2.7.4. summary of clinical safety - 独立行政法人 ... Summary of Clinical Safety 2 TABLE OF...

CONFIDENTIAL GM2003/00048/002.7.4 Summary of Clinical Safety

1

Module 2.7.4

Summary of Clinical Safety

Copyright 2003 the GlaxoSmithKline group of companies. All rights reserved.Unauthorized copying or use of this information is prohibited.


2

TABLE OF CONTENTS

PAGE

1. EXPOSURE TO THE DRUG ....................................................................................61.1. Overall Safety Evaluation Plan and Narratives of Safety Studies ..................6

1.1.1. Data Cut-Off Dates.........................................................................81.1.2. Clinical Studies: Description of Studies and Populations................8

1.1.2.1. Description of studies ...................................................81.1.2.1.1. Pivotal study CNA30021 ...........................81.1.2.1.2. Ongoing GSK-sponsored studies..............81.1.2.1.3. Other studies ............................................9

1.1.2.2. Populations for analysis ................................................91.2. Overall Extent of Exposure..........................................................................10

1.2.1. Pivotal Study CNA30021..............................................................121.2.2. Ongoing GSK-Sponsored and GSK-Supported Studies ...............121.2.3. Post-Marketing Experience ..........................................................12

1.3. Demographic and Other Characteristics of Study Population ......................131.3.1. Pivotal Study CNA30021..............................................................131.3.2. Other Studies ...............................................................................15

1.4. Subject Accountability .................................................................................151.4.1. Pivotal Study CNA30021..............................................................15

2. ADVERSE EVENTS ...............................................................................................162.1. Analysis of Adverse Events.........................................................................16

2.1.1. Common Adverse Events.............................................................172.1.1.1. All adverse events ......................................................17

2.1.1.1.1. Pivotal study CNA30021 .........................172.1.1.2. Drug-related adverse events.......................................18

2.1.1.2.1. Pivotal study CNA30021 .........................182.1.2. Deaths .........................................................................................20

2.1.2.1. Pivotal study CNA30021 .............................................202.1.2.2. Ongoing GSK-sponsored studies................................202.1.2.3. Other studies ..............................................................20

2.1.3. Other Serious Adverse Events .....................................................212.1.3.1. Pivotal study CNA30021 .............................................212.1.3.2. Ongoing GSK-sponsored studies................................212.1.3.3. Other studies ..............................................................22

2.1.4. Other Significant Adverse Events.................................................222.1.4.1. Severe/Grade 3 to 4 adverse events...........................22

2.1.4.1.1. Pivotal study CNA30021 .........................222.1.4.2. Adverse events leading to permanent

treatment discontinuation............................................232.1.4.2.1. Pivotal study CNA30021 .........................23

2.1.4.3. Pregnancies................................................................242.1.4.3.1. Pivotal study CNA30021 .........................24

2.1.5. Analysis of Adverse Events by Organ System orSyndrome ....................................................................................252.1.5.1. Abacavir hypersensitivity reactions reported in

CNA30021 ..................................................................262.1.5.2. Ongoing GSK-sponsored studies................................31


3

2.1.5.3. Other studies ..............................................................322.1.5.4. Signs and symptoms of abacavir HSR in post-

marketing experience .................................................322.1.5.5. Hypersensitivity risk management ..............................32

2.2. Narratives ...................................................................................................32

3. CLINICAL LABORATORY EVALUATIONS ............................................................323.1. Laboratory Data Collection and Analysis.....................................................32

3.1.1. Pivotal Study CNA30021..............................................................333.2. Laboratory Values Over Time .....................................................................33

3.2.1. Pivotal Study CNA30021 - Use of ABC once dailycompared with twice daily in combination with 3TC andEFV once daily in treatment-naïve HIV-1 infected adults..............33

3.3. Grade 3 to 4 Treatment-Emergent Laboratory Abnormalities ......................333.3.1. Pivotal Study CNA30021 - Use of ABC once daily

compared with twice daily in combination with 3TC andEFV once daily in treatment-naïve HIV-1 infected adults..............33

4. VITAL SIGNS, PHYSICAL FINDINGS, AND OTHER OBSERVATIONSRELATED TO SAFETY ..........................................................................................34

5. SAFETY IN SPECIAL GROUPS AND SITUATIONS ..............................................355.1. Intrinsic Factors...........................................................................................35

5.1.1. Gender Subgroup Analysis of Grade 3 to 4 AEs andLaboratory Abnormalities in Pivotal Study CNA30021..................35

5.1.2. Race Subgroup Analysis of Grade 3 to 4 AEs andLaboratory Abnormalities in Pivotal Study CNA30021..................35

5.2. Extrinsic Factors .........................................................................................355.3. Drug Interactions.........................................................................................365.4. Use in Pregnancy and Lactation..................................................................375.5. Overdose ....................................................................................................395.6. Drug Abuse.................................................................................................405.7. Withdrawal and Rebound............................................................................405.8. Effects on Ability to Drive or Operate Machinery or Impairment of

Mental Ability...............................................................................................40

6. POST-MARKETING DATA.....................................................................................40

7. APPENDIX .............................................................................................................42


4

Abbreviations

3TC Lamivudine (EPIVIR�)ABC Abacavir (ZIAGEN�)ABC/3TC FDC Abacavir/lamivudine fixed dose combinationACTG AIDS Clinical Trials GroupAE Adverse event (experience)AIDS Acquired Immunodeficiency SyndromeALT Alanine aminotransferase (SGPT)APGAR Newborn score of Appearance, Pulse, Grimace, Activity,

RespirationAPV Amprenavir (AGENERASE�)ART Antiretroviral therapyAST Aspartate aminotransferase (SGOT)AUC0-∞ Area under the drug-concentration-time curve from time 0 and

extrapolated to infinityAUC0-τ, ss Area under the drug-concentration-time curve from 0 to time t at

steady stateBID Twice daily dosing (Bis In Die)Cmax Maximum concentration of drug in the body at time, tmaxCmax, ss Maximum concentration of drug in the body at time, tmax, at steady

stateCBV-TP Carbovir triphosphateCD4+ Helper-inducer T-lymphocyte surface antigenCDC Centers for Disease Control and PreventionCPK Creatinine phosphokinaseCRF Case report formCSR Clinical study reportDNA Deoxyribonucleic acidEDD Estimated delivery dateEFV Efavirenz (Sustiva� or Stocrin�)GCSP Global Clinical Safety and PharmacovigilanceGI GastrointestinalGSK GlaxoSmithKlineHIV-1 Human Immunodeficiency Virus Type 1HSR Hypersensitivity reactionITT Intent-to-TreatKS Kaposi's sarcomaLFT Liver Function TestMedDRA Medical Dictionary for Regulatory ActivitiesNDA New Drug ApplicationNNRTI Non-nucleoside reverse transcriptase inhibitorNOS Not otherwise specifiedNRTI Nucleoside reverse transcriptase inhibitorOAD Once dailyOCEANS Operating Companies Event Accession & Notification System

(GlaxoSmithKline safety surveillance database)PCR Polymerase chain reaction


5

PI Protease inhibitorRNA Ribonucleic acidSAE Serious adverse event (experience)SIDS Sudden infant death syndromeTDF Tenofovir disoproxil fumarate (Viread�)Tmax Time of maximum plasma concentrationZDV Zidovudine (RETROVIR�)


6

1. EXPOSURE TO THE DRUG

1.1. Overall Safety Evaluation Plan and Narratives of SafetyStudies

The aim of treatment for human immunodeficiency virus type 1 (HIV-1) disease is toextend both length and quality of life. As eradication of HIV is not currently feasible,preventing disease progression while maintaining quality of life is best achieved by welltolerated, compact regimens which minimize viral replication.

A high rate of adherence to antiretroviral therapy (ART) is recognized as an importantpredictor of treatment success and poor adherence is one of the primary reasons fortherapy failure. Lower levels of adherence have been associated with the development ofdrug resistance, increased likelihood of virologic failure, and increased morbidity andmortality [Paterson, 2000; Carmona, 2000; Walsh, 2000]. There is evidence thatsimplified regimens with reduced pill numbers and dose frequencies improve adherence[Bartlett, 2001; Vibhagool, 2001].

Towards the goal of simplifying therapy, GlaxoSmithKline (GSK) undertook a clinicaldevelopment program with the aim of combining two antiretrovirals with establishedsafety and efficacy, abacavir sulfate (abacavir, ABC, ZIAGEN�) and lamivudine (3TC,EPIVIR�) in a single product to be administered once daily. GSK have also conductedstudies that provided positive supportive data for the use of ABC and 3TC as anucleoside reverse transcriptase inhibitor (NRTI) backbone in combination therapy.

Data in this submission support the use of ABC dosed once daily. A clinicalpharmacology study (CNA10905) was conducted to investigate the intracellular half-lifeof carbovir triphosphate (CBV-TP), the active moiety of ABC. Pivotal trial CNA30021provides safety, efficacy, and durability data to support both once daily dosing of ABCand the use of ABC plus 3TC as a NRTI backbone for combination therapy regimens.Results of the pivotal bioequivalence study, CAL10001, support use of the newcombination tablet. Safety data from studies CAL10001 and CNA10905 are found inModule 2 [m2, Section 2.7.1 and Section 2.7.2, respectively].

In this Summary of Clinical Safety, data demonstrating the safety of ABC + 3TC, insubjects with HIV-1 infection are provided from the pivotal study, CNA30021, arandomized, double-blind clinical study in ART-naïve HIV-1 infected adults. This studywas designed to evaluate the antiviral efficacy and safety profile of ABC 600mg oncedaily versus ABC 300mg twice daily as a component of triple therapy. The safety profile

� ZIAGEN is a Trade Mark of the GlaxoSmithKline group of companies.

Registered in US Patent and Trademark Office.

� EPIVIR is a Trade Mark of the GlaxoSmithKline group of companies.Registered in US Patent and Trademark Office.


7

of the registered once daily regimen for 3TC has already been well characterized throughclinical trials and post-marketing surveillance.

The key safety concern with ABC is the hypersensitivity reaction (HSR). This event is awell described syndrome labeled for all ABC-containing products which, althoughpotentially life-threatening, is well managed in practice largely as a result of GSKeducational programs. Serious morbidity or mortality is rare. GSK uses a conservativecase definition for ABC HSR and applies this to both post-marketing (spontaneous) andclinical trial adverse event (AE) reports. All AE reports where signs and symptoms areindicative of a possible HSR to ABC are considered HSR cases (and recorded on theGSK adverse events (AE) database as such) unless there are clear alternative causes ofthe AEs (for example, an infection confirmed by laboratory tests). AE reports of possibleHSRs included in safety analyses are therefore comprehensive and result in a degree ofover-reporting.

Safety data with ABC and/or 3TC are also presented for ongoing GSK-sponsored andother ongoing GSK-supported studies, where 600mg ABC was administered once dailyand/or 300mg 3TC was administered once daily. A Tabular Listing of All ClinicalStudies referenced in this submission can be found in Module 5 (m5, Section 5.2) of thisapplication.

Conventions for Reporting Treatment Groups

The conventions for reporting the treatment groups in the pivotal safety study aredescribed in Table 1.

Table 1 Conventions for Reporting Treatment Groups in ABC + 3TC PivotalSafety Trial

Population/Protocol Number

Treatment GroupsAbbreviation

Treatment Received

CNA30021 ABC once daily ABC 600mg OAD + ABC placebo BID +3TC 300mg OAD + EFV 600mg OAD

ABC twice daily ABC 300mg BID + ABC placebo OAD +3TC 300mg OAD + EFV 600mg OAD

Note: ABC=abacavir, BID=twice daily, EFV=efavirenz (Sustiva�, Stocrin*), OAD=once daily, 3TC=lamivudine.

� Sustiva is a Trade Mark of Bristol-Myers Squibb Company.


* Stocrin is a Trade Mark of Merck Company.


8

1.1.1. Data Cut-Off Dates

The cut-off for clinical trial safety data included in this submission is 200 . Forthe ongoing GSK-supported studies, data were collected from 200 through

200 .

1.1.2. Clinical Studies: Description of Studies and Populations

A Tabular Listing of All Clinical Studies using ABC once daily and/or 3TC once dailycan be found in Module 5 (m5, Section 5.2) of this application.

1.1.2.1. Description of studies

1.1.2.1.1. Pivotal study CNA30021

Use of ABC once daily compared with twice daily in combination with 3TC andEFV once daily in treatment-naïve HIV-1 infected adults

CNA30021 was a Phase III, 1:1 randomized, double-blind, international multicenterstudy of ART naïve, HIV-1 infected subjects designed to evaluate the antiviral efficacyand safety profile of ABC 600mg once daily versus ABC 300mg twice daily, as acomponent of triple drug therapy including 3TC 300mg once daily and EFV 600mg oncedaily in ART-naïve HIV-1 infected adults over at least 48 weeks duration. Enrollmentwas stratified by screening plasma HIV-1 RNA to two strata (≤100,000 and >100,000copies/mL).

Subjects were centrally randomized 1:1 to one of the following treatment groups:

• ABC (600mg once daily) + ABC (0mg twice daily) + 3TC (300mg once daily) + EFV(600mg once daily)

• ABC (0mg once daily) + ABC (300mg twice daily) + 3TC (300mg once daily) + EFV(600mg once daily).

1.1.2.1.2. Ongoing GSK-sponsored studies

CAL30001 - Use of ABC/3TC FDC once daily compared with ABC twice daily + 3TConce daily in combination with TDF and a new PI or NNRTI, in treatment-experienced HIV-1 infected adults

CAL30001 is an ongoing, randomized, open-label, parallel group, multicenter study toevaluate treatment with the fixed dose combination (FDC) of ABC/3TC (600mg/300mg)once-daily versus ABC (300mg) twice daily and 3TC (300mg) once daily in combinationwith tenofovir disoproxil fumerate (TDF, Viread�) once daily and a new protease

� Viread is a Trade Mark of the Gilead Sciences.



9

inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) for 48 weeks inART-experienced HIV-1 infected subjects with virologic failure.

ESS30008 � Use of ABC/3TC FDC once daily compared with ABC + 3TC twice dailyas a component of a triple combination regimen in treatment-experienced HIV-1infected adults

ESS30008 is an ongoing, 48-week, open-label, randomized, multicenter study of thesafety and efficacy of the ABC/3TC FDC administered once daily versus ABC + 3TCadministered twice daily in combination with a PI or NNRTI in ART-experiencedsubjects with virologic suppresssion and currently receiving ABC and 3TC as singleentities. Subjects were stratified according to PI or NNRTI use and randomized 1:1 toone of two treatment regimens:

• ABC 300mg twice daily + 3TC 150mg twice daily + baseline PI or NNRTI

• ABC 600mg/3TC 300mg FDC once daily + baseline PI or NNRTI.

ESS30009 - Use of ABC/3TC FDC once daily as a component of a triplecombination regimen in treatment-naïve HIV-1 infected adults

ESS30009 is an ongoing, randomized, open-label, multicenter study of the safety andefficacy of EFV versus TDF when administered in combination with the ABC/3TC FDCtablet as a once daily regimen in ART-naïve HIV-1 infected subjects.

• Eligible subjects were stratified at entry according to screening HIV-1 plasma RNAlevel <100,000 copies/mL and ≥100,000 copies/mL, and randomized 1:1 to receiveone of the following ART regimens for 48 weeks:

• EFV 600mg once daily + ABC 600mg/3TC 300mg FDC once daily

• TDF 300mg once daily + ABC 600mg/3TC 300mg FDC once daily (this treatmentgroup was discontinued after interim analyses due to virologic non-response).

Shortly after initiation of this study, GSK received reports from investigators of poorvirologic response in subjects receiving TDF + ABC/3TC. An unplanned interimanalysis was conducted to assess virologic non-response. These results are presented inSection 2.3 of the Summary of Clinical Efficacy, (m2, Section 2.7.3).

1.1.2.1.3. Other studies

Safety data with ABC and/or 3TC are also presented for other ongoing GSK-supportedstudies which were GSK-supported, where 600mg ABC was administered once dailyand/or 300mg 3TC was administered once daily. A Tabular Listing of All ClinicalStudies using ABC once daily and/or 3TC once daily and referenced in this submissioncan be found in Module 5 (m5, Section 5.2) of this application.

1.1.2.2. Populations for analysis

Safety analyses for the pivotal study CNA30021 were performed for the SafetyPopulation, which was the population of subjects who received at least one dose of study


10

medication. Subject accountability was based on the All Randomized SubjectsPopulation, which included all subjects randomized into the study, whether or not theyreceived study treatment. Demography and baseline characteristics were based on theIntent-to-Treat (ITT) - Exposed Population which was defined as all subjects randomizedand exposed to at least one dose of study medication.

1.2. Overall Extent of Exposure

This section summarizes exposure to ABC + 3TC when used in combination in thestudies included in this submission. In addition, there is extensive post-marketingexperience with ZIAGEN twice daily and EPIVIR administered once or twice daily.

A total of 770 subjects received at least one dose of ABC and 3TC; of these, 384 subjectsreceived ABC 600mg once daily and 3TC 300mg once daily.

The number of subjects enrolled and exposed to at least one dose of randomized ABCand/or 3TC as a component of the randomized study drug regimen in the pivotal study issummarized in Table 2.


11

Table 2 Total Number of Subjects in the Pivotal Study

Protocol Number No. Subjectsrandomized

in Study

No. SubjectsExposed to at

Least One Doseof Randomized

ABC OAD


Least OneDose of

Randomized3TC OAD


Least One Doseof Randomized

ABC BID


Least One Dose ofRandomized ABC

and 3TC combined(either OAD or BID)

Pivotal Safety PopulationCNA30021 (ABC OAD, ABC BID, 3TC OAD) 784 384 770 386 770

Source Data: Table 12.3 of CNA30021 Clinical Study Report (CSR)


12

1.2.1. Pivotal Study CNA30021


A total of 784 subjects were randomized to receive ABC once daily (392 subjects) orABC twice daily (392 subjects) during CNA30021. A total of 770 subjects actuallyreceived at least one dose of study medication.

