritmetcr Uric Aad Uric Acid fiT=m Crertinino Total Bilirubrn Potassium Tctal Win&n Total hiirubtn UrU LD (LDH) Uraa ToWi Pmtein Total Protcm Ltboratory Result 6 85 9 1.3 5.5 1.3 1.3 1.2 24 226 2 Reference Range 27-7.8mg/dL 2.7 - 7.8 mg/dL ll-46WL 0.6 - 1.2 mgidL 0.1 - - 1.1 mEiaA 33 5 mgldL 0.1-1.1 mg/dL

6 - 20 mgldL
116 - 213 U/L 0.1~ 1 1 mg/dC 8-2OrWdL 116-ntjun S-2OmgldL 6.3 - 8 g/dL

20
24

8.3

6,3 - 6 gldL

J

Page 4 1

M/16/03

EL/W-K-06-000079 -_

Elan Phwmacouttulr. Inc. Skcbxcn* (metaxalonc)

Protocol No. ELNl51607-105

Table 14.1.4.5: Listing of Abnormal Chemistry Laboratory Vaiues a! Screening by Subject (conf’ d)
SUbpCl No. 36 36

Labamtoly
RGMJtl 10.4 8.5

Reference

Range

8 d- 10.3 mg/dL
6.3 - 8 aldL

Table 14.1.4.6: listing of Abnormal Chemistry laboratory Values During Study Period I by Subject The following Period I check-in dinical chemistry laboratory test results were outside the reference range and deemed not clinically significant bv the medical investioator. .

r 3ueJea
No. 1 1 1 5 3 4 4 6 3 12 12 12 14 16 ?(I f7 I7 17 16 16 19 :i 20 22 24 27

Laboratory

Laboratory
RGSUlt

PInmeter
Creatinm Phc$hwnur Total Protiwn umr Phosphomur YncAad Crertinint Totat Protein Urns potrrsium Phosphorous PhQsphorour Total Bilmtbtn Totrt Protein lb4 Cre8tinlne uma Cmrtintne LO (LDH) Um8 Total Protam Uru Nbumm Tow Prwein U))$) LO (LDH) LO ILDH)

Reference

Range

14

i:: 21
4.7 8.0 ;a 23 5.1 5

5
1.7 8.2

22
1.3 27

21 81 23 ii.: 219 2% 214 83

i

0.6-12WdL 2 3 - 4.6 rn+i 6.3 - 8.0 g/dL a-2OmgdL 2.3 - 4.6 m#dL 2.7 - 7.8 m@dL 0.6 - 1.2 n?$dL 6.3 - 6.0 g/d1 8-2OmgfdL 3.8 - 5 0 n-iE@L 2.3 -4.6 fng/dL 2.3 - 4.6 mgldL 0.1 - 1.1 mg/dL 6 3 - 8.0 gldt S-ZOmg/dL 0.6 - 1.2 mg/dL 8-2Or@dL 0.6 - 1.2 mg/dL 116-213UIL 8 - 20 mpldL 6.3 - 8.0 g/dL 8 - 20 mg/dL 3.9 - 5.2 gldL 6.3 - 8.0 g/dL 116 - 213 U/L 8 - 20 mgdC 116-213Wt. 116-213UtL 6.3 - a.0gldi

Page 42

04/16m3

ELAN-K-06-000080

Elan Phwrnaceubalt, Skelrxmn* (mem*PlOne)

Inc

Protocol No. ELN15f607-f05

Table 14.1,4.6: Listing of Abnom?af Chemistry Laboratorv Values During Study Period I by Subject Icont’ d) .
Subject No. 28 l.abontoty Parameter Total Protcm Potarstum Urea l.&omrofy Retult 8.4 Reference Range 6.3 - 8.0 o/dL 3.8 - 5.0 niEe 8 - 20 mgkk 2.7 - - 7.6 n’ 6.3 8.0 g/dL tg/dL 2.7 - 7.8 mg/UL 0.6 - 1.2 mg/dL 2.7..7.UmgtdL 23-M6.3 -- 8.0 U/L 116 213 gldL 3.0 - 5.0 m&5 116-213UIL 6 - 20 rng/dL 2.3 - 4.6 mg/dL 96 - 101 m E @ 6.3 - 8.0 gldL 6.3-8.0 g/dL 8 - 20 mg/dL 8-2OmgIdL