Table 3 summarizes the extent of exposure to study drug for CNA30021 by treatmentgroup.

Table 3 Extent of Exposure to ABC (Safety Population - CNA30021)

ABC OADN=384

ABC BIDN=386

Total Days on Treatment Median 372 367 Range 1-585 1-581Length of Exposure - n(%) <8 weeks 57 (15%) 49 (13%) >8 to ≤16 weeks 13 (3%) 13 (3%) >16 to ≤24 weeks 6 (2%) 5 (1%) >24 to 48 weeks 39 (10%) 51 (13%) >48 weeks 269 (70%) 268 (69%)Source Data: Table 14.1 of CNA30021 CSR

The length of exposure to study treatment was similar between each study group. A totalof 269 (70%) subjects in the ABC once daily group and 268 (69%) subjects in the ABCtwice daily group had greater than 48 weeks of exposure to the full dose of randomizedstudy drug (ABC).

1.2.2. Ongoing GSK-Sponsored and GSK-Supported Studies

The Listing of All Clinical Studies in Module 5 (m5, Section 5.2) provides the overallextent of exposure (length of study) for the other studies.

1.2.3. Post-Marketing Experience

No information is available on the ABC/3TC fixed dose combination (FDC) tablet, as theproduct is currently not marketed.


13

1.3. Demographic and Other Characteristics of Study Population



Key baseline and demographic characteristics for the ITT-Exposed Population arepresented in Table 4.


14

Table 4 Key Baseline and Demographic Characteristics (ITT-ExposedPopulation � CNA30021)

CharacteristicABC OAD

N=384ABC BID

N=386TOTALN=770

Age in Years, median (min,max) 36 (18, 71) 36 (18, 71) 36 (18, 71)Gender, n (%)

MaleFemale

32361

(84%)(16%)

30482

(79%)(21%)

627143

(81%)(19%)

Race, n (%)WhiteBlackAmerican HispanicAsianOther

207996010

8

(54%)(26%)(16%)(3%)(2%)

207111

5585

(54%)(29%)(14%)(2%)(1%)

414210115

1813

(54%)(27%)(15%)(2%)(2%)

Randomization Strata, n (%)HIV-1 RNA≤100,000 copies/mLHIV-1 RNA>100,000 copies/mL

217167

(57%)(43%)

217169

(56%)(44%)

434336

(56%)(44%)

Baseline Values, median (range)HIV-1 RNA PCR (log10 copies/mL)HIV-1 RNA PCR (copies/mL)(range)CD4+ cell count (cells/mm3 )CD8+ cell count (cells/mm3 )

4.91 (3.05-6.99)81,684

(1,127-9,872,576)264 (21-918)

787 (140-4741)

4.87 (2.60-6.59)74,894

(399-3,893,696)259 (37-886)

771 (95-2568)

4.89 (2.60-6.99)78,521

(399-9,872,576)262 (21-918)

779 (95-4741)Confirmed Hepatitis, n (%)

Hepatitis B surface antigenHepatitis C antibodyHepatitis B and C co-infected

1855

2

(5%)(14%)(<1%)

1647

1

(4%)(12%)(<1%)

34102

3

(4%)(13%)(<1%)

CDC Classification of HIV, n (%)Class A � asymptomaticClass B � symptomatic, no AIDSClass C � AIDSMissing

2986323

0

(78%)(16%)(6%)

2857030

1

(74%)(18%)(8%)(<1%)

583133

531

(76%)(17%)(7%)(<1%)

Other non � CDC HIV-1 AssociatedCondition, n (%)

Yes 9 (2%) 21 (5%) 30 (4%)Data Source Tables 12.9, Table 12.10, Table 12.12, Table 12.13, and Table 12.14 of CNA30021 CSRPCR = Polymerase Chain Reaction

Of the total ITT-Exposed population, 81% were male and the age range was 18-71 years.At baseline, the median plasma HIV-1 RNA was 4.89 log10 copies/mL (range 2.60 - 6.99log10 copies/mL) and median CD4+ cell count was 262 cells/mm3 (range 21 - 918cells/mm3). Demographic and baseline characteristics were well matched between thetwo treatment groups.


15

1.3.2. Other Studies

The Listing of All Clinical Studies in Module 5 (m5, Section 5.2) provides the availabledemographic data (median age, race, and gender) for the other studies (COL30399,COL30482, COL40263, and PENTA 13 [EPV40002]).

1.4. Subject Accountability



Subject disposition in CNA30021 is summarized in Table 5.

Table 5 Subject Disposition (All Randomized Subjects - CNA30021)

ABC OADn (%)

ABC BIDn (%)

Totaln (%)

Total Randomized (N) 392 392 784 Not treated 8 6 14Treated 384 386 770 Completed 290 (76%) 294 (76%) 584 (76%) Discontinued 94 (24%) 92 (24%) 186 (24%) <48 weeks of treatment 58 (15%) 63 (16%) 121 (16%) ≥48 weeks of treatment1 36 (9%) 29 (8%) 65 (8%)Reason for Discontinuation Number discontinued 94 92 186 Adverse event 22 (23%) 25 (27%) 47 (25%) Consent withdrawn 12 (13%) 9 (10%) 21 (11%) Lost to follow-up 32 (34%) 35 (38%) 67 (36%) Clinical progression 1 (1%) 1 (1%) 2 (1%) Protocol violation 4 (4%) 2 (2%) 6 (3%) Insufficient viral load response 6 (6%) 5 (5%) 11 (6%) Other 17 (18%) 15 (16%) 32 (17%)Source Data: Table 12.3 and Table 12.5 of CNA30021 CSR1. Subjects who discontinued after 48 weeks of treatment may have been counted as responders at the 48-week

analysis.

Of all subjects randomized, 14 (2%) never received treatment (eight subjects in the ABConce daily group and six subjects in the ABC twice daily group). The majority ofsubjects (76%) in both treatment groups completed at least 48 weeks of treatment.Reasons for subjects' premature discontinuation were collected on the end of study recordand were comparable between treatment groups.

The number of subjects discontinuing any component of their randomized treatmentregimen and reasons for discontinuation are summarized in Table 6.


16

Table 6 Summary of Treatment Discontinuation (ITT-ExposedPopulation - CNA30021)

ABC OAD ABC BIDDrug Discontinued: ABC OAD 3TC EFV ABC BID 3TC EFVDiscontinuedTreatment (n):

109 95 96 105 95 97

Reason - n (%)1

Adverse event 53 (49%) 26 (27%) 31 (32%) 45 (43%) 29 (31%) 38 (39%) Consent withdrawn 11 (10%) 14 (15%) 13 (14%) 10 (10%) 11 (12%) 7 (7%) Lost to follow-up 26 (24%) 29 (31%) 30 (31%) 30 (29%) 32 (34%) 31 (32%) Clinical progression 1 (<1%) 1 (1%) 1 (1%) 1 (<1%) 1 (1%) 1 (1%) Protocol violation 2 (2%) 1 (1%) 1 (1%) 2 (2%) 2 (2%) 2 (2%) Insufficient viral load 4 (4%) 6 (6%) 5 (5%) 3 (3%) 4 (4%) 4 (4%) Other 12 (11%) 18 (19%) 15 (16%) 14 (13%) 16 (17%) 14 (14%)Source Data: Table 12.7 of CNA30021 CSR1. Specified by site personnel for each individual drug on the treatment record

The number of subjects who prematurely discontinued any study drug in either treatmentgroup was generally similar when compared between treatment groups. Overall, thereasons for study drug discontinuation were similar between treatment groups. Therewas no evidence of a trend of subjects routinely withdrawing consent or being lost tofollow-up due to AEs with time of onset near to the time of premature treatmentdiscontinuation (Table 20).

Further information on subject accountability can be found in the CNA30021 ClinicalStudy Report (CSR) in Module 5 (m5, Section 5.3.5.1), [GSK Document NumberRM2002/00296/00].

2. ADVERSE EVENTS

2.1. Analysis of Adverse Events

Pivotal study CNA30021 results are coded using Medical Dictionary for RegulatoryActivities (MedDRA) terms as outlined in the protocol. AEs were tabulated by treatmentgroup, maximum intensity, seriousness, and attributability to study drug as assessed byinvestigators. Treatment emergent Grade 3 or Grade 4 AEs were also summarized anddescribed by the distribution of time to event using Kaplan-Meier product-limit survivalmethods. Grade 2 to 4 AEs, severe/Grade 3 or 4 AEs, serious adverse events (SAEs) andAEs leading to discontinuation are summarized for the pivotal study CNA30021. Datafor all grades of AEs are provided in the CNA30021 CSR (m5, Section 5.3.5.1).

This safety summary summarizes the most common Grade 2 to 4 AEs considered by theinvestigator to be drug related for the CNA30021 study.


17

Adverse Event Collection

Information regarding AE collection for the pivotal study can be found in the study reportlocated in Module 5 (m5, Section 5.3.5.1).

2.1.1. Common Adverse Events

2.1.1.1. All adverse events



In CNA30021, the majority of the subjects in each treatment group experienced at leastone AE during the conduct of the study (ABC once daily, 362/384 [94%]; ABC twicedaily, 362/386 [94%]). Incidences of AEs were generally comparable between treatmentgroups. However, the incidence of fatigue (15%) was lower in the ABC once daily groupcompared with the ABC twice daily group (20%) (Table 14.8 of CNA30021 CSR).

Grade 2 to 4 AEs with an incidence of ≥5% in either treatment group in CNA30021 aresummarized in Table 7.


18

Table 7 Most Common (Greater than or equal to 5% Incidence) Grade 2 to 4Adverse Events (Safety Population - CNA30021)

Adverse Event1

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY Grade 2 to 4 AE 267 (70%) 276 (72%)Drug hypersensitivity2,3 35 (9%) 27 (7%)Insomnia 26 (7%) 36 (9%)Depression 25 (7%) 26 (7%)Diarrhea4 21 (5%) 25 (6%)Nausea 21 (5%) 25 (6%)Headache 21 (5%) 21 (5%)Rash4 21 (5%) 19 (5%)Fatigue 20 (5%) 29 (8%)Dizziness 19 (5%) 19 (5%)Pyrexia 19 (5%) 13 (3%)Abnormal dreams 15 (4%) 19 (5%)Anxiety 12 (3%) 20 (5%)Source Data: Table 14.10 of CNA30021 CSR1. MedDRA AE coding dictionary2. There was one subject in the ABC once daily group (Subject 02*) and two subjects in the ABC twice daily

group (Subjects 03* and 04*) that reported drug hypersensitivity to ABC (Grade 1, study drug related).3. Subject 05* in the ABC twice daily group reported drug hypersensitivity to trimethoprim and sulfamethoxazole

(not related to study drug).4. Not Otherwise Specified (NOS) in accordance with MedDRA coding convention

Incidences of Grade 2 to 4 AEs were generally comparable between treatment groups.

Additional details regarding ABC HSR are presented in Section 2.1.5.

2.1.1.2. Drug-related adverse events

Because AE data were collected on the entire study drug regimen in the pivotal study, itwas rarely possible for investigators to specify an individual study drug as being relatedto the AE. In this section events considered by the study investigators to be related tostudy drugs are referred to as �drug-related� AEs.



Table 8 summarizes the most common drug-related AEs occurring in ≥10% of subjects ineither treatment group.

mqw36690

*；新薬承認情報提供時におきかえた


19

Table 8 Most Common (Greater than or equal to 10% Incidence) Drug-Related Adverse Events (Safety Population - CNA30021)

Drug-Related Adverse Event1

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY drug-related AE 283 (74%) 276 (72%)Dizziness 73 (19%) 64 (17%)Nausea 53 (14%) 66 (17%)Abnormal dreams 62 (16%) 56 (15%)Insomnia 54 (14%) 61 (16%)Fatigue 31 (8%) 43 (11%)Source Data: Table 14.12 of CNA30021 CSR1. MedDRA AE coding dictionary

Incidences of drug-related AEs were generally comparable between the treatment groups.

Table 9 summarizes the drug-related Grade 2 to 4 AEs occurring in ≥5% of subjects ineither treatment group.

Table 9 Most Common (Greater than or Equal to 5% Incidence) Drug-RelatedGrade 2 to 4 Adverse Events (Safety Population - CNA30021)

Drug-Related Adverse Event1

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY Drug-related Grade 2 to 4 AE 150 (39%) 158 (41%)Drug hypersensitivity 35 (9%) 26 (7%)Insomnia 16 (4%) 28 (7%)Abnormal dreams 15 (4%) 19 (5%)Source Data: Table 14.13 of CNA30021 CSR1. MedDRA AE coding dictionary

A total of 150 (39%) subjects in the ABC once daily group and 158 (41%) subjects in theABC twice daily group experienced at least one Grade 2 to 4 drug-related AE during thestudy. Incidences of Grade 2 to 4 drug-related AEs were generally comparable betweentreatment groups.

Details regarding ABC HSR are presented in Section 2.1.5.


20

2.1.2. Deaths

2.1.2.1. Pivotal study CNA30021


Fatal AEs are summarized in Table 10.

Table 10 Fatal Adverse Events (Safety Population - CNA30021)

Fatal Adverse Events1Subject Number

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY Fatal Event 2 (<1%) 3 (1%)Cardiac arres 06* 1 (<1%) 0Azotemia2

Renal failure (acute) 07* 1 (<1%)

1 (<1%)00

Sepsis 08* 0 1 (<1%)Death3 (undetermined cause) 09* 0 1 (<1%)Edema peripheralNeck massLymphoma

10* 000

1 (<1%)1 (<1%)1 (<1%)

Source Data: Table 14.17 and Case Narratives of CNA30021 CSR1. MedDRA AE coding dictionary2. Investigator considered cause of death to be related to lymphoma.3. Not Otherwise Specified (NOS) in accordance with MedDRA coding convention

There were five subject fatalities (two subjects in the ABC once daily group and threesubjects in the ABC twice daily group) and one fatality in the offspring of a study subject(see pregnancies, Section 2.1.4.3). None of the fatalities were considered by theinvestigator to be attributable to study drug. Subject narratives for each of the fatalitiesare provided in the CNA30021 CSR in Module 5 (m5, Section 5.3.5.1).

2.1.2.2. Ongoing GSK-sponsored studies

No deaths have been reported in the clinical studies CAL30001, ESS30008 andESS30009 during the reporting period (01 Jan 2003 to 31 May 2003).

2.1.2.3. Other studies

One fatality from Kaposi�s sarcoma occurred during COL40263 and was not consideredby the investigator to be related to study medication. Approximately 96 subjects wererandomized to this study during the reporting period. The subject narrative is provided inModule 5 (m5, Section 5.3.5.3).

No deaths have been reported in COL30399, COL30482, and PENTA 13 (EPV40002).

mqw36690



21

2.1.3. Other Serious Adverse Events

2.1.3.1. Pivotal study CNA30021


Case narratives for SAEs for the pivotal safety study CNA30021 can be found in the CSRin Module 5 (m5, Section 5.3.5.1).

The most common SAEs (occurring in >1 subject in either treatment group) aresummarized in Table 11.

Table 11 Most Common (Greater than 1 Subject) Serious Adverse Events(Safety Population - CNA30021)

Serious Adverse Event1

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY SAE 66 (17%) 62 (16%)Drug hypersensitivity2 36 (9%) 28 (7%)Pneumonia3 4 (1%) 5 (1%)Ectopic pregnancy 2 (<1%) 0Suicidal ideation 1 (<1%) 5 (1%)Suicide attempt 1 (<1%) 2 (<1%)Diarrhea3 1 (<1%) 2 (<1%)Dehydration 1 (<1%) 2 (<1%)Bronchitis3 0 2 (<1%)Cellulitis 0 2 (<1%)Source Data: Table 14.18 of CNA30021 CSR1. MedDRA AE coding dictionary2. In accordance with GSK policy all cases of ABC HSR were classified as SAEs regardless of seriousness3. Not Otherwise Specified (NOS) in accordance with MedDRA coding convention

Incidences of SAEs were generally comparable between treatment groups with 17% ofsubjects in the ABC once daily group experiencing a SAE compared with 16% ofsubjects in the ABC twice daily group.

Details regarding ABC HSR are presented in Section 2.1.5.


Case narratives for SAEs in the ongoing GSK-sponsored studies are provided in Module5 (m5, Section 5.3.5.3). A table summarizing the number of SAEs in each study ispresented in Table 12.


22

Table 12 Summary of non-fatal SAEs in the ongoing GSK-sponsored Studies

GSK OngoingStudy

No. SubjectsRandomized in

Study1

No. ABC HSRs(No. Subjects2)

No. Other SAEs(No. Subjects2)

Total SAEs(No. Subjects2)

CAL30001 186 7 (7) 6 (4) 13 (11)ESS30008 260 0 (0) 5 (4) 5 (4)ESS30009 283 17 (17)3 2 (2)3 19 (18)3

Source Data: OCEANS database from 01 Jan 2003 through 31 May 20031. Approximate number of subjects randomized up to 31 May 20032. Number of subjects reporting an event (subjects could report more than one event)3. One subject (Subject 11*) initially developed an ABC HSR then went on to develop the SAE of dermatitis

medicamentosa to EFV following discontinuation of ABC. This subject is included in population numbers forboth number of subjects developing an HSR and number of subjects developing an Other SAE.


There were 11 non-fatal SAEs (six ABC HSRs and five other SAEs of duodenitis,gastritis, esophageal ulcer, dehydration, and dysphagia) reported in eight subjects inCOL40263 (the dehydration and dysphagia were associated with the fatal event ofKaposi�s sarcoma already described for this study in Section 2.1.2.3). With the exceptionof the six ABC HSRs, none of the other SAEs were considered by the investigator to berelated to study medication. Approximately 96 subjects were randomized to this studyduring the reporting period. Case narratives for these SAEs are provided in Module 5(m5, Section 5.3.5.3).

No SAEs were reported in COL30399, COL30482, and PENTA 13 (EPV40002).

2.1.4. Other Significant Adverse Events

2.1.4.1. Severe/Grade 3 to 4 adverse events



Severe/Grade 3 to 4 AEs occurring in >1% of subjects in either treatment group aresummarized in Table 13.

mqw36690



23

Table 13 Most Common (Greater than 1% Incidence) Severe/Grade 3 to 4Adverse Events (Safety Population - CNA30021)

Severe/Grade 3 to 4 Adverse Events1ABC OAD

N=384n (%)

ABC BIDN=386n (%)

Subjects with ANY Grade 3 to 4 AE 101 (26%) 86 (22%)Drug hypersensitivity 19 (5%) 8 (2%)Increased creatine phosphokinase 10 (3%) 4 (1%)Increased aspartate aminotransferase 7 (2%) 5 (1%)Depression 6 (2%) 6 (2%)Diarrhea2 6 (2%) 0Increased alanine aminotransferase 5 (1%) 7 (2%)Source Data: Table 14.14 of CNA30021 CSR1. MedDRA AE coding dictionary2. Not Otherwise Specified (NOS) in accordance with MedDRA coding convention

Both treatment groups showed similar overall incidences of severe/Grade 3 to 4 AEs.

2.1.4.2. Adverse events leading to permanent treatment discontinuation



AEs leading to study drug discontinuation, with an incidence of greater than or equal tothree subjects in either group during the conduct of the study, are summarized inTable 14. Because AE data were collected on the entire study drug regimen, it was rarelypossible to specify an AE as being related to an individual study drug.


24

Table 14 Most Common (Greater than or equal to 3 subjects) Adverse EventsLeading to Permanent Treatment Discontinuation (Safety Population- CNA30021)

Adverse Event Leading to StudyDrug Discontinuation1

ABC OADN=384n (%)

ABC BIDN=386n (%)

Subjects with ANY AE leading tostudy drug discontinuation

60 (16%) 59 (15%)

Drug hypersensitivity 36 (9%) 28 (7%)Abnormal dreams 1 (<1%) 4 (1%)Depression 1 (<1%) 4 (1%)Insomnia 1 (<1%) 4 (1%)Diarrhea2 2 (<1%) 3 (<1%)Rash 4 (1%) 3 (<1%)Dizziness 0 3 (<1%)Source Data: Table 14.21 of CNA30021 CSR1. MedDRA AE coding dictionary2. Not Otherwise Specified (NOS) in accordance with MedDRA coding convention

The type and frequency of AEs leading to permanent treatment discontinuation reportedin each treatment group were similar: 16% (60/384) of subjects in the ABC once dailygroup and 15% (59/386) of subjects in the ABC twice daily group.

2.1.4.3. Pregnancies



Eleven female subjects became pregnant during the conduct of this study, seven of whomwere randomized to the ABC once daily group and four of whom were randomized to theABC twice daily group.

Of the seven subjects randomized to the ABC once daily group, two underwent surgeryfor ectopic pregnancies. One subject elected to terminate the pregnancy andsubsequently continued in the study, and one had a spontaneous abortion. Neither thespontaneous abortion nor the two cases of ectopic pregnancy were considered by theinvestigator to be attributable to study drug. One subject gave birth to a healthy infant.Pregnancy outcomes are pending for the two remaining subjects with estimated deliverydates (EDD) of 11 September 2003 and 25 November 2003.

Of the four subjects who became pregnant in the ABC twice daily group, one gave birthto a healthy female neonate in an uncomplicated delivery, however the infant diedapproximately one month later of sudden infant death syndrome (SIDS); the mother wassubsequently lost to follow up. The SIDS event was not considered by the investigator tobe attributable to study drug. Two subjects elected to terminate their pregnancies.


25

Follow-up is being conducted for the fourth subject (with an EDD of 13 April 2003) todetermine the outcome of the pregnancy.

Subject narratives for the pregnancy cases are provided in the CNA30021 CSR inModule 5 (m5, Section 5.3.5.1).

2.1.5. Analysis of Adverse Events by Organ System or Syndrome

Abacavir Hypersensitivity Reaction

The most clinically significant AE associated with ABC use to date is a drug-related HSRthat occurs in approximately 5% of subjects exposed to ABC. A broad understanding ofABC HSR has been acquired from clinical trials, post-marketing experience andnonclinical research activities. More than 36,700 subjects have been exposed to ABC-containing products in clinical trials. Approximately 434,000 patient-years of post-marketing experience have been generated during the past 4.5 years up to the end ofJune 2003. As illustrated in changes to the product labeling over time, guidance toprescribers has progressed from close surveillance of symptoms of rash and fever toassessment of a syndrome with multi-organ system involvement.

GSK has developed an effective HSR risk management program as a result of acontinuous process of minimizing risk through communication of ABC�s risk/benefitprofile in professional product labeling, education of health care professionals andpatients, a pharmacogenetics/genomic strategy, and epidemiology programs. For moredetails, refer to module 1 (m1, Section 1.8.1).

GSK recognizes that there may be concerns about the potential increased risk ofdeveloping an ABC HSR with ABC 600mg administered once daily. There is notheoretical basis for this concern since there is not a simple dose-response relationship foridiosyncratic drug reactions. In addition, neither the most widely accepted theory forexplaining these reactions (the hapten hypothesis, in which a reactive metabolite binds toa protein forming an adduct that triggers the reaction) nor an alternative theory (thedanger hypothesis in which the reaction is triggered by a sensitized immune system)depend on drug exposure or drug levels [Naisbitt, 2003]. Data from three clinical trials(CNAA2001, CNAB2002, and CNAB3001) utilizing multiple ABC 600mg doses do notsuggest a difference in ABC HSR rates with dose escalation. Results of these trialsrelating to the use of higher doses of ABC relative to HSR are discussed in the ClinicalOverview (m2, Section 2.5).

GSK also recognizes the concerns about the HSR to ABC in the marketed products,ZIAGEN and TRIZIVIR�, and the potential added concern that multiple marketedproducts containing ABC could lead to confusion and, thus, accidental rechallenge inpatients who have experienced an ABC HSR. GSK has implemented significant

� TRIZIVIR is a Trade Mark of the GlaxoSmithKline group of companies.



26

educational activities to alert health care professionals and patients to the risk of HSR andto avoid rechallenge with either ZIAGEN or TRIZIVIR. GSK is committed toeducating health care professionals and patients about the risk of developing an ABCHSR to the ABC/3TC FDC tablet and about avoiding rechallenge with ABC-containingproducts. Cases involving HSR to ABC and rechallenge reactions are closely monitoredby GSK. To date, no HSR rechallenge cases have been received in which the decision torestart ZIAGEN or TRIZIVIR was due to a lack of knowledge of the ABC componentof the formulation.

GSK is committed to continue to educate health care providers on HSR and to monitorthe risk of HSR, rechallenge HSR and HSR-related death, following the introduction ofthe ABC/3TC FDC tablet to the market.

2.1.5.1. Abacavir hypersensitivity reactions reported in CNA30021

In pivotal study CNA30021, the possible HSR rate (as recorded in the Case Report Form[CRF]) of 9% in the ABC once daily group was similar to 7% in the ABC twice dailygroup. The incidence of ABC HSR in this study was similar to other studies in whichHSR reports were solicited using the ABC HSR CRF module. This incidence is likely toreflect the proactive method of data collection, investigator education and the loweredthreshold for reporting HSR in the presence of overlapping drug toxicities, rather than atrue incidence [Hernandez, 2003].

The majority of subjects in both groups who reported an ABC HSR also reported theoccurrence of rash as a primary symptom associated with the HSR event (ABC oncedaily 81% [29/36]; ABC twice daily 71% [20/28]).

Clinical signs and symptoms associated with ABC HSR in CNA30021

The incidence of rash and other signs and symptoms reported with ABC HSR wereconsistent with the syndrome as it is described in the current labeling for ABC-containingproducts.

Table 15 provides the summary of clinical signs and symptoms reported by subjects whohad an ABC HSR.


27

Table 15 Clinical Signs and Symptoms Associated with ABC HSR (SafetyPopulation - CNA30021 and Historical Sample)

Symptoms Reported

ABC OADN = 36n (%)

ABC BIDN = 28n (%)

Historical SampleN=206n (%)

Rash 29 (81%) 20 (71%) 125 (61%) Fever 22 (61%) 14 (50%) 136 (66%) Fatigue 21 (58%) 11 (39%) 40 (19%) Malaise 18 (50%) 16 (57%) 123 (60%) Headache 17 (47%) 7 (25%) 82 (40%) Nausea 16 (44%) 12 (43%) 100 (49%) Chills 14 (39%) 11 (39%) 71 (34%) Myalgia 12 (33%) 8 (29%) 72 (35%) Diarrhea 10 (28%) 6 (21%) 66 (32%) Vomiting 9 (25%) 5 (18%) 63 (31%) Arthralgia 8 (22%) 4 (14%) 53 (26%) Dyspnea 9 (25%) 7 (25%) 56 (27%) Cough 7 (19%) 7 (25%) 46 (22%) Tachycardia 7 (19%) 2 (7%) 36 (17%) Edema 5 (14%) 6 (21%) 18 (9%) Conjunctivitis 5 (14%) 3 (11%) 19 (9%) Pharyngitis 4 (11%) 5 (18%) 25 (12%) Other mucosal lesions 4 (11%) 1 (4%) 8 (4%) Hypotension 4 (11%) 0 13 (6%) Other 1 10 (28%) 10 (36%) 72 (35%) Stomatitis 2 (6%) 2 (7%) 8 (4%) Abdominal pain 3 (8%) 12 (43%) 56 (27%) Wheezing 1 (3%) 0 1 (<1%)Source Data: Table 21 and Table 221. Symptoms reported by the investigators that were not specified on the HSR CRF Module. The symptoms

captured in �Other� that matched the pre-printed symptoms were remapped accordingly. This table differs slightlyfrom Table 14.25 of the CNA30021 CSR due to the remapping of the �Other� category

As shown in Figure 1, in general the presentation and/or frequency of HSR associatedsigns and symptoms reported in the ABC once daily group and the ABC twice dailygroup are comparable, with the exception of abdominal pain. Because the number ofsubjects reporting individual symptoms is small, the numerical differences seen in Figure1 are unlikely to result in a difference in the clinical management of HSR. As seen inTable 16 and Figure 2, when individual symptoms were reported by category, such asgastrointestinal symptoms (including nausea, vomiting, diarrhea and abdominal pain),respiratory symptoms, etc., the clinical presentation was similar in subjects receivingABC twice daily or once daily.


28

Figure 1 HSR symptoms Reported with a Frequency Greater than or equal to10% of HSR cases in CNA30021

0102030405060708090

100Pe

rcen

tage

RashFev

er

Malaise

Fatigue

Nause

aChills

Headac

he

Myalgia

Other

Diarrh

ea

Dyspnea

Abd Pain

Cough

Vomiting

Arthral

gia

Edema

Pharyngitis

Tachyc

ardia

Conjunctivit

is

Symptom

ABC OAD (N=36) ABC BID (N=28)

Source Data: Table 21

As shown in Table 16, the incidence and clinical presentation of ABC HSR are similarbetween ABC once daily and ABC twice daily in CNA30021.


29

Table 16 Comparison of ABC HSRs Reported in the ABC Once Daily and ABCTwice Daily Groups in Pivotal CNA30021 Study

ABC OAD ABC BIDHSR Frequency1 36/384 (9%) 28/386 (7%)HSR Severity Hospitalizations due to ABC HSR

5/384 (1%) 3/386 (<1%)

Deaths due to ABC HSR 0 0Median Time to Onset of ABCHSR

9 days 9 days

Major Symptoms of ABC HSR Rash 29/36 (81%) 20/28 (71%) Constitutional 27/36 (75%) 24/28 (86%) Fever 22/36 (61%) 14/28 (50%) Gastrointestinal 21/36 (58%) 13/28 (46%) Respiratory 13/36 (36%) 12/28 (43%)Source Date: Table 14.23 of CNA30021 CSR and Table 231. ABC HSR rate reported in the pivotal CNA30021 study.

Comparison of clinical symptoms of ABC HSR reported in CNA30021 with otherclinical trials using the ABC HSR CRF module (historical sample)

Figure 2 compares the frequencies of signs and symptoms of ABC HSR reported byinvestigators in pivotal study CNA30021 with a previous ad hoc analysis performed onall clinical trials using the ABC HSR CRF module with an authorized database through31 December 2002. This previous analysis [Ziagen NDA 20-977:S-011, Module 2.7.4,Section 2.1.5.2] summarized 206 HSR cases in 9 clinical trials involving 2670 patients.For both analyses, ABC HSR CRF modules were completed; therefore, both analysesprovide the most comprehensive symptom information regarding ABC HSR in clinicaltrials.


30

Figure 2 Relative Frequencies of ABC HSR Event Groupings in CNA30021relative to an Historical Sample

0102030405060708090

100Pe

rcen

tage

Constitutio

nal

Fever/

Chills GI

Rash/ S

kin

Respira

tory

Symptom Group

ABC OAD (N=36) ABC BID (N=28) Historical (N=206)Source Data: Table 24 and Table 25

The relative frequencies of ABC HSR event groupings in CNA30021 are comparable tothose observed in the previous analysis. Constitutional symptoms and rash were the mostfrequently reported events in HSR cases in CNA30021 followed closely by fever/chills,gastrointestinal symptoms and respiratory symptoms.


31

Table 17 Frequency of Combinations of ABC HSR Symptoms1 in CNA30021and Historical Sample using the ABC HSR CRF Module

ABC OADN = 36

ABC BIDN = 28

HistoricalSampleN = 206

Three or more symptoms 75% 71% 77%GI and Constitutional 3% 4% 5%Skin (including rash) Only2 17% 11% 3%Skin and Constitutional 0 7% 3%Rash and Fever 3% 4% 2%Constitutional and Fever 0 0 2%Constitutional and Respiratory 0 4% 1%Skin and GI 0 0 1%Other 3% 0 4%Source Data: Table 26 and Table 271. All categories were mutually exclusive2. As reported by investigators in the HSR CRF module

In approximately 80% of clinical trial cases, at least three diagnostic categories werereported with the diagnosis of HSR which indicates that the ABC HSR presents withmultiple signs and symptoms. The combinations of symptoms in these reported ABCHSR cases are consistent with the syndrome as described in the current product labeling.

Time to onset of ABC HSR in CNA30021 and the historical sample

The median time to onset of ABC HSR symptoms was 9 days for the once daily andtwice daily treatment groups in CNA30021 and also for the historical sample. Themajority (90%) of ABC HSRs occurred within the first six weeks of ABC exposure. Thisis consistent with the current ABC product labeling.


ABC HSRs reported for the ongoing studies (01 Jan 2003 until 31 May 2003) are asfollows:

• CAL30001: 7/186 (4%);

• ESS30009: 17/283 (6%);

• ESS30008: 0/260 (0%).All antiretrovial drugs, including ABC, were used open-label in each of these threestudies. Also, each study used the ABC HSR CRF module for data collection. Casenarratives for reports of suspected ABC HSR from GSK- sponsored studies up to 31 May2003 are provided in Module 5 (m5, Section 5.3.5.3).


32


There were six cases of ABC HSR reported in COL40263 (6/96 subjects) up to 31 May2003. There were no ABC HSRs reported in COL30399, COL30482, and PENTA 13(EPV40002) during the reporting period.

Case narratives for reports of suspected ABC HSR from other studies, (period 1 January2003 through 31 May 2003) from the OCEANS Safety database are provided in Module5 (m5, Section 5.3.5.3).

2.1.5.4. Signs and symptoms of abacavir HSR in post-marketing experience

The signs and symptoms of ABC HSR reported in CNA30021 are comparable with thehistorical sample (N=206) which has been previously shown to be similar to post-marketing ZIAGEN and TRIZIVIR data (ZIAGEN NDA 20-977:S-011, 13 June 2003).

2.1.5.5. Hypersensitivity risk management

GSK is committed to educating health care professionals and patients about the risk ofdeveloping an ABC HSR to the ABC/3TC FDC and about avoiding rechallenge withABC-containing products. To minimize this risk, GSK has implemented appropriateeducational programs. For an outline of the educational programs, refer to Module 1(m1, Section 1.8.1).

2.2. Narratives

Pivotal study CNA30021

Case narratives for deaths, SAEs and pregnancies for the pivotal safety study CNA30021can be found in Module 5 (m5, Section 5.3.5.1), Study Report RM2002/00296/00.

Ongoing GSK-sponsored studies and other studies

Case narratives for deaths and SAEs from ongoing GSK-sponsored studies and otherstudies (01 Jan 2003 through 31 May 2003) are provided from the OCEANS safetydatabase in Module 5 (m5, Section 5.3.5.3). Case narratives from these studies aregrouped into the following sections: SAEs involving a Fatal Outcome, SAEs Meeting theGlobal Clinical Safety and Pharmacovigilance (GCSP) Case Definition of AbacavirHypersensitivity, and Other SAEs.

3. CLINICAL LABORATORY EVALUATIONS

3.1. Laboratory Data Collection and Analysis

Routine hematology and clinical chemistry tests were performed as specified for eachstudy. Laboratory test results were compared to normal ranges for each laboratory


33

analyte. Laboratory toxicity data were collected in association with clinical laboratorydata, and results of graded toxicity assessments are presented in this section.



Serum chemistry and hematology evaluations were performed at Screening, Day 1,Weeks 2, 4, 8, and 12, and every 12 weeks thereafter until the last subject reached 48weeks of treatment, and at all unscheduled visits.

All clinical laboratory tests were performed by a centralized laboratory facility. Thespecific clinical laboratory tests included for this study are described in Section 5.6.3.4 ofthe CNA30021 CSR in Module 5 (m5, Section 5.3.5.1).

Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or otherabnormal assessments (e.g., electrocardiograms, X-rays, vital signs) that were judged bythe investigator to be clinically significant were to have been recorded as AEs or SAEs ifthey met the definition of an AE or SAE.