50
31 :: 33 34

Total Pnxekn Uric Aad
UnCAEld Cmebntnc Ufkkid cwbon Dioxlee Total (LDH) LO Protein

z :: 37

Potauwm LD KDH) 3: WeI9 Phosphorous 40 Chloride 42 44 Total Protein Tot& Protem 46 Urea 46 Urea 47 Data 6ource: Appends 16.2.7.2

Table 14.1.4.7: Listing of Abnormal Chemistry Laboratory Values During Study Period 11by Subjecl The foltewing Period II check-in clinical chemistry laboratorytest results were outside the reference range and deemed not clinically significant by the medical investigator.
Subpit .No 4 :: to 19 :o" 24 27 Labomtory Parameter

Cmstuxnc
Magneatum Croatinine CmMnine I.0 (LDH) LO (LDH) Magneswm

Laboratory Result 14

Reference

Range

Nbumin AST G-l

1.3 1.4 245 221 17 5: 76 4.7 4.8 237 215 3.7 22

::6’ 55

Al.1 (OPT)
:: A61 (GOT) GGT 29 Magnesium 33 Phosphorous 36 37 LO (LDH) 43 LD (LOH) 44 00tassrum 47 C&on Dloxlee Data Source: Appcndlx 16.2.7.2

0.6 - 1.2 rr~/dL i a - 2 7m$dL 3.9 - 5.2 gML 71-46 UIL 0.6 - 1.2 mgldL 0.6 - 1.2 m@dL 116-213UIL 116 - 213 U/L 1 .B - t.?mgIdL 0 - 50 U/L 11-46 un 0 - 59 U/L 1.6 - 2.7mgldL 2.3 - 4 6 mg/dL 116-213UR 116 - 213 ‘ J/L 38-SmEalL 23 - 34 mmOl5

Page 43

04lY6lO3

ELAN-K-06-000081 - -- -

Proloool No. ELNlSt607-105

table 14.1 .II: Listing of Abnormal Chemistry Laboratory Values at Study Bit by Subject The following exit clinical chemistry laboratory test results were outside the reference range and deemed not clinically significant by the medical investigator. No repeat measurements were requested. smReference Range . . “R”“, bktz2 No.
3 4 7 7 12 12 16 19 19 19 20 20 :: :: :i :: 34 iti 37 41 TZEn Total Protein Tot8l Protein Tot& Proten Aibumm UdCW TOW Protem LD fl.DH) AU (Got, Amumin ‘ 10

Total Protein
war
Total Eihbin

2

Total Pmteln
l.h* Albumtn

‘ 11-46UlL 3.9 - 6.2 g&L 6.3 - 8.0 DldL 6 - 20 m$dL 0.1 - 1.1 mg/dL 6.3 - 8.0 g/r&

8 - 20 mgldL
3.9 - 5.2 O/dL 0 - 50 UIL S-2Owdl 116-213 UfL 8 - 20 mgldL 2.3 - 4.6 W~L 6.3 - 8.0 gldl. lf6-213UIL 3.8 - 5.0 m&q/l. 6.3 - 6.0 gldL 6.3 - 13.0 g/dL 6.3 - 8.0 gldL 6.3-8.Og/dL 3.9 - 5.2 @dL 2.7 - 7.8 mg/dL 6.3 - 8.0 g/dL 116-213WL 3.9 - 6.2 a/dL 6.3 - 8.0 $/dL 8 - 20 m&IL

ALT [OPT) urea LD$-y’
Ptmsphofous
TOW Pfuwirl LO (LDH)