Clinically significant abnormal laboratory findings or other abnormal assessments thatwere detected after study drug administration or that were present at baseline andworsened following the start of study drug were reported as AEs or SAEs.

3.2. Laboratory Values Over Time

3.2.1. Pivotal Study CNA30021 - Use of ABC once daily compared withtwice daily in combination with 3TC and EFV once daily intreatment-naïve HIV-1 infected adults

Neither the ABC once daily nor the ABC twice daily treatment groups had significantchanges in their median clinical chemistry values over 48 weeks of treatment. Medianchanges from baseline in all clinical chemistry parameters and in hematology laboratoryassessments were generally small and comparable between the treatment groups.

3.3. Grade 3 to 4 Treatment-Emergent Laboratory Abnormalities

3.3.1. Pivotal Study CNA30021 - Use of ABC once daily compared withtwice daily in combination with 3TC and EFV once daily intreatment-naïve HIV-1 infected adults

Grade 3 to 4 treatment-emergent abnormalities are summarized in Table 18.


34

Table 18 Grade 3 to 4 Treatment-Emergent Laboratory Abnormalities (SafetyPopulation - CNA30021)

Grades 3 to 4

ABC OADN=384n (%)

ABC BIDN=386n (%)

Laboratory Abnormalities Grade 3

Grade4

Grade3/4

Grade3

Grade4

Grade3/4

Clinical Chemistry Elevated ALT 14 (4%) 9 (2%) 23 (6%) 18 (5%) 6 (2%) 24 (6%) Elevated AST 10 (3%) 13 (3%) 23 (6%) 9 (2%) 5 (1%) 14 (4%) Alkaline phosphatase 1 (<1%) 0 1 (<1%) 0 1 (<1%) 1 (<1%) Amylase 13 (3%) 2 (<1%) 15 (4%) 12 (3%) 0 12 (3%) Bilirubin 0 2 (<1%) 2 (<1%) 1 (<1%) 1 (<1%) 2 (<1%) Creatine phosphokinase 13 (3%) 31 (8%) 44 (12%) 13 (3%) 22 (6%) 35 (9%) Creatinine 0 0 0 0 1 (<1%) 1 (<1%) Glucose 4 (1%) 1 (<1%) 5 (1%) 5 (1%) 0 5 (1%) Sodium 2 (<1%) 0 2 (<1%) 1 (<1%) 0 1 (<1%) Triglycerides 13 (3%) 5 (1%) 18 (5%) 13 (3%) 8 (2%) 21 (6%)Hematology Hemoglobin 0 1 (<1%) 1 (<1%) 0 0 0 Neutrophils absolute 6 (2%) 3 (<1%) 9 (2%) 4 (1%) 1 (<1%) 5 (1%) Platelets 2 (<1%) 0 2 (<1%) 2 (<1%) 0 2 (<1%) White blood cells 0 0 0 1 (<1%) 0 1 (<1%)Source Data: Table 14.31 and Table 14.32 of CNA30021 CSR

Incidences of specific treatment-emergent Grade 3 or 4 clinical chemistry andhematology abnormalities were generally low (≤5%) and comparable between treatmentgroups. There were 44 (12%) subjects in the ABC once daily group and 35 (9%) subjectsin the ABC twice daily group who had treatment-emergent abnormal Grade 3 and 4creatine phosphokinase laboratory values.

4. VITAL SIGNS, PHYSICAL FINDINGS, AND OTHEROBSERVATIONS RELATED TO SAFETY

Information regarding physical findings and other observations related to safety can befound in the individual study reports. Vital signs were not collected for the pivotal study.There were no unexpected events in physical findings and other observations related tosafety.


35

5. SAFETY IN SPECIAL GROUPS AND SITUATIONS

5.1. Intrinsic Factors

5.1.1. Gender Subgroup Analysis of Grade 3 to 4 AEs and LaboratoryAbnormalities in Pivotal Study CNA30021

Overall, there were only minor differences seen in the sub-analyses of Grade 3 to 4 orsevere AEs by gender, with no apparent trends.

Clinical chemistry abnormalities for males and females were generally comparable to theoverall Safety Population in both the ABC once daily and the ABC twice daily treatmentgroups.

The male subgroup analysis of clinical chemistry abnormalities was also similar to that offemales with the exception of increased creatine phosphokinase. Males in the ABC oncedaily group had a higher frequency of Grade 3 and 4 creatine phosphokinase (12%)compared with females (8%); likewise, males in the twice daily group had a higherfrequency of Grade 3 and 4 creatine phosphokinase (11%) compared with females(0 subjects). Grade 3 to 4 elevations in CPK were rarely associated with Grade 3 to 4elevations in transaminases (AST and/or ALT) and may therefore be of muscular origin.Gender differences in this parameter may therefore be a result of increased muscle massand/or strenuous exercise in males relative to females.

Hematology laboratory abnormalities for males and females were generally comparableto the overall Safety Population in both the ABC once daily and the ABC twice dailytreatment groups. Hematology laboratory assessments for females were comparable tothe male subgroup analyses.

Laboratory abnormalities were generally comparable between the ABC once daily andABC twice daily groups within each gender sub-group.

5.1.2. Race Subgroup Analysis of Grade 3 to 4 AEs and LaboratoryAbnormalities in Pivotal Study CNA30021

Overall, there were only minor differences seen in the sub-analyses of Grade 3 to 4 orsevere AEs by race with no apparent trends (Table 14.16 of CNA30021 CSR).

5.2. Extrinsic Factors

Listings of AEs in subjects with Hepatitis B/C co-infection and subjects without co-infection are found in Table 28 and Table 29, respectively. The incidence and type ofAEs were similar regardless of whether subjects were co-infected or not. In addition theincidence of specific AEs in co-infected subjects did not differ between subjects takingABC once daily and those taking ABC twice daily.


36

5.3. Drug Interactions

A full range of interaction studies have been provided in regulatory submissions for theindividual components. Since the mechanisms of action of ABC and 3TC did not suggestany additional risk in combining ABC and 3TC, no additional clinical drug interactionstudies have been conducted by GSK. Information (e.g., abstracts) from the literature onthe individual components are provided for non-GSK sponsored studies in Module 5 (m5,Section 5.4). The results of three non-GSK-sponsored studies evaluating druginteractions with ABC have been published [Bart, 2001; Kearney, 2003; Morse, 2000].

In one study, administration of ABC 600mg twice daily (twice the recommended dose)plus amprenavir (APV, AGENERASE�) 1200mg twice daily for a median of 14 daysresulted in a median 35% decrease in methadone blood concentrations in 5 opiate-addicted, HIV-infected subjects receiving methadone maintenance therapy (median dose,50 mg/day) [Bart, 2001]. Two subjects reported several episodes of nausea in themorning before the intake of their daily methadone doses, which was compatible with anopioid withdrawal reaction. The clinical investigators felt that since it is not metabolizedby CYP3A4, ABC was unlikely to have been responsible for any effect on methadone.APV-related induction of CYP3A4 was believed to have been responsible for thereduction in methadone blood concentrations. However, a GSK pharmacokineticinteraction study CNA1012 suggested that ABC may increase plasma clearance ofmethadone and may require an increased methadone dose in a small number of subjects.

In study protocol ACTG372B, 2 weeks of adefovir dipivoxil (Hepsera�) 60-120mg oncedaily was shown not to affect the pharmacokinetics of ABC [Morse, 2000].

In the third non-GSK-sponsored study, the single-dose pharmacokinetics of ABC (dosenot stated) were evaluated in 8 healthy subjects before and after 13 days of a TDFregimen (dosage not stated) dosed with food [Kearney, 2003]. Following TDFcoadministration, the mean ABC AUC0-∞ (area under the drug-concentration-time curvefrom time 0 and extrapolated to infinity) and Cmax (maximum concentration of drug in thebody at time, tmax) values were 10% and 12% higher than baseline values, which theinvestigators deemed clinically insignificant. Following ABC co-administration, themean TDF AUC0-τ, ss (area under the drug-concentration-time curve from 0 to time t atsteady state) and Cmax, ss (maximum concentration of drug in the body at time, tmax, atsteady state) values were similar to historical data.

One non-GSK-sponsored study investigating a possible drug interaction between 3TCand TDF has been published [Kearney, 2001]. In this multiple-dose, randomized,crossover study in 15 healthy subjects, steady-state pharmacokinetics of TDF werecalculated following 7 days of TDF 300 mg once daily alone and after 7 days of

� AGENERASE is a Trade Mark of the GlaxoSmithKline group of companies.


� Hepsera is a Trade Mark of Gilead Sciences, Inc.Registered in US Patent and Trademark Office.


37

concurrent 3TC 150 mg twice daily. Conversely, steady-state 3TC pharmacokineticswere calculated following 7 days of 3TC 150 mg twice daily alone and after 7 days ofconcurrent TDF 300 mg once daily. Coadministration of 3TC had no significant effecton the pharmacokinetics of TDF, the mean ratios (together/alone) for AUC0-τ, ss and Cmaxbeing 0.96 and 1.02, respectively. Coadministration of TDF with 3TC delayed the 3TCTmax (time of maximum plasma concentration) by 0.9 hours and reduced the 3TC Cmax(mean ratio, 0.76), but did not affect the 3TC AUC0-τ, ss (mean ratio, 0.97). The studyinvestigators stated that the observed changes in 3TC pharmacokinetics during TDFcoadministration were not clinically important.

ESS30009 is a randomized (1:1), open-label, multicenter study that was designed toevaluate the safety and durability of EFV + ABC/3TC once daily versus TDF +ABC/3TC once daily over 48 weeks in approximately 306 ART-naïve subjects. Subjectswith plasma HIV-1 RNA ≥5000 copies/mL were eligible for inclusion. The primaryendpoint is the proportion of subjects with plasma HIV-1 RNA <50 copies/mL atWeek 48.

Shortly after initiation of this study, reports of poor virologic response in subjectsreceiving TDF + ABC/3TC were observed. Results from an expedited unplannedanalysis showed a total of 49% and 48% of patients reaching 8 and 12 weeks of therapymet failure criteria in the TDF + ABC/3TC group versus 5% at both 8 and 12 weeks inthe EFV + ABC/3TC group. Preliminary genotypes of viral isolates from 14 patientswith virologic non-response taking the TDF + ABC/3TC regimen have shown all 14isolated had the M184V mutation in HIV reverse transcriptase. In addition, 8 of the 14(57%) isolates also had the K65R mutation. Based on these results, the TDF + ABC/3TCtreatment arm of this study was recently terminated. The nature of any interactionbetween components of this regimen is being investigated. Preliminary study resultsindicate that ABC/3TC should not be used with TDF as part of triple antiretroviraltherapy.

5.4. Use in Pregnancy and Lactation

There are no adequate and well-controlled studies of ABC and/or 3TC in pregnantwomen. ZIAGEN and EPIVIR should be used during pregnancy only if the potentialbenefits outweigh the risk.

A search of the literature concerning the use of ABC and/or 3TC during pregnancyprovided the following information. Puga et al [Puga, 2001] performed a retrospectivepatient chart review of all births to HIV-infected mothers occurring during 2000-2001 atthe Children's Diagnostic and Treatment Center in Ft. Lauderdale, Florida. Of the 36mothers, 29 (81%) received COMBIVIR� + ABC, 6 (17%) received TRIZIVIR, andone (2%) received ABC + 3TC + d4T. Treatment was initiated at a mean of 9.5 weeksgestation (range, 0-24 weeks), with 25% of the women receiving treatment at conception.

� COMBIVIR is a Trade Mark of the GlaxoSmithKline group of companies.



38

Review of the data from the 36 mother-infant pairs showed all women delivered a singlelive birth with a mean gestational age of 39 weeks. No birth defects occurred, no AEs orsuspected ABC-related HSRs were reported, and normal growth parameters in all 36infants were seen at 6 months of age. Thirty-five infants tested HIV-negative bydeoxyribonucleic acid (DNA)-polymerase chain reaction (PCR) at 1, 4, and 6 months.There was one case of transmission of HIV from mother to infant occurring in a motherco-infected with hepatitis C, the mother admitted not taking any ABC doses during herpregnancy.

The May 2003 report from the Antiretroviral Pregnancy Registry stated that sufficientnumbers of first trimester human exposures to 3TC have been monitored to detect at leasta 2-fold increase in risk of overall birth defects [Antiretroviral Pregnancy RegistrySteering Committee, 2003]. Upon review of these data, the Registry concluded that 3TChas demonstrated no effect on the occurrence of birth defects. The prevalence of birthsbearing defects among 940 live births monitored through 31 January 2003 was 3.0%(95% confidence interval: 2.0%, 4.3%) following first trimester 3TC exposure and 2.1%(95% confidence interval: 1.4%, 2.9%) following second/third 3TC exposure. Theserates were no greater than the total prevalence rate of birth defects (3.1%) in the U.S.population based on CDC surveillance data [Public Health Service Task Force, 2003].Antiretroviral Pregnancy Registry data for ABC are insufficient to allow comparisons ofbirth defect prevalence rates with rates seen in the general population. Through 31January 2003, birth defects have been noted in 6 of 140 neonates following first trimestermaternal ABC exposure and in 4 of 151 neonates following second/third trimester ABCexposure [Antiretroviral Pregnancy Registry Steering Committee, 2003].

The African perinatal trial (PETRA) compared three regimens of 3TC + zidovudine(ZDV, RETROVIR�) (A: during pregnancy starting at 36 weeks� gestation, during labor,and through 1 week postpartum; B: as with regimen A, but without the prepartumcomponent; and C: intrapartum 3TC + ZDV only) with placebo for prevention oftransmission [Saba, 2002]. Of 1797 pregnancies, Week 6 HIV-1 transmission rates were5.7% for group A, 8.9% for group B, 14.2% for group C, and 15.3% for the placebogroup. Infant mortality before Week 6 was 1.1%, 2.2%, 3.0%, and 2.6% in these groups,respectively. In the 1501 infants born to the treated women, there were no differencesbetween any of the 3TC + ZDV groups and the placebo group in birthweight (median, 3.1kg in all groups), APGAR scores (Newborn score of Appearance, Pulse, Grimace,Activity, Respiration) 5 minutes after birth, incidence of neurological events, birthdefects, or grade 3 or 4 laboratory abnormalities.

A small Phase I study in South Africa evaluated the safety and pharmacokinetics of 3TCalone or in combination with ZDV in 20 HIV-infected pregnant women [Moodley, 1998].Therapy was started at 38 weeks gestation, continued through labor, and given for 1 weekfollowing birth to the infants. 3TC was well tolerated and 3TC pharmacokinetics inpregnant women were similar to those observed in non-pregnant adults. No woman or

� RETROVIR is a Trade Mark of the GlaxoSmithKline group of companies.



39

neonate discontinued treatment because of an AE. Two neonates died at ages 5 and 6months and 4 experienced serious AEs, none of which were considered treatment-related.

In the SIMBA Study, 199 infants were administered 3TC syrup 2 mg/kg twice daily forthe first 30 days after birth, 4 mg/kg twice daily as long as they were being breastfed andfor 4 weeks post-breastfeeding [Vyankandondera, 2003]. The median duration ofbreastfeeding was 106 days (range: 87, 158 days). HIV transmission occurred in 6% ofthe neonates during the intra-uterine period, 1% <4 months after birth, and 1% >4 monthsafter birth. As the risk of postnatal transmission of HIV is normally 10-15%, the findingsof SIMBA suggested that neonatal administration of 3TC can greatly reducebreastfeeding-related HIV transmission.

In ANRS 075, HIV transmission rates were compared between neonates born to 899HIV-infected pregnant women who had received ZDV monotherapy and neonates born to445 HIV-1-infected pregnant women who had received ZDV (the ACTG 076 prophylaxisregimen) + 3TC 150 mg twice daily [Mandelbrot, 2001]. The latter 3TC regimen wasinitiated at 32 weeks� gestation and continued through delivery. Neonates received 3TC2 mg/kg twice daily for 6 weeks. The transmission rate was significantly lower in theZDV + 3TC group than in the ZDV-alone control group (1.6% vs 6.6%, p<0.001). TheZDV + 3TC group had a significantly lower hemoglobin level at birth (p=0.004) and at 1month (p<0.001), and a significantly lower neutrophil count at birth (p<0.001). Therewere no differences between the study groups with respect to gestational age, incidenceof stillbirths, neonatal head circumference, or birth defects.

Information (e.g., abstracts) from the literature for non-GSK conducted studies isprovided in Module 5 (m5, Section 5.4).

5.5. Overdose

For the purposes of this summary, an overdose was considered as any dose above thedaily recommended dose. Single doses up to 1200mg and daily doses up to 1800mg ofABC have been administered orally to subjects in clinical studies. Single doses up to1400mg daily of 3TC have been administered orally to subjects in clinical studies. Nounexpected adverse reactions were reported for either drug. The effects of higher dosesare not known.

Limited data are available on the consequences of ingestion of acute overdoses of 3TCand ABC in humans. No known fatalities have been attributed to 3TC overdose to date.One case of sudden death has occurred in a patient who may or may not have taken anoverdose of ABC in combination with multiple drugs. Pulmonary embolism andpneumonia with pneumothorax were also cited as a possible cause of the death; the causeof death per death certificate was AIDS, although an autopsy was not performed.

If overdosage occurs the patient should be monitored, and standard supportive treatmentapplied as required. It is not known whether ABC can be removed by peritoneal dialysisor hemodialysis. Since 3TC is dialysable, continuous hemodialysis could be used in thetreatment of overdosage, although this has not been studied. There is no known antidotefor ABC or 3TC.


40

One report of possible overdose with ABC occurred in the pivotal study CNA30021(Subject 12*). This involved a dosing error in a subject who developed ABC HSR.The dose administered and sequence of events were unclear but the presumed dose was900mg once daily for two days. Further details may be found in the case narrative whichis located in the CNA30021 CSR in Module 5 (m5, Section 5.3.5.1).

5.6. Drug Abuse

This class of compounds has no known drug abuse potential.

5.7. Withdrawal and Rebound

This class of compounds has no known drug withdrawal or rebound potential.