5.1 xi
6.1 8.5 3.6 2.2 ;i: 3.7 6.2 22

Albumin

t

Total Prutem 46 UNa .-_-_ Dao source: Appwwx 16.2.72

44

The HIV antibody and hepatitis 6 surface antigen screen, and hepatitis C antibody were non-reactive and negative, respectively, for all subjects. The screening, Period 1 and Period 11check-in, and exit urinalysis values were unremarkable. The pregnancy screen at the screening visit Period I and Period II check-in, and study exit was negative for all female subjects. The drug abuse screen at the screenrng visit, Period I and Period II check-in was negative for all subjects

Page 4d

W/16/rJ3

ELAN-K-06-000682

Elan Phamuceulmls. Skrlrxm* (wUlone)

Inc.

Protocol No ELN151607.105

There were no clinically significant changes in the clinical laboratory measurements over the course of the study. which could be with reasonabty associated the foimuiations under invdstigation. All clinical laboratory values were reviewed by the medical investigator and follow-up completed as requested.

Page 45

ou15/03

ELAN-K-06-000083

Elan Pharmacmutliql8. Inc. Skcl8xin’ (mmtwmlonm) 15. 1 REFERENCE LIST

Protocol NO. ELN151607-10s

Department of Heatth and Human Services, FDA. ICH. Good Clinicrl Practica: Consolideted Guideline. May 9, 1997. Federal Register, Vol. 62, No 90,25892-25709. EMEA No& for Guidance on Goad Clinical Practice (ICH Topic E6, Step 5). January ??, 1997. Monagraphs from Physician’ Desk Reference. Medical Economics s Company: Mot-vale, NJ, 2001. Elenbaas JK. Centralty acting oral skeletal muscle relaxants. Am J Hosp Phann 1900;37:1313-23. Mauri JL et al. Physical Exenise and improvement of liver oxidate metabolism in the eiderty. Eur J Appl Physiol2000 Jan;8 1(l-2):62-6. Willmore LJ. Choice and use of newer anticonvulsant drugs in older patientsDrugs Agin 2090 Dec:17(6):441-52. WItmore LJ. Antiepileptic drug therapy in the olderly. Pharmacol Ther 1998 Apn76(7):9-16. Bemus I et al. Anticonvulsant therapy in aged patients. Clinical pharmacokinetic considerations. Drugs Aging 1997 Apr;10(4):278-69.

2 3 4 5 6 7 8

Page 46

M/16103

ELAN-K-06-000084

Elan Pharmacbubmls, Inc. Skelad (nnetaxalone)

Pmtocol No. ELNtSlbOl-705

16.

APPENDJCES - TAILE 16.1 Study Information

OF CONTENTS

16.1.1 16.1.2 16.1.3 16.1.4 16.7.5 16.1.6 16.1.7 16.1.6 16.1.9 16.t.10

Protocol and Protocol Amendments Sample Case Report Form lnstituttonal Review Board and Representative Informed Consent Documents List of Investigators Signature of Principal Investigator Randomization Scheme Cartlflc8te of Analysis Documentation of Statistical Methods Documentation of Inter-Laboratory Standardization Methods and Procedures Publicatiins Based on the Study

16.1 .l 1 Important Publications Referenced in Report 16.:2 Subject Data Listings 16.2.1 16.22 16.2.3 16.2.4 Discontinued Subjects Protocol Deviations Subjects Exduded from the Pharmacokinetic Analysis Demographic data Data

,16.2.5 Phsma Concentration Data and Pharmacoklnetic 16.2.6 16.2.7 lndiviiusl Adverse Event Listings Listing of Individual Laboratory Measurements

Page 47

04ll&a3

ELAN-K-06-000085

Elan PhwnmcmutiQb. InC. Skelaxin” (metaxalone)

Prolad

NO. kLNl61607-103

I 6.x Case Report Form 15.3.1 case Report Forms (for deaths, other serious adverse events, and withdraw&s due to adverse events) 16.3.2 Other Case Report Forms 16.4 individual Subject Data Listings

.

Page 48

04/l 6m3

ELAN-K.06-000086