5.8. Effects on Ability to Drive or Operate Machinery orImpairment of Mental Ability

This class of compounds has no known effects on one�s ability to drive or operatemachinery or impairment of mental ability.

6. POST-MARKETING DATA

No information is available on the ABC/3TC fixed dose combination (FDC) tablet, as theproduct is currently not marketed.

SAFETY CONCLUSIONS

In the large pivotal study, CNA30021, the safety results of ABC 600mg once daily versusABC 300mg twice daily in combination with 3TC 300mg once daily and EFV 600mgonce daily were comparable in treatment-naïve subjects with HIV-1 infection:

• The incidence of AEs, treatment-emergent AEs, severe or serious AEs weresimilar between the ABC once daily and ABC twice daily treatment groups.The safety results demonstrated that both regimens had acceptable safetyprofiles in subjects and that safety profiles were comparable over 48 weeks ofrandomized treatment exposure.

• The incidence and presentation of ABC HSR reported by study investigatorswere similar in the ABC once daily group (9%) as compared with the ABCtwice daily group (7%). The incidence of ABC HSR was comparable to otherstudies specifically soliciting HSR reports using the HSR CRF module and islikely to reflect a conservative method of data collection. The presentation ofsigns and symptoms reported with ABC HSR were consistent with the syndromeas it is described in the current product labeling.

• There were no study subject fatalities attributed by investigators to eithertreatment regimen.

mqw36690



41

• Consistent with previous studies, there was no evidence in CNA30021indicating ABC once daily contributed to any new undefined adverse clinicalmanifestation.

The ABC HSR syndrome has been well-characterized through extensive study in clinicaltrials and through post-marketing use. Conservative guidance for diagnosis andmanagement of ABC HSR has been developed and disseminated to prevent seriousoutcomes and rechallenge. No changes to the currently recommended approach to thediagnosis and management of suspected ABC HSR are indicated based on the availabledata from clinical trials and post-marketing surveillance.

Overall, the safety data in this submission support the following conclusions:

• ABC once daily has an acceptable safety profile and is not associated with increasedtoxicity relative to twice daily dosing;

• ABC + 3TC forms a convenient, once daily NRTI backbone.


42

7. APPENDIX


43

Table 19 Tabular List of Pivotal Clinical Trials

ProtocolNumber

(Number andlocation ofCenters)

StudyDesign1

Treatments2,3 Form4 Total No.SubjectsEnrolledin Study

Number ofSubjects

ReceivingABC OAD +

3TC OADTherapy5

Duration ofExposure

to ABCOAD + 3TC

OADTherapy6

Age Range(median)% Male/Female

(%Black/White/Other)

Full Report

Pivotal Study

CNA30021120internationalsites

DB,Rand,MC,Cont,Nai

600mg ABC OAD +300mg 3TC OAD +EFV vs. 300mgABC BID + 3TC300mg OAD + EFV

ABC 300mgSulf Tab +3TC 150mg+ EFV600mg

784 384 48-72weeks

18-71 (36)81/1927/54/19

GSK DocumentNumberRM2002/00296/00Module 5(m5, Section5.3.5.1)

1. Cont: Controlled, DB: Double-blind, MC: Multicenter, Nai: Treatment-naïve patients, Rand: Randomized2. ABC: Abacavir, 3TC: lamivudine, EFV: efavirenz;3. Medications dosed at standard, approved doses unless otherwise noted.4. Sulf: Sulfate, Tab: Tablets5. ABC once daily dose is 600mg; 3TC once daily dose is 300mg.6. Unless otherwise noted, indicates intended length of study.

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ Subjects With Any Event 26 (70%) 26 (65%) Psychiatric disorders Subjects with Any Event 14 (38%) 15 (38%) Depression 4 (11%) 4 (10%) Insomnia 4 (11%) 4 (10%) Abnormal dreams 2 (5%) 5 (13%) Anxiety 2 (5%) 3 (8%) Mental disorder NOS 0 2 (5%) Agitation 0 1 (3%) Confusional state 0 1 (3%) Dissociation 0 1 (3%) Euphoric mood 0 1 (3%) Irritability 1 (3%) 0 Mood disorder NOS 1 (3%) 0 Restlessness 0 1 (3%) Suicidal ideation 0 1 (3%) Gastrointestinal disorders Subjects with Any Event 10 (27%) 13 (33%) Nausea 0 6 (15%) Diarrhoea NOS 3 (8%) 1 (3%)Gastrointestinal disorders continues ... NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 1 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

44

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ ... continuing Gastrointestinal disorders Dyspepsia 2 (5%) 2 (5%) Vomiting NOS 1 (3%) 3 (8%) Abdominal pain upper 2 (5%) 0 Toothache 2 (5%) 0 Abdominal discomfort 0 1 (3%) Flatulence 1 (3%) 0 Frequent bowel movements 1 (3%) 0 Gastrointestinal 0 1 (3%) irritation Gastrooesophageal reflux 0 1 (3%) disease Hiatus hernia 0 1 (3%) Hyperacidity 0 1 (3%) Lip pain 1 (3%) 0 Loose stools 1 (3%) 0 Respiratory, thoracic andmediastinal disorders Subjects with Any Event 7 (19%) 8 (20%) Cough 1 (3%) 3 (8%) Bronchitis NOS 1 (3%) 1 (3%)Respiratory, thoracic and mediastinal disorders continues ... NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 2 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

45

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ ... continuing Respiratory, thoracic and mediastinal disorders Nasal congestion 1 (3%) 1 (3%) Rhinitis NOS 0 2 (5%) Sinus congestion 1 (3%) 1 (3%) Wheezing 0 2 (5%) Allergic sinusitis 1 (3%) 0 Asthma NOS 0 1 (3%) Dyspnoea 1 (3%) 0 Dyspnoea exertional 0 1 (3%) Laryngitis NOS 1 (3%) 0 Pharyngolaryngeal pain 0 1 (3%) Pulmonary mass 1 (3%) 0 Rhinorrhoea 0 1 (3%) Throat irritation 1 (3%) 0 Skin and subcutaneous tissuedisorders Subjects with Any Event 8 (22%) 7 (18%) Rash NOS 2 (5%) 3 (8%) Dry skin 3 (8%) 0 Night sweats 1 (3%) 1 (3%) Acrochordons 0 1 (3%)Skin and subcutaneous tissue disorders continues ... NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 3 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

46

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ ... continuing Skin and subcutaneous tissue disorders Contusion 0 1 (3%) Dermatitis NOS 1 (3%) 0 Rash macular 1 (3%) 0 Rash maculo-papular 0 1 (3%) General disorders andadministration site conditions Subjects with Any Event 4 (11%) 10 (25%) Fatigue 2 (5%) 4 (10%) Asthenia 0 2 (5%) Chest pain 1 (3%) 0 Chest tightness 0 1 (3%) Drug withdrawal syndrome 0 1 (3%) Ill-defined disorder NOS 0 1 (3%) Mass NOS 1 (3%) 0 Pain NOS 0 1 (3%) Pyrexia 0 1 (3%) NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 4 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

47

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ Infections and infestations Subjects with Any Event 8 (22%) 6 (15%) Nasopharyngitis 3 (8%) 1 (3%) Abscess oral 1 (3%) 0 Bronchitis acute NOS 0 1 (3%) Condyloma acuminatum 0 1 (3%) Dermatophytosis NOS 0 1 (3%) Fungal infection NOS 1 (3%) 0 Fungal rash NOS 1 (3%) 0 Gingival infection 1 (3%) 0 Herpes simplex 0 1 (3%) Madura foot 1 (3%) 0 Pneumonia NOS 0 1 (3%) Scabies infestation 1 (3%) 0 Tinea barbae 0 1 (3%) Tinea cruris 1 (3%) 0 Tinea pedis 0 1 (3%) Urinary tract infection 0 1 (3%) NOS Vaginal candidiasis 0 1 (3%) NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 5 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

48

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ Nervous system disorders Subjects with Any Event 3 (8%) 10 (25%) Dizziness 0 5 (13%) Headache 2 (5%) 3 (8%) Somnolence 0 3 (8%) Hypoaesthesia 0 2 (5%) Disturbance in attention 0 1 (3%) Dysgeusia 0 1 (3%) Migraine NOS 1 (3%) 0 Tremor 0 1 (3%) Ear and labyrinth disorders Subjects with Any Event 2 (5%) 1 (3%) Deafness NOS 1 (3%) 0 Tympanic membrane 1 (3%) 0 perforation Vertigo 0 1 (3%) Investigations Subjects with Any Event 2 (5%) 1 (3%) Blood pressure increased 1 (3%) 0 Weight decreased 0 1 (3%)Investigations continues ... NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 6 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

49

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ ... continuing Investigations Weight increased 1 (3%) 0 Blood and lymphatic systemdisorders Subjects with Any Event 1 (3%) 1 (3%) Lymph node pain 0 1 (3%) Neutropenia 1 (3%) 0 Injury, poisoning andprocedural complications Subjects with Any Event 1 (3%) 1 (3%) Animal bite 0 1 (3%) Tooth injury 1 (3%) 0 Reproductive system and breastdisorders Subjects with Any Event 1 (3%) 1 (3%) Dysmenorrhoea 0 1 (3%) Genital pruritus male 1 (3%) 0 NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 7 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

50

Protocol: CNA30021 -- ABC+3TC FDC(Data as of: June 27, 2003) Table 20 Summary of All Adverse Events Subjects With Treatment Withdrawal Due to Loss to Follow Up or Consent Withdrawn BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=37) (N=40)------------------------------------------------------------------------------------------ Congenital, familial andgenetic disorders Subjects with Any Event 1 (3%) 0 Carnitine deficiency 1 (3%) 0 Metabolism and nutritiondisorders Subjects with Any Event 0 1 (3%) Hyperlipidaemia NOS 0 1 (3%) Musculoskeletal and connectivetissue disorders Subjects with Any Event 1 (3%) 0 Back pain 1 (3%) 0 Bone pain 1 (3%) 0 Vascular disorders Subjects with Any Event 0 1 (3%) Hypertension NOS 0 1 (3%) NOTE: Events summarized with onset date within 21 days of randomized study drugdiscontinuation (i.e., ABC) or date of last contact withthe subject (when lost to follow up) or events with no resolution or resolutionwithin 21 days of treatment discontinuation.hz39798:US/cna2/a30021/programs/fda/ae_dc.sas 05SEP03 14:28 Page 8 of 8

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

51

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 21 Signs and Symptoms of Abacavir Hypersensitivity ABC OAD+3TC+EFV ABC BID+3TC+EFVEvent (N=36) (N=28)------------------------------------------------------------------------------------------ Subjects With Any Event 36(100%) 28(100%)Rash 29 (81%) 20 (71%)Fever 22 (61%) 14 (50%)Malaise 18 (50%) 16 (57%)Fatigue 21 (58%) 11 (39%)Nausea 16 (44%) 12 (43%)Chills 14 (39%) 11 (39%)Headache 17 (47%) 7 (25%)Myalgia 12 (33%) 8 (29%)Other 10 (28%) 10 (36%)Diarrhea 10 (28%) 6 (21%)Dyspnea 9 (25%) 7 (25%)Abdominal pain 3 (8%) 12 (43%)Cough 7 (19%) 7 (25%)Vomiting 9 (25%) 5 (18%)Arthralgia 8 (22%) 4 (14%)Edema 5 (14%) 6 (21%)Pharyngitis 4 (11%) 5 (18%)Tachycardia 7 (19%) 2 (7%)Conjunctivitis 5 (14%) 3 (11%)Other mucosal lesions 4 (11%) 1 (4%)Hypotension 4 (11%) 0Stomatitis 2 (6%) 2 (7%)Wheezing 1 (3%) 0 tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 1 of 2

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

52

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 21 Signs and Symptoms of Abacavir Hypersensitivity TotalEvent (N=64)------------------------------------------------------------------------------------------ Subjects With Any Event 64(100%)Rash 49 (77%)Fever 36 (56%)Malaise 34 (53%)Fatigue 32 (50%)Nausea 28 (44%)Chills 25 (39%)Headache 24 (38%)Myalgia 20 (31%)Other 20 (31%)Diarrhea 16 (25%)Dyspnea 16 (25%)Abdominal pain 15 (23%)Cough 14 (22%)Vomiting 14 (22%)Arthralgia 12 (19%)Edema 11 (17%)Pharyngitis 9 (14%)Tachycardia 9 (14%)Conjunctivitis 8 (13%)Other mucosal lesions 5 (8%)Hypotension 4 (6%)Stomatitis 4 (6%)Wheezing 1 (2%) tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 2 of 2

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

53

Population: Historical Sample Table 22 Signs and Symptoms of Abacavir Hypersensitivity (Historical Smple) All SubjectsEvent (N=206)------------------------------------------------------------------------------------------ Subjects With Any Event 206(100%)Fever 136 (66%)Rash 125 (61%)Malaise 123 (60%)Nausea 100 (49%)Headache 82 (40%)Myalgia 72 (35%)Other 72 (35%)Chills 71 (34%)Diarrhea 66 (32%)Vomiting 63 (31%)Abdominal pain 56 (27%)Dyspnea 56 (27%)Arthralgia 53 (26%)Cough 46 (22%)Fatigue 40 (19%)Tachycardia 36 (17%)Pharyngitis 25 (12%)Conjunctivitis 19 (9%)Edema 18 (9%)Hypotension 13 (6%)Other mucosal lesions 8 (4%)Stomatitis 8 (4%)Wheezing 1 (<1%) tme14427:US/hiv_agg/ziagen/hsr/march_2003/hsr_crf.sas 12MAY03 21:45 Page 1 of 1

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

54

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 23 Time to Onset of ABC HSR HSR CRF Module -------------------------- Days ABC OAD+3TC ABC BID+3TC Total --------------------------------------------------------------- Days n 36 28 64 1 1 (3%) 2 (7%) 3 (5%) 2 3 (8%) 3 (11%) 6 (9%) 3 1 (3%) 2 (7%) 3 (5%) 5 1 (3%) 0 1 (2%) 6 0 1 (4%) 1 (2%) 7 2 (6%) 2 (7%) 4 (6%) 8 8 (22%) 3 (11%) 11 (17%) 9 5 (14%) 3 (11%) 8 (13%) 10 4 (11%) 1 (4%) 5 (8%) 11 1 (3%) 1 (4%) 2 (3%) 12 2 (6%) 2 (7%) 4 (6%) 13 2 (6%) 2 (7%) 4 (6%) 15 0 1 (4%) 1 (2%) 17 1 (3%) 0 1 (2%) 18 1 (3%) 0 1 (2%) 19 1 (3%) 0 1 (2%) 20 0 1 (4%) 1 (2%) 23 1 (3%) 0 1 (2%) 25 0 1 (4%) 1 (2%) 27 1 (3%) 0 1 (2%) 37 0 1 (4%) 1 (2%) 49 0 1 (4%) 1 (2%) 87 0 1 (4%) 1 (2%) 384 1 (3%) 0 1 (2%) tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 1 of 2

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

55

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 23 Time to Onset of ABC HSR HSR CRF Module -------------------------- Days ABC OAD+3TC ABC BID+3TC Total --------------------------------------------------------------- Days n 36 28 64 Mean 20 14 17 SD 62.6 17.9 48.2 Median 9 9 9 Min. 1 1 1 Max. 384 87 384 tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 2 of 2

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

56

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 24 Relative Frequencies of ABC HSR Event Groupings HSR CRF Module -------------------------- Characteristic Category ABC OAD+3TC ABC BID+3TC Total ------------------------------------------------------------------------- Constitutional n 36 28 64 No 9 (25%) 4 (14%) 13 (20%) Yes 27 (75%) 24 (86%) 51 (80%) Fever n 36 28 64 No 14 (39%) 11 (39%) 25 (39%) Yes 22 (61%) 17 (61%) 39 (61%) GI n 36 28 64 No 15 (42%) 15 (54%) 30 (47%) Yes 21 (58%) 13 (46%) 34 (53%) Rash n 36 28 64 No 7 (19%) 8 (29%) 15 (23%) Yes 29 (81%) 20 (71%) 49 (77%) Respiratory n 36 28 64 No 23 (64%) 16 (57%) 39 (61%) Yes 13 (36%) 12 (43%) 25 (39%) tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 1 of 1

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

57

Population: Historical Sample Table 25 Relative Frequencies of ABC HSR Event Groupings (Historical Sample) Characteristic Category Value ------------------------------------------- Constitutional n 206 No 36 (17%) Yes 170 (83%) Fever n 206 No 63 (31%) Yes 143 (69%) GI n 206 No 77 (37%) Yes 129 (63%) Rash n 206 No 81 (39%) Yes 125 (61%) Respiratory n 206 No 117 (57%) Yes 89 (43%) tme14427:US/hiv_agg/ziagen/hsr/march_2003/hsr_crf.sas 12MAY03 21:45 Page 1 of 1

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

58

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 26 Frequency of Combinations of ABC HSR Symptoms In Clinical Trials Using the ABC HSR CRF Module HSR CRF Module -------------------------- Combination/Category ABC OAD+3TC ABC BID+3TC Total ------------------------------------------------------------------------------ n 36 28 64 3 or more Symptoms 27 (75%) 20 (71%) 47 (73%) Constitution and GI 1 (3%) 1 (4%) 2 (3%) Skin (Including Rash) only 6 (17%) 3 (11%) 9 (14%) Constitution and Skin 0 2 (7%) 2 (3%) Rash and Fever 1 (3%) 1 (4%) 2 (3%) Constitution and Respiratory 0 1 (4%) 1 (2%) Other 1 (3%) 0 1 (2%) tme14427:US/cna2/a30021/programs/tme14427/hsr_crf.sas 26AUG03 10:57 Page 1 of 1

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

59

Population: Historical Sample Table 27 Frequency of Combinations of ABC HSR Symptoms (Historical Sample) In Clinical Trials Using the ABC HSR CRF Module Combination/Category Value ------------------------------------------------ n 206 3 or more Symptoms 158 (77%) Constitution and GI 10 (5%) Skin (Including Rash) only 7 (3%) Constitution and Skin 7 (3%) Rash and Fever 5 (2%) Constitution and Fever 4 (2%) Constitution and Respiratory 3 (1%) Skin and GI 3 (1%) Other 9 (4%) tme14427:US/hiv_agg/ziagen/hsr/march_2003/hsr_crf.sas 12MAY03 21:45 Page 1 of 1

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

60

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ Subjects With Any Event 62 (87%) 54 (87%) Gastrointestinal disorders Subjects with Any Event 34 (48%) 32 (52%) Nausea 18 (25%) 14 (23%) Abdominal pain NOS 8 (11%) 9 (15%) Diarrhoea NOS 10 (14%) 6 (10%) Vomiting NOS 4 (6%) 6 (10%) Dyspepsia 5 (7%) 4 (6%) Haemorrhoids 4 (6%) 1 (2%) Loose stools 3 (4%) 2 (3%) Abdominal pain upper 2 (3%) 2 (3%) Flatulence 1 (1%) 2 (3%) Abdominal distension 0 2 (3%) Toothache 1 (1%) 1 (2%) Abdominal pain lower 0 1 (2%) Abdominal tenderness 1 (1%) 0 Anal fissure 1 (1%) 0 Cheilitis 1 (1%) 0 Constipation 0 1 (2%) Duodenal ulcer perforation 0 1 (2%) Gastrointestinal 0 1 (2%) irritation Gastrointestinal upset 1 (1%) 0Gastrointestinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 1 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

61

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Gastrointestinal disorders Gastrooesophageal reflux 0 1 (2%) disease Haematemesis 0 1 (2%) Hiatus hernia 0 1 (2%) Oral soft tissue disorder 1 (1%) 0 NOS Periodontitis 1 (1%) 0 Proctitis NOS 0 1 (2%) Rectal ulcer 1 (1%) 0 Reflux oesophagitis 0 1 (2%) Stomatitis 1 (1%) 0 Umbilical hernia NOS 1 (1%) 0 Psychiatric disorders Subjects with Any Event 33 (46%) 24 (39%) Abnormal dreams 12 (17%) 10 (16%) Insomnia 12 (17%) 9 (15%) Depression 7 (10%) 3 (5%) Anxiety 2 (3%) 2 (3%) Mood disorder NOS 3 (4%) 1 (2%) Euphoric mood 1 (1%) 2 (3%) Irritability 2 (3%) 0 Mood swings 2 (3%) 0 Nightmare 1 (1%) 1 (2%)Psychiatric disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 2 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

62

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Psychiatric disorders Sleep disorder NOS 2 (3%) 0 Stress symptoms 2 (3%) 0 Suicidal ideation 0 2 (3%) Anger 1 (1%) 0 Confusional state 0 1 (2%) Hallucination NOS 1 (1%) 0 Libido increased 1 (1%) 0 Mental disorder NOS 0 1 (2%) Restlessness 1 (1%) 0 Social avoidant behaviour 0 1 (2%) Suicide attempt 0 1 (2%) Tearfulness 1 (1%) 0 Infections and infestations Subjects with Any Event 30 (42%) 19 (31%) Nasopharyngitis 7 (10%) 4 (6%) Sinusitis NOS 3 (4%) 5 (8%) Upper respiratory tract 6 (8%) 1 (2%) infection NOS Pneumonia NOS 2 (3%) 3 (5%) Condyloma acuminatum 2 (3%) 2 (3%) Candidal infection NOS 2 (3%) 1 (2%) Folliculitis 3 (4%) 0 Herpes simplex 2 (3%) 1 (2%)Infections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 3 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

63

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Herpes viral infection NOS 2 (3%) 1 (2%) Influenza 0 3 (5%) Pharyngitis 2 (3%) 1 (2%) Ear infection NOS 1 (1%) 1 (2%) Fungal infection NOS 1 (1%) 1 (2%) Oral candidiasis 2 (3%) 0 Upper respiratory tract 0 2 (3%) infection viral NOS Urinary tract infection 2 (3%) 0 NOS Vaginal candidiasis 0 2 (3%) Beta haemolytic 1 (1%) 0 streptococcal infection Bronchitis acute NOS 1 (1%) 0 Cellulitis 1 (1%) 0 Dermatophytosis NOS 0 1 (2%) Erysipelas 1 (1%) 0 Eye infection NOS 1 (1%) 0 Furuncle 1 (1%) 0 Gastroenteritis viral NOS 1 (1%) 0 Hepatitis C 1 (1%) 0 Lobar pneumonia NOS 1 (1%) 0 Lower respiratory tract 0 1 (2%) infection NOSInfections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 4 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

64

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Meningitis bacterial NOS 1 (1%) 0 Neurosyphilis 1 (1%) 0 Papilloma viral infection 1 (1%) 0 NOS Pneumonia primary atypical 0 1 (2%) Postoperative infection 0 1 (2%) Pyelonephritis NOS 0 1 (2%) Pyelonephritis acute NOS 1 (1%) 0 Secondary syphilis 1 (1%) 0 Staphylococcal infection 1 (1%) 0 Syphilis NOS 1 (1%) 0 Tinea barbae 0 1 (2%) Tinea cruris 1 (1%) 0 Tinea pedis 1 (1%) 0 Vaginal infection NOS 0 1 (2%) Vaginosis fungal NOS 0 1 (2%) Nervous system disorders Subjects with Any Event 26 (37%) 21 (34%) Headache 13 (18%) 10 (16%) Dizziness 9 (13%) 8 (13%) Somnolence 3 (4%) 4 (6%) Hypoaesthesia 3 (4%) 2 (3%) Disturbance in attention 1 (1%) 1 (2%)Nervous system disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 5 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

65

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Nervous system disorders Dysgeusia 2 (3%) 0 Paraesthesia 0 2 (3%) Memory impairment 0 1 (2%) Migraine NOS 0 1 (2%) Neurological disorder NOS 1 (1%) 0 Peripheral neuropathy NOS 0 1 (2%) Radiculopathy NOS 1 (1%) 0 Syncope 1 (1%) 0 Skin and subcutaneous tissuedisorders Subjects with Any Event 23 (32%) 20 (32%) Rash NOS 12 (17%) 8 (13%) Dry skin 1 (1%) 3 (5%) Night sweats 1 (1%) 3 (5%) Pruritus 2 (3%) 2 (3%) Rash maculo-papular 1 (1%) 1 (2%) Acne NOS 1 (1%) 0 Alopecia 1 (1%) 0 Cold sweat 1 (1%) 0 Dermatitis NOS 1 (1%) 0 Dermatitis contact 1 (1%) 0 Eczema 0 1 (2%) Ingrowing nail 1 (1%) 0Skin and subcutaneous tissue disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 6 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

66

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Skin and subcutaneous tissue disorders Neurodermatitis 1 (1%) 0 Pityriasis 0 1 (2%) Psoriasis 0 1 (2%) Rash erythematous 1 (1%) 0 Rash pruritic 1 (1%) 0 Skin burning sensation 0 1 (2%) Sweating increased 1 (1%) 0 Urticaria NOS 0 1 (2%) General disorders andadministration site conditions Subjects with Any Event 21 (30%) 18 (29%) Fatigue 8 (11%) 8 (13%) Asthenia 8 (11%) 3 (5%) Pyrexia 5 (7%) 2 (3%) Pain NOS 4 (6%) 0 Oedema peripheral 1 (1%) 2 (3%) Chest pain 0 2 (3%) Rigors 2 (3%) 0 Chest tightness 0 1 (2%) Drug withdrawal syndrome 0 1 (2%) Feeling cold 1 (1%) 0 Influenza like illness 0 1 (2%) Lethargy 1 (1%) 0General disorders and administration site conditions continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 7 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

67

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing General disorders and administration site conditions Mass NOS 0 1 (2%) Thirst 1 (1%) 0 Respiratory, thoracic andmediastinal disorders Subjects with Any Event 19 (27%) 17 (27%) Cough 6 (8%) 4 (6%) Bronchitis NOS 3 (4%) 6 (10%) Pharyngolaryngeal pain 4 (6%) 3 (5%) Dyspnoea 1 (1%) 4 (6%) Nasal congestion 3 (4%) 2 (3%) Asthma NOS 0 2 (3%) Productive cough 1 (1%) 1 (2%) Respiratory tract 1 (1%) 1 (2%) congestion Rhinitis NOS 1 (1%) 1 (2%) Rhinorrhoea 0 2 (3%) Sinus congestion 1 (1%) 1 (2%) Wheezing 1 (1%) 1 (2%) Allergic sinusitis 1 (1%) 0 Breath sounds decreased 1 (1%) 0 Dyspnoea exacerbated 1 (1%) 0 Epistaxis 0 1 (2%) Hoarseness 0 1 (2%)Respiratory, thoracic and mediastinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 8 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

68

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Respiratory, thoracic and mediastinal disorders Maxillary sinusitis 1 (1%) 0 Paranasal sinus 0 1 (2%) hypersecretion Investigations Subjects with Any Event 14 (20%) 15 (24%) Alanine aminotransferase 5 (7%) 8 (13%) increased Aspartate aminotransferase 6 (8%) 4 (6%) increased Blood amylase increased 3 (4%) 2 (3%) Blood triglycerides 0 3 (5%) increased Liver function test 2 (3%) 1 (2%) abnormal Weight decreased 1 (1%) 2 (3%) Blood creatine 1 (1%) 1 (2%) phosphokinase increased Blood glucose increased 1 (1%) 1 (2%) Blood in stool 1 (1%) 0 Blood pressure increased 1 (1%) 0 Body temperature increased 1 (1%) 0 Catheterisation cardiac 1 (1%) 0 Weight increased 0 1 (2%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 9 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

69

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ Musculoskeletal and connectivetissue disorders Subjects with Any Event 17 (24%) 9 (15%) Back pain 5 (7%) 3 (5%) Pain in extremity 4 (6%) 3 (5%) Myalgia 4 (6%) 2 (3%) Arthralgia 2 (3%) 3 (5%) Neck pain 1 (1%) 1 (2%) Bone pain 1 (1%) 0 Contractures NOS 1 (1%) 0 Extremity contracture 1 (1%) 0 Joint swelling 1 (1%) 0 Muscle cramp 1 (1%) 0 Muscle spasms 0 1 (2%) Muscle weakness NOS 0 1 (2%) Neck mass 0 1 (2%) Spondylitis NOS 1 (1%) 0 Immune system disorders Subjects with Any Event 8 (11%) 5 (8%) Drug hypersensitivity 7 (10%) 5 (8%) Seasonal allergy 1 (1%) 0 +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 10 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

70

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ Metabolism and nutritiondisorders Subjects with Any Event 8 (11%) 3 (5%) Anorexia 4 (6%) 2 (3%) Appetite decreased NOS 3 (4%) 1 (2%) Diabetes mellitus NOS 1 (1%) 0 Polydipsia 1 (1%) 0 Ear and labyrinth disorders Subjects with Any Event 8 (11%) 2 (3%) Vertigo 6 (8%) 1 (2%) Deafness NOS 1 (1%) 0 Deafness bilateral 1 (1%) 0 Hypoacusis 0 1 (2%) Injury, poisoning andprocedural complications Subjects with Any Event 5 (7%) 5 (8%) Animal bite 1 (1%) 0 Drug toxicity NOS 0 1 (2%) Electric shock 0 1 (2%) Epicondylitis 0 1 (2%) Excoriation 1 (1%) 0 Eye injury NOS 1 (1%) 0 Hand fracture 0 1 (2%)Injury, poisoning and procedural complications continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 11 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

71

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Injury, poisoning and procedural complications Ligament injury NOS 1 (1%) 0 Rib fracture 0 1 (2%) Road traffic accident 0 1 (2%) Skin laceration 1 (1%) 0 Tooth injury 0 1 (2%) Wrist fracture 0 1 (2%) Reproductive system and breastdisorders Subjects with Any Event 4 (6%) 4 (6%) Breast pain 2 (3%) 0 Breast mass NOS 0 1 (2%) Dysmenorrhoea 0 1 (2%) Erectile dysfunction NOS 1 (1%) 0 Genital pruritus female 0 1 (2%) Menses delayed 1 (1%) 0 Menstruation irregular 0 1 (2%) Post coital bleeding 0 1 (2%) Blood and lymphatic systemdisorders Subjects with Any Event 4 (6%) 3 (5%) Anaemia NOS 1 (1%) 1 (2%) Lymphadenopathy 2 (3%) 0Blood and lymphatic system disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 12 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

72

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ ... continuing Blood and lymphatic system disorders Iron deficiency anaemia 0 1 (2%) Lymph node pain 0 1 (2%) Neutropenia 1 (1%) 0 Neoplasms benign, malignantand unspecified (incl cystsand polyps) Subjects with Any Event 3 (4%) 2 (3%) Cyst NOS 2 (3%) 0 Skin papilloma 1 (1%) 1 (2%) Lymphoma NOS 0 1 (2%) Cardiac disorders Subjects with Any Event 1 (1%) 3 (5%) Palpitations 0 2 (3%) Tachycardia NOS 1 (1%) 1 (2%) Vascular disorders Subjects with Any Event 4 (6%) 0 Flushing 2 (3%) 0 Heat stroke 1 (1%) 0 Hypertension NOS 1 (1%) 0 +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 13 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

73

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 28 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects with Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=71) (N=62)------------------------------------------------------------------------------------------ Eye disorders Subjects with Any Event 2 (3%) 1 (2%) Conjunctivitis 1 (1%) 1 (2%) Dry eye NOS 1 (1%) 0 Eye redness 1 (1%) 0 Lacrimation increased 0 1 (2%) Hepatobiliary disorders Subjects with Any Event 1 (1%) 1 (2%) Hepatotoxicity NOS 0 1 (2%) Jaundice NOS 1 (1%) 0 Renal and urinary disorders Subjects with Any Event 1 (1%) 1 (2%) Chromaturia 0 1 (2%) Haematuria 1 (1%) 0 Congenital, familial andgenetic disorders Subjects with Any Event 0 1 (2%) Colour blindness NOS 0 1 (2%) Social circumstances Subjects with Any Event 0 1 (2%) Drug abuser NOS 0 1 (2%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t1.sas 26AUG03 10:44 Page 14 of 14

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

74

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ Subjects With Any Event 300 (96%) 310 (96%) Infections and infestations Subjects with Any Event 181 (58%) 191 (59%) Nasopharyngitis 45 (14%) 51 (16%) Upper respiratory tract 35 (11%) 35 (11%) infection NOS Herpes simplex 17 (5%) 26 (8%) Sinusitis NOS 19 (6%) 18 (6%) Influenza 16 (5%) 18 (6%) Condyloma acuminatum 8 (3%) 13 (4%) Pharyngitis 14 (4%) 6 (2%) Folliculitis 5 (2%) 12 (4%) Pneumonia NOS 5 (2%) 9 (3%) Gastroenteritis NOS 6 (2%) 6 (2%) Herpes zoster 3 (<1%) 9 (3%) Otitis media NOS 7 (2%) 5 (2%) Otitis externa NOS 6 (2%) 5 (2%) Syphilis NOS 7 (2%) 4 (1%) Tinea pedis 6 (2%) 5 (2%) Urinary tract infection 1 (<1%) 10 (3%) NOS Scabies infestation 4 (1%) 5 (2%) Upper respiratory tract 6 (2%) 3 (<1%) infection viral NOSInfections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 1 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

75

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Ear infection NOS 3 (<1%) 5 (2%) Tooth abscess 4 (1%) 4 (1%) Tooth infection 4 (1%) 4 (1%) Herpes viral infection NOS 2 (<1%) 5 (2%) Oral candidiasis 3 (<1%) 4 (1%) Respiratory tract 4 (1%) 3 (<1%) infection NOS Tinea cruris 5 (2%) 2 (<1%) Nail fungal infection NOS 4 (1%) 2 (<1%) Body tinea 3 (<1%) 2 (<1%) Cellulitis 1 (<1%) 4 (1%) Furuncle 1 (<1%) 4 (1%) Hordeolum 4 (1%) 1 (<1%) Lower respiratory tract 3 (<1%) 2 (<1%) infection NOS Molluscum contagiosum 2 (<1%) 3 (<1%) Skin and subcutaneous 3 (<1%) 2 (<1%) tissue abscess NOS Vaginal candidiasis 3 (<1%) 2 (<1%) Viral infection NOS 3 (<1%) 2 (<1%) Fungal infection NOS 2 (<1%) 2 (<1%) Gastroenteritis viral NOS 1 (<1%) 3 (<1%) Hepatitis A 3 (<1%) 1 (<1%) Pharyngitis streptococcal 3 (<1%) 1 (<1%)Infections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 2 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

76

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Tinea NOS 1 (<1%) 3 (<1%) Bronchitis acute NOS 0 3 (<1%) Candidal infection NOS 0 3 (<1%) Eye infection NOS 1 (<1%) 2 (<1%) Impetigo NOS 2 (<1%) 1 (<1%) Infection NOS 2 (<1%) 1 (<1%) Proctitis herpes 0 3 (<1%) Sinusitis acute NOS 0 3 (<1%) Skin fungal infection NOS 1 (<1%) 2 (<1%) Staphylococcal infection 0 3 (<1%) Balanitis candida 1 (<1%) 1 (<1%) Chlamydial infection NOS 1 (<1%) 1 (<1%) Conjunctivitis bacterial 2 (<1%) 0 NOS Gonorrhoea NOS 1 (<1%) 1 (<1%) Helicobacter infection 0 2 (<1%) Hepatitis C 1 (<1%) 1 (<1%) Madura foot 1 (<1%) 1 (<1%) Oral fungal infection NOS 2 (<1%) 0 Orchitis NOS 1 (<1%) 1 (<1%) Pneumocystis carinii 1 (<1%) 1 (<1%) pneumonia Rhinovirus infection NOS 1 (<1%) 1 (<1%) Sinobronchitis 1 (<1%) 1 (<1%)Infections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 3 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

77

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Tinea barbae 0 2 (<1%) Tonsillitis 0 2 (<1%) Tonsillitis acute NOS 2 (<1%) 0 Tooth caries NOS 0 2 (<1%) Vaginitis bacterial NOS 1 (<1%) 1 (<1%) Vaginosis fungal NOS 0 2 (<1%) Vulval abscess 2 (<1%) 0 Abscess NOS 1 (<1%) 0 Abscess limb 0 1 (<1%) Abscess oral 1 (<1%) 0 Anal abscess 0 1 (<1%) Appendicitis 1 (<1%) 0 Bacteraemia 0 1 (<1%) Beta haemolytic 0 1 (<1%) streptococcal infection Catheter related infection 0 1 (<1%) Cervicitis human papilloma 0 1 (<1%) virus Conjunctivitis infective 0 1 (<1%) Dermatophytosis NOS 0 1 (<1%) Diarrhoea infectious 1 (<1%) 0 Erythema chronicum migrans 1 (<1%) 0 Eyelid infection NOS 1 (<1%) 0 Foot infection fungal NOS 0 1 (<1%)Infections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 4 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

78

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Fungal rash NOS 1 (<1%) 0 Genital infection 0 1 (<1%) Gingival infection 1 (<1%) 0 HIV infection 1 (<1%) 0 Haemorrhoid infection 1 (<1%) 0 Hookworm infection 0 1 (<1%) Infected insect bite 0 1 (<1%) Meningitis pneumococcal 0 1 (<1%) Nail infection NOS 0 1 (<1%) Nail tinea 0 1 (<1%) Oral infection 1 (<1%) 0 Otitis media acute NOS 0 1 (<1%) Otitis media serous NOS 0 1 (<1%) Otitis media suppurative 1 (<1%) 0 NOS Papilloma viral infection 1 (<1%) 0 NOS Perianal abscess 0 1 (<1%) Peritonsillitis 0 1 (<1%) Pharyngitis bacterial 1 (<1%) 0 Pneumonia bacterial NOS 1 (<1%) 0 Pneumonia pneumococcal 0 1 (<1%) Primary syphilis 0 1 (<1%) Pyelonephritis NOS 0 1 (<1%)Infections and infestations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 5 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

79

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Infections and infestations Rectal abscess 1 (<1%) 0 Sepsis NOS 0 1 (<1%) Skin infection 0 1 (<1%) Strongyloidiasis 0 1 (<1%) Tinea capitis 0 1 (<1%) Tracheobronchitis 0 1 (<1%) Trichomoniasis 1 (<1%) 0 Urethritis 1 (<1%) 0 Urethritis chlamydial 1 (<1%) 0 Vaginal infection NOS 0 1 (<1%) Vaginitis 0 1 (<1%) Gastrointestinal disorders Subjects with Any Event 174 (56%) 186 (57%) Nausea 69 (22%) 75 (23%) Diarrhoea NOS 56 (18%) 68 (21%) Vomiting NOS 28 (9%) 31 (10%) Abdominal pain NOS 23 (7%) 23 (7%) Dyspepsia 23 (7%) 22 (7%) Abdominal pain upper 14 (4%) 14 (4%) Loose stools 8 (3%) 11 (3%) Toothache 9 (3%) 10 (3%) Constipation 8 (3%) 9 (3%) Haemorrhoids 11 (4%) 6 (2%)Gastrointestinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 6 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

80

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Gastrointestinal disorders Flatulence 5 (2%) 6 (2%) Abdominal distension 6 (2%) 4 (1%) Gastrooesophageal reflux 5 (2%) 4 (1%) disease Mouth ulceration 4 (1%) 5 (2%) Cheilitis 3 (<1%) 5 (2%) Dry mouth 4 (1%) 4 (1%) Gastritis NOS 3 (<1%) 5 (2%) Aphthous stomatitis 4 (1%) 3 (<1%) Frequent bowel movements 2 (<1%) 3 (<1%) Hyperacidity 3 (<1%) 2 (<1%) Abdominal pain lower 1 (<1%) 3 (<1%) Gastrointestinal upset 1 (<1%) 3 (<1%) Abdominal discomfort 1 (<1%) 2 (<1%) Anal fissure 1 (<1%) 2 (<1%) Gingival pain 0 3 (<1%) Gingivitis 0 3 (<1%) Oral soft tissue disorder 2 (<1%) 1 (<1%) NOS Abdominal tenderness 1 (<1%) 1 (<1%) Anal ulcer 2 (<1%) 0 Dysphagia 0 2 (<1%) Gastrointestinal 2 (<1%) 0 irritationGastrointestinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 7 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

81

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Gastrointestinal disorders Gingival bleeding 0 2 (<1%) Glossodynia 0 2 (<1%) Haematemesis 1 (<1%) 1 (<1%) Hypoaesthesia oral 1 (<1%) 1 (<1%) Lip dry 1 (<1%) 1 (<1%) Odynophagia 1 (<1%) 1 (<1%) Oral mucosal blistering 1 (<1%) 1 (<1%) Pruritus ani 1 (<1%) 1 (<1%) Rectal discharge 1 (<1%) 1 (<1%) Rectal haemorrhage 1 (<1%) 1 (<1%) Salivary hypersecretion 2 (<1%) 0 Abdominal strangulated 1 (<1%) 0 hernia Anal disorder NOS 0 1 (<1%) Anal fistula 1 (<1%) 0 Bowel sounds abnormal 0 1 (<1%) Cheilosis 0 1 (<1%) Colitis NOS 0 1 (<1%) Colitis ulcerative 1 (<1%) 0 Colon spastic 0 1 (<1%) Epigastric discomfort 1 (<1%) 0 Food poisoning NOS 0 1 (<1%) Gingival swelling 1 (<1%) 0 Haemorrhoidal haemorrhage 1 (<1%) 0Gastrointestinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 8 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

82

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Gastrointestinal disorders Halitosis 1 (<1%) 0 Inguinal hernia NOS 1 (<1%) 0 Irritable bowel syndrome 0 1 (<1%) Lip pain 1 (<1%) 0 Lip ulceration 0 1 (<1%) Melaena 1 (<1%) 0 Oesophageal discomfort 1 (<1%) 0 Oesophagitis NOS 1 (<1%) 0 Periodontitis 1 (<1%) 0 Proctalgia 1 (<1%) 0 Rectal disorder NOS 1 (<1%) 0 Rectal tenesmus 0 1 (<1%) Sensitivity of teeth 1 (<1%) 0 Stomatitis 0 1 (<1%) Tongue blistering 1 (<1%) 0 Tongue eruption 1 (<1%) 0 Tongue papillary 0 1 (<1%) hypertrophy NOS Tongue ulceration 0 1 (<1%) Tooth impacted 1 (<1%) 0 Umbilical hernia NOS 0 1 (<1%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 9 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

83

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ Psychiatric disorders Subjects with Any Event 150 (48%) 168 (52%) Insomnia 61 (19%) 76 (23%) Abnormal dreams 51 (16%) 50 (15%) Depression 35 (11%) 43 (13%) Anxiety 18 (6%) 27 (8%) Euphoric mood 15 (5%) 15 (5%) Nightmare 13 (4%) 12 (4%) Mood swings 6 (2%) 6 (2%) Sleep disorder NOS 7 (2%) 5 (2%) Libido decreased 2 (<1%) 8 (2%) Stress symptoms 2 (<1%) 7 (2%) Confusional state 1 (<1%) 6 (2%) Depressed mood 4 (1%) 3 (<1%) Irritability 4 (1%) 3 (<1%) Nervousness 5 (2%) 2 (<1%) Agitation 4 (1%) 2 (<1%) Suicidal ideation 1 (<1%) 5 (2%) Disorientation 2 (<1%) 2 (<1%) Mood alteration NOS 3 (<1%) 1 (<1%) Aggression 2 (<1%) 1 (<1%) Dissociation 1 (<1%) 2 (<1%) Panic attack 2 (<1%) 1 (<1%) Illusion 1 (<1%) 1 (<1%) Restlessness 0 2 (<1%)Psychiatric disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 10 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

84

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Psychiatric disorders Suicide attempt 1 (<1%) 1 (<1%) Adjustment disorder NOS 1 (<1%) 0 Affect lability 0 1 (<1%) Apathy 0 1 (<1%) Attention 1 (<1%) 0 deficit/hyperactivity disorder Bruxism 1 (<1%) 0 Crying 1 (<1%) 0 Decreased interest 1 (<1%) 0 Delusion NOS 0 1 (<1%) Drug dependence 0 1 (<1%) Emotional disturbance NOS 1 (<1%) 0 Feeling of despair 0 1 (<1%) Flat affect 1 (<1%) 0 Hallucination, visual 1 (<1%) 0 Major depressive disorder 1 (<1%) 0 NOS Mental disorder NOS 0 1 (<1%) Panic disorder NOS 0 1 (<1%) Social avoidant behaviour 1 (<1%) 0 Tearfulness 0 1 (<1%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 11 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

85

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ Nervous system disorders Subjects with Any Event 153 (49%) 150 (46%) Dizziness 79 (25%) 74 (23%) Headache 52 (17%) 58 (18%) Somnolence 18 (6%) 19 (6%) Hypoaesthesia 13 (4%) 10 (3%) Paraesthesia 5 (2%) 6 (2%) Memory impairment 4 (1%) 5 (2%) Disturbance in attention 4 (1%) 4 (1%) Migraine NOS 5 (2%) 3 (<1%) Peripheral neuropathy NOS 4 (1%) 2 (<1%) Tremor 2 (<1%) 4 (1%) Balance impaired NOS 1 (<1%) 4 (1%) Dysgeusia 2 (<1%) 2 (<1%) Sinus headache 1 (<1%) 2 (<1%) Tension headache 2 (<1%) 1 (<1%) Amnesia 1 (<1%) 1 (<1%) Burning sensation NOS 1 (<1%) 1 (<1%) Convulsions NOS 1 (<1%) 1 (<1%) Depressed level of 1 (<1%) 1 (<1%) consciousness Hypersomnia 1 (<1%) 1 (<1%) Muscle contractions 1 (<1%) 1 (<1%) involuntary Neuropathy NOS 0 2 (<1%)Nervous system disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 12 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

86

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Nervous system disorders Stupor 2 (<1%) 0 Anosmia 0 1 (<1%) Ataxia 1 (<1%) 0 Carpal tunnel syndrome 0 1 (<1%) Coordination abnormal NOS 1 (<1%) 0 Dysarthria 0 1 (<1%) Dystonia 1 (<1%) 0 Facial palsy 1 (<1%) 0 Facial paresis 1 (<1%) 0 Hypertonia 0 1 (<1%) Loss of consciousness 0 1 (<1%) Mental impairment NOS 0 1 (<1%) Neuralgia NOS 1 (<1%) 0 Neuropathic pain 1 (<1%) 0 Neurotoxicity NOS 1 (<1%) 0 Post herpetic neuralgia 0 1 (<1%) Psychomotor hyperactivity 1 (<1%) 0 Scotoma 0 1 (<1%) Sleep apnoea syndrome 0 1 (<1%) Speech disorder 1 (<1%) 0 Syncope vasovagal 1 (<1%) 0 Transient ischaemic attack 1 (<1%) 0 Trismus 0 1 (<1%) Tunnel vision 1 (<1%) 0Nervous system disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 13 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

87

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Nervous system disorders Visual field defect NOS 1 (<1%) 0 Skin and subcutaneous tissuedisorders Subjects with Any Event 136 (43%) 132 (41%) Rash NOS 50 (16%) 49 (15%) Pruritus 20 (6%) 20 (6%) Night sweats 16 (5%) 15 (5%) Dry skin 10 (3%) 7 (2%) Dermatitis NOS 8 (3%) 7 (2%) Skin lesion NOS 3 (<1%) 12 (4%) Eczema 9 (3%) 4 (1%) Rash macular 7 (2%) 5 (2%) Erythema 4 (1%) 7 (2%) Rash maculo-papular 7 (2%) 4 (1%) Urticaria NOS 9 (3%) 1 (<1%) Acne NOS 6 (2%) 3 (<1%) Dermatitis medicamentosa 3 (<1%) 5 (2%) Rash generalised 3 (<1%) 5 (2%) Sweating increased 4 (1%) 4 (1%) Rash papular 3 (<1%) 4 (1%) Rash pruritic 5 (2%) 2 (<1%) Seborrhoeic dermatitis 4 (1%) 3 (<1%) Dyshidrosis 4 (1%) 1 (<1%)Skin and subcutaneous tissue disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 14 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

88

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Skin and subcutaneous tissue disorders Rash erythematous 1 (<1%) 4 (1%) Alopecia 2 (<1%) 2 (<1%) Penile ulceration 2 (<1%) 2 (<1%) Contusion 1 (<1%) 2 (<1%) Exanthem 2 (<1%) 1 (<1%) Psoriasis 3 (<1%) 0 Skin discolouration 1 (<1%) 2 (<1%) Swelling face 1 (<1%) 2 (<1%) Dermatitis contact 1 (<1%) 1 (<1%) Dermatitis exfoliative NOS 2 (<1%) 0 Dermatosis 1 (<1%) 1 (<1%) Ecchymosis 1 (<1%) 1 (<1%) Eosinophilic pustular 1 (<1%) 1 (<1%) folliculitis Lipodystrophy acquired 2 (<1%) 0 Neurodermatitis 1 (<1%) 1 (<1%) Paronychia 2 (<1%) 0 Photosensitivity reaction 2 (<1%) 0 NOS Rash scaly 0 2 (<1%) Seborrhoea 1 (<1%) 1 (<1%) Skin burning sensation 0 2 (<1%) Skin disorder NOS 0 2 (<1%) Acrochordons 0 1 (<1%)Skin and subcutaneous tissue disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 15 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

89

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Skin and subcutaneous tissue disorders Actinic keratosis 0 1 (<1%) Cold sweat 0 1 (<1%) Dandruff 1 (<1%) 0 Dermographism 0 1 (<1%) Erythema nodosum 1 (<1%) 0 Face oedema 1 (<1%) 0 Heat rash 1 (<1%) 0 Hyperkeratosis 1 (<1%) 0 Nail discolouration 1 (<1%) 0 Nail disorder NOS 1 (<1%) 0 Periorbital oedema 1 (<1%) 0 Photodermatosis 1 (<1%) 0 Pigmentation disorder NOS 0 1 (<1%) Pityriasis 1 (<1%) 0 Prurigo 1 (<1%) 0 Rosacea 1 (<1%) 0 Scar 0 1 (<1%) Skin chapped 1 (<1%) 0 Skin hyperpigmentation 0 1 (<1%) Skin irritation 1 (<1%) 0 Skin nodule 0 1 (<1%) Telangiectasia 0 1 (<1%) Xeroderma 1 (<1%) 0 +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 16 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

90

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ General disorders andadministration site conditions Subjects with Any Event 119 (38%) 126 (39%) Fatigue 50 (16%) 68 (21%) Pyrexia 37 (12%) 33 (10%) Asthenia 12 (4%) 12 (4%) Chest pain 8 (3%) 11 (3%) Malaise 8 (3%) 8 (2%) Ill-defined disorder NOS 5 (2%) 9 (3%) Pain NOS 6 (2%) 8 (2%) Influenza like illness 5 (2%) 8 (2%) Oedema peripheral 4 (1%) 9 (3%) Rigors 4 (1%) 6 (2%) Feeling abnormal 6 (2%) 2 (<1%) Feeling drunk 4 (1%) 4 (1%) Lethargy 2 (<1%) 4 (1%) Hangover 3 (<1%) 2 (<1%) Chest tightness 0 4 (1%) Hyperpyrexia 2 (<1%) 2 (<1%) Xerosis 1 (<1%) 3 (<1%) Feeling hot 3 (<1%) 0 Sluggishness 3 (<1%) 0 Feeling hot and cold 0 2 (<1%) Feeling jittery 1 (<1%) 1 (<1%) Mass NOS 2 (<1%) 0General disorders and administration site conditions continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 17 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

91

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing General disorders and administration site conditions Adverse drug reaction NOS 1 (<1%) 0 Chest discomfort 0 1 (<1%) Death NOS 0 1 (<1%) Gait abnormal 1 (<1%) 0 Granuloma NOS 0 1 (<1%) Injection site pain 1 (<1%) 0 Localised oedema 0 1 (<1%) Lower extremity mass 1 (<1%) 0 Sudden infant death 0 1 (<1%) syndrome Thirst 1 (<1%) 0 Respiratory, thoracic andmediastinal disorders Subjects with Any Event 102 (33%) 121 (37%) Cough 30 (10%) 41 (13%) Pharyngolaryngeal pain 31 (10%) 26 (8%) Bronchitis NOS 16 (5%) 19 (6%) Nasal congestion 17 (5%) 14 (4%) Dyspnoea 9 (3%) 14 (4%) Sinus congestion 8 (3%) 10 (3%) Respiratory tract 6 (2%) 10 (3%) congestion Productive cough 4 (1%) 11 (3%)Respiratory, thoracic and mediastinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 18 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

92

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Respiratory, thoracic and mediastinal disorders Rhinorrhoea 8 (3%) 7 (2%) Rhinitis allergic NOS 4 (1%) 8 (2%) Epistaxis 1 (<1%) 5 (2%) Paranasal sinus 4 (1%) 2 (<1%) hypersecretion Rhinitis NOS 2 (<1%) 4 (1%) Wheezing 0 5 (2%) Asthma NOS 3 (<1%) 1 (<1%) Dyspnoea exertional 2 (<1%) 2 (<1%) Sinus pain 2 (<1%) 2 (<1%) Throat irritation 2 (<1%) 2 (<1%) Allergic sinusitis 1 (<1%) 2 (<1%) Hoarseness 1 (<1%) 2 (<1%) Pleuritic pain 1 (<1%) 2 (<1%) Postnasal drip 2 (<1%) 1 (<1%) Rhinitis seasonal 1 (<1%) 2 (<1%) Sneezing 2 (<1%) 1 (<1%) Upper respiratory tract 1 (<1%) 2 (<1%) congestion Dry throat 0 2 (<1%) Laryngitis NOS 1 (<1%) 1 (<1%) Rhonchi 0 2 (<1%) Asthma exercise induced 0 1 (<1%) Breath sounds decreased 0 1 (<1%)Respiratory, thoracic and mediastinal disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 19 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

93

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Respiratory, thoracic and mediastinal disorders Bronchospasm NOS 1 (<1%) 0 Chronic obstructive 1 (<1%) 0 airways disease Haemoptysis 1 (<1%) 0 Hypoventilation 1 (<1%) 0 Obstructive airways 1 (<1%) 0 disorder NOS Pleurisy 1 (<1%) 0 Pulmonary embolism 1 (<1%) 0 Pulmonary hypertension NOS 1 (<1%) 0 Pulmonary mass 1 (<1%) 0 Rales 0 1 (<1%) Sputum discoloured 1 (<1%) 0 Throat lesion 1 (<1%) 0 Tonsillar ulcer 1 (<1%) 0 Musculoskeletal and connectivetissue disorders Subjects with Any Event 74 (24%) 77 (24%) Back pain 21 (7%) 24 (7%) Arthralgia 12 (4%) 22 (7%) Myalgia 13 (4%) 10 (3%) Pain in extremity 10 (3%) 13 (4%) Muscle cramp 2 (<1%) 5 (2%)Musculoskeletal and connective tissue disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 20 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

94

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Musculoskeletal and connective tissue disorders Local swelling 2 (<1%) 3 (<1%) Musculoskeletal stiffness 4 (1%) 1 (<1%) Neck pain 3 (<1%) 2 (<1%) Arthritis NOS 1 (<1%) 3 (<1%) Facial pain 1 (<1%) 3 (<1%) Flank pain 2 (<1%) 2 (<1%) Groin pain 3 (<1%) 1 (<1%) Tendonitis 1 (<1%) 3 (<1%) Bone spur 2 (<1%) 1 (<1%) Joint swelling 2 (<1%) 1 (<1%) Pain in jaw 1 (<1%) 2 (<1%) Muscle spasms 2 (<1%) 0 Musculoskeletal chest pain 2 (<1%) 0 Axillary mass 0 1 (<1%) Bone lesion NOS 0 1 (<1%) Bone pain 1 (<1%) 0 Bursitis 1 (<1%) 0 Buttock pain 0 1 (<1%) Cervical spasm 0 1 (<1%) Chondritis 0 1 (<1%) Contractures NOS 1 (<1%) 0 Costochondritis 1 (<1%) 0 Ganglion 0 1 (<1%)Musculoskeletal and connective tissue disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 21 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

95

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Musculoskeletal and connective tissue disorders Intervertebral disc 1 (<1%) 0 herniation Limb discomfort NOS 0 1 (<1%) Lumbar disc lesion 1 (<1%) 0 Muscle twitching 0 1 (<1%) Myopathy 1 (<1%) 0 Osteoarthritis NOS 1 (<1%) 0 Osteoporosis NOS 0 1 (<1%) Plantar fasciitis 1 (<1%) 0 Trigger finger 1 (<1%) 0 Investigations Subjects with Any Event 53 (17%) 50 (15%) Blood creatine 11 (4%) 9 (3%) phosphokinase increased Blood triglycerides 9 (3%) 8 (2%) increased Weight decreased 8 (3%) 6 (2%) Blood amylase increased 5 (2%) 8 (2%) Aspartate aminotransferase 6 (2%) 4 (1%) increased Alanine aminotransferase 5 (2%) 4 (1%) increased Blood glucose increased 4 (1%) 3 (<1%)Investigations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 22 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

96

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Investigations Blood pressure increased 4 (1%) 3 (<1%) Weight increased 4 (1%) 2 (<1%) Heart rate increased 4 (1%) 1 (<1%) Liver function test 2 (<1%) 3 (<1%) abnormal Blood alkaline phosphatase 1 (<1%) 3 (<1%) increased Smear cervix abnormal 2 (<1%) 2 (<1%) Blood in stool 1 (<1%) 2 (<1%) Neutrophil count decreased 0 3 (<1%) Blood albumin increased 0 2 (<1%) Blood cholesterol 2 (<1%) 0 increased Blood urine 0 2 (<1%) Syphilis test positive 0 2 (<1%) Blood iron decreased 1 (<1%) 0 Blood lactic acid 1 (<1%) 0 increased Blood pressure decreased 0 1 (<1%) Blood sodium decreased 1 (<1%) 0 Blood testosterone 1 (<1%) 0 decreased Bone density decreased 0 1 (<1%) Cardiac murmur NOS 1 (<1%) 0Investigations continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 23 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

97

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Investigations Haemoglobin decreased 1 (<1%) 0 Heart rate irregular 0 1 (<1%) Intraocular pressure 1 (<1%) 0 increased Lipase increased 0 1 (<1%) Lipids NOS increased 0 1 (<1%) Mammogram abnormal 0 1 (<1%) Transaminases increased 0 1 (<1%) Tuberculin test positive 0 1 (<1%) X-ray NOS chest abnormal 0 1 (<1%) Immune system disorders Subjects with Any Event 38 (12%) 34 (10%) Drug hypersensitivity 29 (9%) 24 (7%) Hypersensitivity NOS 4 (1%) 4 (1%) Seasonal allergy 3 (<1%) 4 (1%) Allergic oedema NOS 1 (<1%) 0 Allergy to arthropod bite 0 1 (<1%) Allergy to arthropod sting 1 (<1%) 0 Atopy 1 (<1%) 0 Food allergy 0 1 (<1%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 24 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

98

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ Metabolism and nutritiondisorders Subjects with Any Event 37 (12%) 34 (10%) Appetite decreased NOS 11 (4%) 8 (2%) Anorexia 8 (3%) 7 (2%) Hyperlipidaemia NOS 4 (1%) 9 (3%) Hypertriglyceridaemia 3 (<1%) 4 (1%) Dehydration 2 (<1%) 3 (<1%) Hyperglycaemia NOS 3 (<1%) 2 (<1%) Appetite increased NOS 3 (<1%) 1 (<1%) Hypercholesterolaemia 1 (<1%) 2 (<1%) Cachexia 1 (<1%) 1 (<1%) Gout 1 (<1%) 1 (<1%) Hypoglycaemia NOS 1 (<1%) 1 (<1%) Hypokalaemia 1 (<1%) 1 (<1%) Diabetes mellitus NOS 1 (<1%) 0 Dyslipidaemia 1 (<1%) 0 Injury, poisoning andprocedural complications Subjects with Any Event 31 (10%) 20 (6%) Arthropod bite 4 (1%) 2 (<1%) Excoriation 3 (<1%) 2 (<1%) Hand fracture 2 (<1%) 1 (<1%) Limb injury NOS 3 (<1%) 0Injury, poisoning and procedural complications continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 25 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

99

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Injury, poisoning and procedural complications Muscle strain 1 (<1%) 2 (<1%) Skin laceration 2 (<1%) 1 (<1%) Thermal burn 2 (<1%) 1 (<1%) Animal bite 1 (<1%) 1 (<1%) Back injury NOS 1 (<1%) 1 (<1%) Foot fracture 0 2 (<1%) Joint sprain 1 (<1%) 1 (<1%) Tooth injury 1 (<1%) 1 (<1%) Ankle fracture 0 1 (<1%) Arthropod sting 1 (<1%) 0 Blood blister 1 (<1%) 0 Clavicle fracture 0 1 (<1%) Corneal abrasion 0 1 (<1%) Face injury 1 (<1%) 0 Foreign body trauma 1 (<1%) 0 Gun shot wound 0 1 (<1%) Heat exhaustion 1 (<1%) 0 Joint dislocation 1 (<1%) 0 Laceration 1 (<1%) 0 Ligament injury NOS 1 (<1%) 0 Mouth injury 0 1 (<1%) Post procedural pain 1 (<1%) 0 Rib fracture 1 (<1%) 0 Scratch 1 (<1%) 0Injury, poisoning and procedural complications continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 26 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

100

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Injury, poisoning and procedural complications Sunburn 1 (<1%) 0 Tendon rupture 1 (<1%) 0 Thoracic vertebral 1 (<1%) 0 fracture Upper limb fracture NOS 0 1 (<1%) Whiplash injury 1 (<1%) 0 Wound NOS 0 1 (<1%) Reproductive system and breastdisorders Subjects with Any Event 24 (8%) 27 (8%) Erectile dysfunction NOS 3 (<1%) 6 (2%) Breast mass NOS 4 (1%) 3 (<1%) Epididymitis NOS 1 (<1%) 2 (<1%) Genital rash 1 (<1%) 2 (<1%) Menorrhagia 2 (<1%) 1 (<1%) Ovarian cyst 2 (<1%) 1 (<1%) Prostatitis 0 3 (<1%) Balanitis NOS 2 (<1%) 0 Genital lesion NOS 0 2 (<1%) Genital pruritus female 0 2 (<1%) Benign prostatic 0 1 (<1%) hyperplasia Breast engorgement 1 (<1%) 0Reproductive system and breast disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 27 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

101

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Reproductive system and breast disorders Cervical dysplasia 0 1 (<1%) Cervicitis NOS 0 1 (<1%) Genital discharge 1 (<1%) 0 Genital pruritus male 1 (<1%) 0 Gynaecomastia 1 (<1%) 0 Menopausal symptoms 0 1 (<1%) Menstruation irregular 0 1 (<1%) Nipple pain 0 1 (<1%) Penile discharge 1 (<1%) 0 Penile pain 1 (<1%) 0 Priapism 1 (<1%) 0 Scrotal sebaceous cysts 1 (<1%) 0 Scrotal ulcer 0 1 (<1%) Sexual dysfunction NOS 1 (<1%) 0 Uterine haemorrhage 1 (<1%) 0 Vaginal discharge 0 1 (<1%) Varicocele 0 1 (<1%) Ear and labyrinth disorders Subjects with Any Event 22 (7%) 22 (7%) Vertigo 5 (2%) 8 (2%) Ear pain 7 (2%) 4 (1%) Tinnitus 5 (2%) 6 (2%) Hypoacusis 2 (<1%) 1 (<1%)Ear and labyrinth disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 28 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

102

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Ear and labyrinth disorders Cerumen impaction 1 (<1%) 1 (<1%) Tympanic membrane 2 (<1%) 0 perforation Deafness NOS 1 (<1%) 0 Deafness unilateral 0 1 (<1%) Ear pruritus 0 1 (<1%) Fluid in middle ear 0 1 (<1%) Hearing impaired 1 (<1%) 0 Motion sickness 1 (<1%) 0 Tympanic membrane 1 (<1%) 0 hyperaemia Vascular disorders Subjects with Any Event 21 (7%) 17 (5%) Hypertension NOS 10 (3%) 6 (2%) Flushing 7 (2%) 4 (1%) Varicose veins NOS 0 3 (<1%) Hypertensive crisis 0 1 (<1%) Hypotension NOS 0 1 (<1%) Iliac artery embolism 1 (<1%) 0 Orthostatic hypotension 0 1 (<1%) Pallor 0 1 (<1%) Petechiae 1 (<1%) 0 Phlebitis NOS 0 1 (<1%)Vascular disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 29 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

103

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Vascular disorders Thrombosis 1 (<1%) 0 Vein discolouration 1 (<1%) 0 Venous insufficiency 1 (<1%) 0 Blood and lymphatic systemdisorders Subjects with Any Event 19 (6%) 16 (5%) Lymphadenopathy 11 (4%) 6 (2%) Neutropenia 4 (1%) 6 (2%) Anaemia NOS 0 4 (1%) Thrombocytopenia 2 (<1%) 1 (<1%) Lymph node pain 1 (<1%) 1 (<1%) Splenomegaly 2 (<1%) 0 Eye disorders Subjects with Any Event 15 (5%) 17 (5%) Conjunctivitis 3 (<1%) 4 (1%) Vision blurred 3 (<1%) 4 (1%) Eye pruritus 2 (<1%) 2 (<1%) Eye redness 2 (<1%) 1 (<1%) Eye irritation 2 (<1%) 0 Visual disturbance NOS 1 (<1%) 1 (<1%) Blepharitis 1 (<1%) 0 Blindness 0 1 (<1%)Eye disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 30 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

104

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Eye disorders Conjunctivitis allergic 0 1 (<1%) Eye allergy 0 1 (<1%) Eye inflammation NOS 0 1 (<1%) Eye swelling 0 1 (<1%) Eyelid oedema 1 (<1%) 0 Photophobia 1 (<1%) 0 Pterygium 1 (<1%) 0 Vitreous floaters 0 1 (<1%) Neoplasms benign, malignantand unspecified (incl cystsand polyps) Subjects with Any Event 13 (4%) 14 (4%) Skin papilloma 8 (3%) 8 (2%) Cyst NOS 0 2 (<1%) Lipoma NOS 2 (<1%) 0 Basal cell carcinoma 0 1 (<1%) Bowen’s disease 0 1 (<1%) Colon cancer NOS 1 (<1%) 0 Kaposi’s sarcoma NOS 0 1 (<1%) Lung nodule 1 (<1%) 0 Lymphoma NOS 1 (<1%) 0 Metastases NOS 1 (<1%) 0 Metastases to bone 1 (<1%) 0Neoplasms benign, malignant and unspecified (incl cysts and polyps) continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 31 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

105

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm NOS 0 1 (<1%) Papilloma NOS 0 1 (<1%) Renal cell carcinoma stage 1 (<1%) 0 unspecified Renal and urinary disorders Subjects with Any Event 13 (4%) 14 (4%) Dysuria 3 (<1%) 3 (<1%) Nephrolithiasis 1 (<1%) 2 (<1%) Pollakiuria 1 (<1%) 2 (<1%) Renal failure acute 1 (<1%) 1 (<1%) Azotaemia 1 (<1%) 0 Chromaturia 0 1 (<1%) Costovertebral angle 0 1 (<1%) tenderness Cystitis NOS 0 1 (<1%) Haematuria 0 1 (<1%) Incontinence NOS 1 (<1%) 0 Kidney enlargement 1 (<1%) 0 Microalbuminuria 1 (<1%) 0 Polyuria 0 1 (<1%) Proteinuria 1 (<1%) 0 Renal colic 1 (<1%) 0 Urethral haemorrhage 1 (<1%) 0Renal and urinary disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 32 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

106

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Renal and urinary disorders Urethral pain 0 1 (<1%) Urethral ulcer 1 (<1%) 0 Urinary bladder polyp 0 1 (<1%) Urinary incontinence 0 1 (<1%) Cardiac disorders Subjects with Any Event 8 (3%) 12 (4%) Palpitations 3 (<1%) 5 (2%) Tachycardia NOS 3 (<1%) 2 (<1%) Ventricular extrasystoles 0 2 (<1%) Acute myocardial 1 (<1%) 0 infarction Atrial fibrillation 0 1 (<1%) Bundle branch block right 0 1 (<1%) Cardiac arrest 1 (<1%) 0 Cardiomyopathy NOS 0 1 (<1%) Congestive cardiac failure 0 1 (<1%) aggravated Myocardial infarction 0 1 (<1%) Surgical and medicalprocedures Subjects with Any Event 8 (3%) 5 (2%) Tooth extraction NOS 3 (<1%) 0Surgical and medical procedures continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 33 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

107

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Surgical and medical procedures Wisdom teeth removal 2 (<1%) 0 Abortion induced NOS 1 (<1%) 0 Cataract extraction 0 1 (<1%) Colostomy closure 1 (<1%) 0 Dental operation NOS 0 1 (<1%) Drug detoxification 0 1 (<1%) Endodontic procedure 1 (<1%) 0 Hysterectomy 0 1 (<1%) Mole excision 1 (<1%) 0 Nasal sinus drainage 0 1 (<1%) Endocrine disorders Subjects with Any Event 3 (<1%) 5 (2%) Hypogonadism 2 (<1%) 2 (<1%) Goitre 0 2 (<1%) Hyperthyroidism 1 (<1%) 0 Thyroid nodule 0 1 (<1%) Hepatobiliary disorders Subjects with Any Event 6 (2%) 1 (<1%) Jaundice NOS 2 (<1%) 1 (<1%) Hepatomegaly 2 (<1%) 0 Cholecystitis acute NOS 1 (<1%) 0 Cholelithiasis 1 (<1%) 0Hepatobiliary disorders continues ... +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 34 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

108

Protocol: CNA30021 -- ABC+3TC FDCPopulation: Safety (Data as of: June 27, 2003) Table 29 Summary of Subjects Reporting Any Adverse Events by Body System For Subjects without Baseline Hepatitis B/C Infection BODY SYSTEM ABC OAD+3TC+EFV ABC BID+3TC+EFV Event (N=313) (N=324)------------------------------------------------------------------------------------------ ... continuing Hepatobiliary disorders Hepatic pain 1 (<1%) 0 Pregnancy, puerperium andperinatal conditions Subjects with Any Event 3 (<1%) 0 Ectopic pregnancy 2 (<1%) 0 Abortion spontaneous NOS 1 (<1%) 0 Congenital, familial andgenetic disorders Subjects with Any Event 2 (<1%) 0 Carnitine deficiency 1 (<1%) 0 Pigmented naevus 1 (<1%) 0 Social circumstances Subjects with Any Event 0 1 (<1%) Drug abuser NOS 0 1 (<1%) +Grouped Term is from MedDRA dictionaryhz39798:US/cna2/a30021/programs/non-csr/ae_t2.sas 26AUG03 10:45 Page 35 of 35

CO

NF

IDE

NT

IAL

GM

2003/00048/002.7.4 S

umm

ary of Clinical S

afety

109

2.7.4. summary of clinical safety - 独立行政法人 ... Summary of Clinical Safety 2 TABLE OF...

Documents

Transcript of 2.7.4. summary of clinical safety - 独立行政法人 ... Summary of Clinical Safety 2 TABLE OF...